Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][O:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:4][CH2:3]1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26].O>N1C=CC=CC=1.C(N(C(C)C)CC)(C)C>[N:14]1[C:13]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:12]=2[S:11][C:10]=1[NH:9][CH2:8][CH:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:24](=[O:27])[CH2:25][CH3:26])[CH2:3][CH2:4]1
Reactant: NC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC(=O)NC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a stirred solution of N2-[(4-aminocyclohexyl)methyl]-4,5-dihydrobenzo[2,3]oxepino[4,5-d][1,3]thiazol-2-amine (0.600 g, 1.49 mmol) in anhydrous pyridine (3 ml) and diisopropylethylamine (3 ml) was added propionyl chloride (0.155 ml, 1.78 mmol) dropwise. The solution was stirred for 1 hour at room temperature and poured into water (60 ml). The solution was extracted with EtOAc and the solvent removed in vacuo to yield a viscous golden oil. The oil was chromatographed on silica-gel eluting with 70% EtOAc/30% hexane to yield 74% (425 mg) of an orange solid: m.p. 70-73° C. 1H-NMR (CDCl3) δ 1.10 (6H, m), 1.60 (1H, broad), 1.83 (3H, m), 2.00 (3H, m), 2.17 (2H, q, J=7.6 Hz), 3.13 (4H, q, J=5.1 Hz), 3.73 (1H, broad), 4.32 (2H, t, J=5.3 Hz), 5.32 (1H, broad), 7.00 (1H, dd, J=6.4 Hz). ESIMS m/z=386 (MH+).
Reaction SMILES: N1C=CC([C:7]2[CH:15]=[C:14]([CH:16]=[O:17])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=CC=1.[N:26]1[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][CH:27]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[N:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:7]2[CH:15]=[C:14]([CH:16]=[O:17])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])=[CH:28][CH:27]=1
Reactant: C=Cc1ccncc1
Reactant: C[Si](C)(C)CCOCn1ncc2c(-c3ccncc3)cc(C=O)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ncc2c(/C=C/c3ccncc3)cc(C=O)cc21
Temperature: 70 °C
Yield: 52.7 %

Procedure:
A solution of 4-(pyridine-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (50 mg, 0.14 mmol) and 4-pyridylethylene (20 μL, 0.19 mmol) in acetonitrile (1.5 mL) was purged with argon. Palladium acetate (2 mg, 0.007 mmol), tri-o-tolylphosphine (4 mg, 0.014 mmol) and DIPEA (50 μL) was added and the mixture was heated to 70° C. for 16 h. Ethyl acetate (50 mL) was added and the mixture was washed with water (2×5 mL), brine (5 mL), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (98:2 EtOAc/MeOH) to give the title compound as a yellow solid (28 mg, 53%). MS ESI [M+H]+, calcd for [C21H25N3O2Si+H]+ 380.2; found m/z 380.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[N:19]=[C:18]([N:29]4[CH2:33][CH2:32][CH2:31][CH:30]4[CH3:34])[N:17]=3)[CH:12]([CH3:35])[CH2:11]2)=[N:4][C:5]([O:8]C)=[CH:6][CH:7]=1>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[N:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[N:19]=[C:18]([N:29]3[CH2:33][CH2:32][CH2:31][CH:30]3[CH3:34])[N:17]=2)[CH:12]([CH3:35])[CH2:11]1
Reactant: COc1ccc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)C(C)C2)n1
Agent: Cl
Product: CC1CN(c2nc(O)ccc2Cl)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCCC2C)n1
Temperature: 25 °C

