Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH:12]2[CH2:17][CH2:16][CH2:15][S:14][CH2:13]2)[CH2:7][C:6]1=[O:18])(=O)[CH2:2][CH3:3].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][CH2:28][O:29][NH2:30])=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[CH:27][CH2:28][O:29][N:30]=[C:1]([C:5]2[C:10](=[O:11])[CH2:9][CH:8]([CH:12]3[CH2:17][CH2:16][CH2:15][S:14][CH2:13]3)[CH2:7][C:6]=2[OH:18])[CH2:2][CH3:3])=[CH:24][CH:25]=1
Reactant: NOCC=Cc1ccc(Br)cc1
Reactant: CCC(=O)C1C(=O)CC(C2CCCSC2)CC1=O
Product: CCC(=NOCC=Cc1ccc(Br)cc1)C1=C(O)CC(C2CCCSC2)CC1=O
Yield: 68.4 %

Procedure:
3.0 g (0.011 mol) of 2-propionyl-5-(3-tetrahydrothiopyranyl)-cyclohexane-1,3-dione and 3.0 g (0.013 mol) of 3-(4-bromophenyl)-prop-2-enyloxyamine in 100 ml of methanolwere stirred at 20° C. for 16 hours. The precipitated reaction product was separated off at 0° C., washed with ice-cold methanol and petroleum ether and dried. Yield: 68.4% mp.: 97°-99° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([O:10][CH:11]=[CH2:12])(=O)[CH3:8].C[C:14]12[O:20][CH:19]1[CH2:18]C(CO)[CH2:16][CH2:15]2>C1(C)C=CC=CC=1>[CH3:12][C:11]12[O:10][CH:7]1[CH2:8][CH:14]([O:20][CH:19]=[CH2:18])[CH2:15][CH2:16]2
Reactant: CC12CCC(CO)CC1O2
Reactant: C=COC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COC1CCC2(C)OC2C1
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture (100 mL) of sodium carbonate (0.06 mol) and toluene was heated to 95° C. 4.2 g of vinyl acetate was added dropwise to the mixture. Next, maintaining the temperature of the reaction mixture, and fifteen minutes later, further the mixture was combined with di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.5 mmol). Next, (6-methyl-7-oxabicyclo[4.1.0]hept-3-yl)methanol (0.05 mol) was added dropwise over for two hours, and a reaction was carried out in a nitrogen atmosphere while adding dropwise 12.6 g of vinyl acetate and holding the reaction temperature at 95° C. After the completion of dropwise addition, the mixture was stirred for one hour. As the result of gas chromatography analysis of the mixture, it is confirmed that there was produced 1-methyl-4-vinyloxy-7-oxabicyclo[4.1.0]heptane represented by following Formula (14) in a yield of 95%. In 1H-NMR (CDCl3) analysis, signals specific to vinyl group were observed at 6.5 ppm, 4.2 ppm, and 4.05 ppm.
Reaction SMILES: N[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([Br:13])=[CH:4][CH:3]=1.N([O-])=[O:15].[Na+].OS(O)(=O)=O>O>[Br:13][C:5]1[C:6]([CH3:12])=[C:7]([C:2]([OH:15])=[CH:3][CH:4]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=N[O-]
Reactant: COC(=O)c1c(N)ccc(Br)c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(O)ccc(Br)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
A 0° C. suspension of Example 106A (1 g, 4.1 mmol) in water (6 mL) was treated dropwise with a solution of NaNO2 (285 mg) in water (1.25 mL), stirred at 0° C. for 15 minutes, then added slowly to a 90° C. solution of concentrated H2SO4 (4 mL) in water (4 mL). The reaction was stirred at 90° C. for 45 minutes, cooled to room temperature, and extracted three times with diethyl ether. The combined extracts were washed with aqueous NaHCO3 and brine, dried (MgSO4), filtered, and concentrated to give 0.87 g of the desired product. MS (ESI(−)) m/e 226 (M−H)−.
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-])=O)=[CH:4][C:3]=1[N+:15]([O-])=O.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+].O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O>CCOC(C)=O.C1COCC1>[NH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[C:3]([NH2:15])[CH:4]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1I
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cc(N)c2ccccc2c1
Yield: 199.7 %