Procedure:
Heat a solution of 4-[4-(3-chloro-6-methoxy-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (120 mg, 0.241 mmol) in concentrated HCl at 90° C. for 24 hours. Cool to room temperature, adjust the pH to 7, and extract with EtOAc. Wash with brine, dry the solution (Na2SO4), and concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with EtOAc:Hexanes (1:4) to afford 5-chloro-6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-methyl-piperazin-1-yl}-pyridin-2-ol as an off-white solid. 1H NMR (300 MHz, CDCl3): δ1.32 (m, 6H, 2×CH3); 1.69 (m, 1H, CH2CH2); 1.91 (m, 1H, CH2CH2); 2.04 (m, 2H, CH2CH2); 3.06 (m, 1H); 3.24 (m, 1H); 3.36 (m, 1H); 3.67 (m, 4H); 4.33 (m, 2H); 4.71 (m, 1H); 6.22 (m, 2H); 7.10 (m, 2H); 7.45 (d, J=8.7 Hz, 1H); 8.01 (m, 2H); 9.27 (br, 1H, OH).
Reaction SMILES: [CH:1]1([CH:6]2[C:11]([O:12][CH3:13])=[CH:10][CH2:9][CH2:8][C:7]2=[O:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+]>C1COCC1>[CH:1]1([C:6]2[C:7](=[O:14])[CH2:8][CH2:9][CH2:10][C:11]=2[O:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC1=CCCC(=O)C1C1CCCC1
Agent: C[O-]
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1=C(C2CCCC2)C(=O)CCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
To a solution of 2-cyclopentyl-3-methoxycyclohex-3-en-1-one (4.3 g) in dry THF (120 mL), sodium methoxide (1.1 g) was added in portions at room temperature. After stirring the reaction mixture at room temperature for 1.5 hours, cooled in an ice bath, and neutralized with sodium hydrogen phosphate solution. The organic layer was separated, aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting product was purified on a column of silica gel (Hex:EtOAc) to give the title compound as yellow liquid (2.82 g, 65.5%). 1H NMR (CDCl3): δ 1.25–1.8 (m, 8H, 4×CH2), 1.96 (m, 2H, CH2), 2.36 (t, 2H, CH2), 2.56 (t, 2H, CH2), 3.22 (m, 1H, CH), 3.79 (s, 3H, OCH3).
Reaction SMILES: C(N(CC)CC)C.Cl.ClC1C=CC(C[C@H](N)CN(C)C)=CC=1.[CH2:23]([O:25][C:26]([CH:28]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[N:29]1CC1C=CC=C(C=O)C=1)=[O:27])[CH3:24].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:23]([O:25][C:26]([CH:28]1[CH2:32][CH2:31][S:30](=[O:33])(=[O:34])[NH:29]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1CCS(=O)(=O)N1Cc1cccc(C=O)c1
Agent: CN(C)C[C@@H](N)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCS(=O)(=O)N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 330.9 %