Procedure:
A suspension of (3) (1.0 g, 2.9 mmol) and SnCl2.2H2O (9.8 g, 436 mmol) in EtOAc (100 mL) was heated at reflux for 30 min. The white suspension was poured onto ice (ca. 100 g), and sat. aq. NaHCO3 was added until the aqueous layer was basic as shown by litmus paper inspection. The mixture was extracted with ethyl acetate, the organic layer was washed with water, dried and the solvent was removed under reduced pressure to give crude 1,3-naphthalenediamine. This material was dissolved in THF (30 mL) and treated with BOC2O (3.0 g). The mixture was heated under reflux for 5 hrs. The solvent was removed and the residue was purified by column chromatography on silica gel. Elution with CH2Cl2 gave naphthalene-1,3-(bis-tertbutoxycarbamate) (4) (0.916 g, 88%) as a brown solid: mp (petroleum ether) 129–131° C.; 1H NMR (CDCl3) δ 7.94 (s, 1H), 7.78 (s, 1H), 7.74 (m, 2H), 7.41 (m, 2H), 6.94 (s, 1H), 6.69 (s, 1H), 1.55 (s, 9H), 1.54 (s, 9H); 13C NMR δ 153.11, 152.75, 135.75, 134.75, 133.69, 128.47, 126.46, 124.36, 122.28, 119.67, 110.57, 110.47, 80.88, 80.57, 28.33. Anal (C20H26N2O4) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.P([O-])([O-])([O-])=[O:21].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11]=1[C:12]([OH:21])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=P([O-])([O-])[O-]
Reactant: O=Cc1c(Cl)nc(-c2ccccc2)c2ccccc12
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1c(Cl)nc(-c2ccccc2)c2ccccc12
Reaction time: 2 h

Procedure:
53.5 g 3-Chloro-1-phenyl-isoquinoline-4-aldehyde are suspended in 1.5 l of acetone and 500 ml of phosphate buffer of pH 7. At 40° C., 40 g of potassium permanganate are introduced portionwise within 2 hours and stirring is continued at this temperature for 2 hours. The excess potassium permanganate is destroyed with 10 g sodium hydrogenosulfite and the solution is concentrated to 500 ml and filtered. The filtrate is brought to pH 4 with concentrated hydrochloric acid followed by thorough extraction with acetic ester. Removal of the solvent in vacuo provides 41.1 g of 3-chloro-1-phenyl-isoquinoline-4 carboxylic acid having a melting point of 208° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)Cn1nnc2c(Br)c(Oc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (1-6) (100 mg, 0.352 mmol, 1.0 equiv.), copper(II) acetate (63.9 mg, 0.352 mmol, 1.0 equiv.), phenylboronic acid (86 mg, 0.704 mmol, 2.0 equiv.) and freshly milled 4 Å molecular sieves were dried in vacuo and then suspended in anhydrous CH2Cl2 (3.5 mL) and TEA (245 μl, 1.760 mmol, 5.0 equiv.). The mixture was stirred ambient temperature for 18 hours, after which the mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified via reverse phase HPLC (water/acetonitrile gradient containing 0.1% TFA) to provide 422. 1H NMR (CDCl3) δ 7.42 (1H, d, J=8.87 Hz), 7.36-7.30 (2H, m), 7.21 (1H, d, J=8.87 Hz), 7.12-7.07 (1H, m), 6.95 (2H, dd, J=7.97, 1.44 Hz), 4.40 (2H, s), 1.06 (9H, s) ppm. LRMS m/z (M+H) 360.0 and 362.0 (intensity ratio ˜1:1) found, 360.1 and 362.1 required.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])#[N:24]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:23]#[N:24])[CH:26]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Solvent: CN1CCCC1=O
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was taken 100 mg of 3-(3-chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (0.31 mmol, 1.00 eq), 61 mg of 3-cyanobenzoyl chloride (0.37 mmol, 1.20 eq), and 500 uL NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield N-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-3-cyano-N-(2-methoxy-ethyl)-benzamide. MS (ES) M+H expected=455.0, found=455.1.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[F:7][C:8]1[CH:18]=[CH:17][C:11](OCC(O)=O)=[CH:10][CH:9]=1>CN(C)C=O.ClCCl>[F:7][C:8]1[CH:18]=[CH:17][C:11]([O:3][CH2:2][C:1]([Cl:6])=[O:5])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COc1ccc(F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COc1ccc(F)cc1
Reaction time: 22 h
Yield: 100.1 %