Procedure:
Triethylamine (214 μL, 1.5 mmol) was added to a solution of (S)-3-(4-chloro-phenyl)-N1,N1-dimethyl-propane-1,2-diamine hydrochloride salt (Intermediate X; 182 mg, 0.73 mmol) in methanol (2 mL). The mixture was stirred for 10 min and then a solution of 2-(3-formyl-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (Intermediate 8 Step 3; 190 mg, 0.61 mmol) in methanol (4 mL) was added under argon. The mixture was stirred at room temperature for 15 min and then cooled in an ice-bath. Solid sodium cyanoborohydride (57.5 mg, 0.9 mmol) and glacial acetic acid (540 μL) were added. The reaction mixture was allowed to warm to room temperature and stir. The progress of the reaction was monitored by LCMS. When the reaction was substantially complete, the solvents were evaporated and ethyl acetate (50 mL) was added. The solution was washed with washed with water (2×10 mL) and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give crude 2-{3-[((S)-4-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (390 mg) as a tacky yellow foam which was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH:33]=[O:34])=[C:21]([CH3:32])[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:23]2)=[CH:18][CH:17]=1>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([CH:33]([C:20]2[C:19]3[C:24](=[CH:25][C:16]([F:15])=[CH:17][CH:18]=3)[N:23]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:21]=2[CH3:32])[OH:34])[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1C=O
Reactant: Clc1cc(Br)cc(N2CCOCC2)c1
Solvent: C1CCOC1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1C(O)c1cc(Cl)cc(N2CCOCC2)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
An oven-dried conical flask was charged with 4-(3-bromo-5-chlorophenyl)-morpholine (0.384 g, 1.390 mmol) and 1.0 mL THF. While this solution was stirring at −78° C. under nitrogen, 2.5M butyllithium hexanes (0.556 mL, 1.390 mmol) was added via syringe. This solution was stirred at −78° C. for 30 minutes. After this time a solution of 7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline-4-carbaldehyde (0.074 g, 0.278 mmol) in 2.0 mL THF was added, and the reaction continued at −78° C. for 45 minutes. Upon completion, the reaction was quenched with satd aqueous ammonium chloride and concd. The resulting material was partitioned between EtOAc and water, and the organic phase was dried over magnesium sulfate and concd. The afforded crude product was purified by column chromatography (silica; 0-50% EtOAc in hexanes) to yield (3-chloro-5-(4-morpholinyl)phenyl)(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)methanol as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (1H, d), 8.35 (1H, m), 8.01 (1H, t), 7.83 (1H, s), 7.71 (1H, d), 7.51 (1H, m), 7.42 (1H, m), 6.97 (1H, s), 6.83 (1H, s), 6.64 (1H, d, J=4.5 Hz), 6.55 (1H, d), 6.51 (1H, s), 3.69 (4H, t, J=4.8 Hz), 3.08 (4H, d, J=3.9 Hz), 2.46 (3H, s). Mass Spectrum (ESI) m/e=464.0 (M+1).
Reaction SMILES: [I-].[OH:2][C@H:3]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][N+:5](C)([CH2:15]C2C=CC=CC=2)[CH2:4]1>[Ag]=O.C(O)C>[CH3:15][N:5]1[CH2:6][C@@H:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:3]([OH:2])[CH2:4]1
Reactant: C[N+]1(Cc2ccccc2)C[C@@H](O)[C@H](Oc2ccccc2)C1
Agent: O=[Ag]
Agent: [I-]
Solvent: CCO
Product: CN1C[C@@H](O)[C@H](Oc2ccccc2)C1
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
A solution of 9.3 g. (22.6 mmol) of trans-3-hydroxy-1-methyl-4-phenoxy-1-phenylmethylpyrrolidinium iodide in 200 ml. of absolute ethanol and 100 ml. of 190 ethanol was stirred at ambient temperature for 0.5 hr. with 2.6 g. (11.3 mmol) of silver oxide. After 0.2 g. more silver oxide was added, the mixture was warmed to 45° C. and stirred for an additional 15 min. The mixture was separated by filtration through Celite, and the volume of the filtrate was reduced to 200 ml. This solution was treated with ca. 0.5 g. of 10% Pd/C catalyst and was shaken with H2 in the Parr reduction apparatus for 3 hr. The suspension was filtered through Celite and the filtrate was concentrated to give 4.3 g. of crystalline solid. This material, when recrystallized from cyclohexane, gave 3.66 g. (84%) of off-white crystals, m.p. 89.0°-90.0° C.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:31]1(B(O)O)[CH:36]=[CH:35]C=[CH:33][CH:32]=1>>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([C:23]2[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=2)[C:15]2[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1ccccc1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-phenylnaphthalen-2-yl)acetic acid (136) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using benzeneboronic acid in the Suzuki reaction, giving the title compound (parent form). 1H-NMR: (400 MHz, MeOH-d4): δ 7.67-7.55 (m, 5H); 7.50-7.48 (m, 1H); 7.41-7.39 (m, 1H); 7.33-7.23 (m, 6H); 5.31 (s, 1H); 2.28 (s, 3H); 1.02 (s, 9H). LCMS-ESI− (m/z): [M−H]− calcd for C29H26ClO3: 457.2; Found: 457.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25]C(=O)C)=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[OH-].[Na+].O.CCOC(C)=O>CC(O)=O>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:15][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][C:4]2[CH2:3][N:2]([CH3:1])[CH2:14][CH2:13][C:12]3=2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc3[nH]c4c(c3c2)CCN(C)C4)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1CCc2c([nH]c3ccc(NS(=O)(=O)c4ccc(N)cc4)cc23)C1
Yield: 70.1 %