Procedure:
Oxalyl chloride (60 mL, 686 mmol) and dimethylformamide (DMF) (8 drops, cat.) were added to a stirred suspension of 2-(4-fluorophenoxy)ethanoic acid (97.3 g, 572 mmol) in dichloromethane (500 mL). After 22 hours, the mixture was concentrated under vacuum to obtain 108 g of 2-(4-fluorophenoxy)ethanoic acid chloride, a compound of formula (Y), as a yellow oil in quantitative yield; 1H NMR (CDCl3) δ 4.90 (s, 2H), 6.84 (m, 2H), 6.99 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7](O)=[O:8].C(N1C=CN=C1)([N:26]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7]([NH2:26])=[O:8]
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(N)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (65 mg, 0.2 mmol) in DMF (82 mL) was added 1,1′-carbonyldiimidazole (39 mg, 0.24 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (300 μL, 2.0 mmol) and stirred for 2 h at room temperature. The reaction mixture was then evaporated. Purification by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) afforded the title compound (57 mg, 87%) as a white solid. MS: m/e=328.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][C@H:14]([CH3:18])[C:15](Cl)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:29][OH:30]>C1(C)C=CC=CC=1>[CH3:29][O:30][C:15](=[O:16])[C@H:14]([O:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[C:4]([F:21])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:20][CH:19]=1)[CH3:18]
Reactant: C[C@@H](Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Cl
Reactant: CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 10.6 g (0.030 mol) of (R)(+)-2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid chloride in 100 ml toluene is added slowly, while stirring into a solution of 4.9 ml (0.035 mol) of triethylamine and 2 ml (0.035mol) of methanol in 40 ml of toluene, that is cooled in an ice/bath. When everything is added, the ice-bath is removed and the reaction mixture is stirred for 3 hours at room temperature. The reaction mixture is then poured into ice-water and the organic material is extracted twice with ethyl acetate. The ethyl acetate layer is washed with a saturated salt solution, dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography over a silicagel column with a hexane/ethyl acetate solution. After evaporation of the solvent, a clear oil, the above ester remains n35D 1.5859, [α]20D =+38.8±0.5 (2 % acetone).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](F)[CH:13]=1>CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: Fc1cccc(Br)c1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2cccc(Br)c2)CC1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 65.3 %

Procedure:
Dissolve 1-methyl-piperidin-4-ol (10.06 g, 87.34 mmol) in DMF (30 mL) and add to a stirred suspension of sodium hydride (5.24 g, 131.01 mmol) in DMF (155 mL). After the addition is complete, heat at 50° C. After 45 min., add a solution of 1-bromo-3-fluoro-benzene (12.2 mL, 109.18 mmol) in DMF (15 mL) and stir and heat at 65° C. After 18 hr., cool to ambient temperature, quench with water (5 mL), remove the DMF under reduced pressure, wash with water (50 mL) and extract with ethyl acetate/hexanes (2/1 mixture, 2×35 mL). Combine the organic layers, dry over magnesium sulfate, filter under reduced vacuum and concentrate to dryness. Purify by flash chromatography using dichloromethane/ammonia (2.0M in methanol) 20/1 as the eluent to give of the title compound (15.4 g, 65%). Mass spectrum (ion spray): m/z=270.0 (M+1); 1H NMR (CDCl3): 7.12 (t, J=8.3 Hz, 1H), 7.07-7.04 (m, 2H), 6.83 (bd, J=8.3 Hz, 1H), 4.35-4.26 (bm, 1H), 2.73-2.64 (bm, 2H), 2.37-2.28 (bm, 5H), 2.05-1.96 (bm, 2H), 1.89-1.79 (bm, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])(=O)C.[Na+].[Br:14]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:14][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: COc1ccccn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Br)cn1
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a suspension of 2-methoxypyridine (10.00 g, 0.09 mol) and sodium acetate (8.27 g, 0.10 mmol) in 30 mL of glacial acetic acid was added a solution of bromine in 20 mL glacial acetic acid while maintaining the reaction temperature below 50° C. After 3 hours, 100 mL of H2O was added and the resulting solution neutralized with cold 2.5 M NaOH. The suspension was extracted with ether (2×200 mL), the combined organics were dried over MgSO4, filtered and evaporated. The crude material was purified on silica gel (eluent: hexane to hexane:ethyl acetate 97:3) and distilled (34-36.5° C./0.05 mm Hg) to give 8.84 g (51.3%) of 5-bromo-2-methoxy-pyridine as a clear colorless liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=3[F:28])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:29]([NH:33][S:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[F:28])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:42]=1)(=[O:36])=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
N-tert-Butyl-3-{4-[6-(2-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide was prepared from 2-(2-chloro-pyridin-4-yl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example E.107) (0.32 g, 0.76 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.23 g, 0.91 mmol) according to the general procedure VI. Obtained as an off-white solid (0.24 g), which was subsequently deprotected.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:27])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2([CH2:19][C:20]#[C:21][Si](C)(C)C)[CH2:18][CH2:17]2)=[CH:10][C:9]=1[CH3:26])[CH3:6])[CH3:2].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:27])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2([CH2:19][C:20]#[CH:21])[CH2:18][CH2:17]2)=[CH:10][C:9]=1[CH3:26])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCC2(CC#C[Si](C)(C)C)CC2)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#CCC1(COc2ccc(OC(C)(C)C(=O)OCC)c(C)c2)CC1
Reaction time: 1.5 h