Procedure:
A solution of N-[4-(2-Methyl-2,3,4,9-tetrahydro-1H-β-carbolin-6-ylsulfamoyl)-phenyl]-acetamide (example 7) (80 mg, 0.2 mmol) in 1 mL of an aqueous 10% de NaOH solution was refluxed for 2 h. The resulting mixture was treated with H2O (25 mL) and EtOAc (25 mL) and neutralized by addition of AcOH glacial. The aqueous phase was washed again with EtOAc and the combined organic extracts dried to afford 50 mg of 4-amino-N-(2-methyl-2,3,4,9-tetrahydro-1H-β-carbolin-6-yl)-benzenesulfonamide as a cream colored amorphous solid, mp 236-237° C. 1H-NMR (300 MHz, DMSO-d6): (ppm) 2.36 (s, 3H); 2.55 (bb, 2H); 2.61 (bb, 2H); 3.45 (bb, 2H); 5.83 (bb, 2H); 6.44 (sys AB, 2H, J=8.7 Hz); 6.68 (dd, 1H, J=8.4, 1.8 Hz); 6.99 (bb, 1H); 7.05 (d, 1H, J=8.4 Hz); 7.25 (sys AB, 2H, J=8.7 Hz); 9.27 (s, 1H); 10.63 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][C:12]([S:19][CH3:20])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>C(#N)C>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:14]2[C:15]3[CH2:16][CH2:17][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][C:10]=3[N:11]=[C:12]([S:19][CH3:20])[N:13]=2)=[CH:30][CH:31]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CSc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CC#N
Product: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(Cc1ccccc1)C2
Yield: 59.7 %

Procedure:
The solution of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidine (915 mg, 3 mmol) from Example 24. B. and 4-tert-butylaniline (537 mg, 3.6 mmol) in acetonitrile (5 mL) was irradiated in microwave at 180° C. for 10 min. Solid thus formed was filtered out and washed by hexanes. Product was obtained as a light brown solid (750 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6](C(O)=O)[NH:5][C:4]=2[CH:3]=1.Cl>N1C2C(=CC=CC=2)C=CC=1.CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[S:9][C:8]2[CH:7]=[CH:6][NH:5][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cc2sc(Cl)cc2[nH]1
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Clc1cc2[nH]ccc2s1
Temperature: 160 °C

Procedure:
A solution of 2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (4 g, prepared by following the procedure described in WO2002/20530), and 0.7 g of Cu powder in 45 mL of quinoline was vented once with nitrogen, and then heated at 160° C. under nitrogen atmosphere for 2 h. The reaction mixture was cooled to r.t. and treated with 150 mL of 3N HCl and diluted with 100 mL of 1:1 EtOAc/hexane. The reaction mixture was then filtered through a pad of silica gel and the filter cake was washed with 200 mL of 1:1 EtOAc/hexanes. The organic phase was separated and washed with 200 mL of brine and dried over Na2SO4. After filtration and concentration, 3.5 g of the crude title compound was obtained as brown oil which was used for the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([C:25]#[N:26])=[C:20]([Cl:27])[CH:19]=3)=[N:14]2)=[O:9])[CH:4]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C=O)C.CCOC(C)=O>[N:29]1([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[C:22]([F:24])[C:21]([C:25]#[N:26])=[C:20]([Cl:27])[CH:19]=4)=[N:14]3)=[O:9])[CH:4]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: c1c[nH]cn1
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(CBr)on1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(Cn2ccnc2)on1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 27.3 %

Procedure:
(S)-5-(Bromomethyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide (0.137 mmol, 0.064 g) was suspended in DMF (5 ml). Imidazole (2.74 mmol, 0.187 g) was added and the resulting mixture was stirred at RT for 2.5 h. The reaction mixture was heated to 60° C. for 1.5 h. The mixture was diluted with EtOAc and washed four times with water. The organic phase was dried, filtered and evaporated. The crude product was purified by preparative HPLC. 0.017 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.15 (d, 3H), 4.31 (d, 2H), 4.37-4.50 (m, 1H), 5.50 (s, 2H), 6.63 (s, 1H), 6.94 (s, 1H), 6.99 (d, 1H), 7.22-7.24 (m, 1H), 7.76 (s, 1H), 7.83 (d, 1H), 7.84-7.88 (m, 1H), 7.96 (s, 1H), 8.81 (d, 1H).
Reaction SMILES: [S-:1][C:2]#[N:3].[C:4]([O:7][C:8](=O)[CH3:9])(=[O:6])[CH3:5]>N1C=CC=CC=1.ClCCl>[C:4]([O:7][CH2:8][CH2:9][S:1][C:2]#[N:3])(=[O:6])[CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: N#C[S-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCSC#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-bromoethanol (7.0 g) and potassium thiocyanate (5.4 g) in methanol (40 ml) was refluxed for 7 hours. After precipitate was filtered off, the filtrate was evaporated under reduced pressure. The residue was suspended in chloroform/methanol (5/1). The precipitate was filtered off. The filtrate was evaporated under reduced pressure to give the thiocyanate (4.4 g). To a mixture of the thiocyanate in pyridine (4.8 ml)/dichloromethane (20 ml) was added acetic anhydride (5.3 ml) in dichloromethane (5 ml) at 5° C. The mixture was stirred at room temperature for 6 hours. The precipitate was filtered off. The filtrate was washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 2-thiocyanatoethyl acetate (5.6 g).
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][C:17]1=[O:28])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>O1CCOCC1.O>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][C:17]1=[O:28]
Reactant: C[C@@](CCn1ccc(-c2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 2 h

Procedure:
HCl (4.0 N in 1,4-dioxane, 20 mL) was added to a solution of (2R)-2-Methyl-2-(methylsulfonyl)-4-(2-oxo-4-phenylpyridin-1(2H)-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (5.15 g, 11.5 mmol) in 1,4-dioxane (100 mL) and water (20 mL). The reaction was continued for 2 hours. The reaction was concentrated in vacuo, upon concentration a white solid precipitated. The solid was triturated with 2-propanol (150 mL) at 50° C. for 30 minutes then collected by filtration. The title compound was obtained as a white solid (3.85 g, 92%) LC-MS m/z 365.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3H) 2.10-2.23 (m, 1H) 2.37-2.48 (m, 1H) 3.11 (s, 3H) 3.69-3.82 (m, 1H) 4.04-4.19 (m, 1H) 6.63-6.68 (m, 1H) 6.70 (d, J=1.76 Hz, 1H) 7.41-7.55 (m, 3H) 7.68-7.75 (m, 2H) 7.77 (d, J=6.83 Hz, 1H) 11.17 (br. s., 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.C(=O)([O-])[O-].[K+].[K+].[C:19]([CH2:21]P(=O)(OCC)OCC)#[N:20].O>O1CCCC1>[C:19](/[CH:21]=[CH:1]/[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:20]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/C#N)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of methyl 3-formylbenzoate (1.00 g, 6.09 mmol) in tetrahydrofuran (10 mL) were added potassium carbonate (1.02 g, 7.31 mmol), diethyl (cyanomethyl)phosphonate (1.29 g, 7.31 mmol) and water (0.2 mL), and the mixture was stirred at 70° C. for 1 hr. To the reaction mixture was added water (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (730 mg, 64%) as colorless needle crystals.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]=1)[CH2:2][CH3:3].[F:11][C:12]([F:33])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:33][C:12]([F:11])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19](/[CH:22]=[C:9]2/[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[N:6][C:7](=[O:10])[S:8]/2)[CH2:18][CH2:17]1
Reactant: CCCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 75 °C
Reaction time: 4 h
Yield: 25.7 %

Procedure:
To a solution of 4-(propylamino)-1,3-thiazol-2(5H)-one (450 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.06 g) in 2-propanol (10 mL) was added piperidinium acetate (413 mg). The reaction mixture was stirred at 75° C. for 4 hr and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether to give the title compound (350 mg).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[C:26]1=[O:32].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:31][N:27]1[CH2:28][CH2:29][CH2:30][C@@H:25]([NH:24][C:13]([C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]=3)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[CH:11]=2)=[O:15])[C:26]1=[O:32]
Reactant: CN1CCC[C@@H](N)C1=O
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC[C@@H](NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(C4CC4)nc23)C1=O
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 0.45 mmol) and (R)-3-amino-1-methyl-piperidin-2-one (115 mg, 0.90 mmol) in DMF (2.4 mL) at room temperature was added triethylamine (0.19 mL, 1.35 mmol) and PyBOP (257 mg, 0.50 mmol). The reaction mixture was stirred overnight then diluted with EtOAc (30 mL) and washed with water (4×30 mL). The combined organic extracts were dried (Na2SO4) and evaporated under vacuum. The crude residue was purified by SiO2 column chromatography (11 g, CH2Cl2/MeOH/NH4OH, 100:0:0 to 94:5.7:0.3) to give 149 mg (74%) of 2-cyclopropyl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-2-oxo-piperidin-3-yl)-amide as a colorless viscous oil.