Procedure:
A solution of 0.201 (0.50 mmol) 2-methyl-2-{2-methyl-4-[1-(3-trimethylsilanyl-prop-2-ynyl)-cyclopropylmethoxy]-phenoxy}-propionic acid ethyl ester in 5 ml THF were treated at 0° C. with 0.55 ml (1 M solution in THF, 0.55 mmol) of n-Bu4NF and stirred for 1.5 h at this temperature. The reaction mixture was then diluted with water and extracted with ether (three times). The organic layers were washed with water, dried (Na2SO4) and evaporated to give 0.152 g of the title compound as light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:15])[CH3:14])[C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[BH4-].[Na+]>[OH-].[Na+]>[CH3:14][CH:13]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[C:6](=[O:8])[O:15]1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CC1OC(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 0.67 h
Yield: 98.6 %

Procedure:
10.0 g (48 mmol) of 2-nitro-6-acetyl-benzoic acid (cf. Horii et al., Yakugaku Zasshi, 1954, 466, and Baker et al., J. Org. Chem. 1952, 17, 164) are dissolved at 40° C. in 50 ml of 2N sodium hydroxide solution and treated with 1.87 g (48 mmol) of sodium borohydride in portions. After 40 minutes, the reaction mixture, which has been cooled, is acidified and the precipitated crystals are filtered off and dried in vacuo; the product consists of 8.4 g of a product mixture of 82% of 2-nitro-6-(1-hydroxyethyl)-benzoic acid; 1H-NMR (DMSO-D6): 8.00 ppm, m, 2H; 7.68 ppm, t, 1H; 5.6 ppm, b, OH; 4.92 ppm, q, 1H; 1.32 ppm, d, 3H; and 18% of 3-methyl-7-nitro-3H-isobenzofuran-1-one; 1H-NMR (DMSO-D6): 8.02 ppm, m, 2H; 7.68 ppm, t, 1H; 5.80 ppm, q, 1H; 1.62 ppm, d, 3H. The acid aqueous phase is then also extracted with ethyl acetate, combined with the crystals obtained above, dried thoroughly over magnesium sulfate and concentrated completely to dryness by evaporation. 9.14 g (98.6%) of pure 3-methyl-7-nitro-phthalide (3-methyl-7-nitro-3H-isobenzofuran-1-one) are thereby obtained; 1H-NMR (CDCl3): 7.92 ppm, d, 1H; 7.88 ppm, t, 1H; 7.72 ppm, d, 1H; 5.63 ppm, q, 1H; 1.72 ppm, d, 3H.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=[O:3])[CH3:2].[C:31](Cl)(=O)CC>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:1](=[O:3])[CH2:2][CH3:31])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCC(=O)Cl
Product: CCO[C@H]1CN(C(=O)CC)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting propionyl chloride and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, DMSO) δ) 7.71, 7.50, 7.41, 6.00, 5.98, 4.68, 4.52, 4.22, 4.11, 3.85–3.39, 2.68, 2.37, 2.25, 1.24–0.85; HRMS (FAB) calcd for C23H30Cl2N4O2+H 465.1824, found 465.1825.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]4[N:31](CO)[CH:32]=[CH:33][C:26]=34)=[O:23])=[CH:19][CH:20]=2)[S:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].O>CO.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]4[NH:31][CH:32]=[CH:33][C:26]=34)=[O:23])=[CH:19][CH:20]=2)[S:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CCSc2cc(C(=O)Nc3ccnc4c3ccn4CO)ccc21)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@H]1CCSc2cc(C(=O)Nc3ccnc4[nH]ccc34)ccc21)OCc1ccccc1
Yield: 70.1 %

Procedure:
The obtained (S)-4-(benzyloxycarbonylamino)-N-(1-hydroxymethylpyrrolo[2,3-b]pyridin-4-yl)thiochromane-7-carboxamide (766 mg) was dissolved in methanol (10 ml) and tetrahydrofuran (20 ml), and an aqueous solution (30 ml) of sodium acetate (5.00 g) was added. The reaction mixture was stirred under reflux for 5 hr and allowed to return to room temperature. Water (100 ml) was added and the precipitated crystals were collected by filtration to give the objective (S)-4-(benzyloxycarbonylamino)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiochromane-7-carboxamide (504 mg) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:1]=2)[CH:4]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: FC(F)(F)c1cn2cc(Br)ccc2n1
Yield: 98 %

Procedure:
To a mixture of 2-amino-5-bromo-pyridine o (11.6 mmol, 2.0 g) in ethanol (50 ml) was added 3-bromo-1,1,1-trifluoroacetone (2.1 equiv., 24.3 mmol, 4.64 g) and potassium carbonate (1.5 equiv., 17.3 mmol, 2.40 g). The mixture was heated at reflux for 24 hours and evaporated under reduced pressure. The residue was partitioned between a diluted aqueous sodium bicarbonate solution (100 ml) and dichloromethane (100 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with diisopropylether (20 ml) and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with petroleum ether (20 ml). The solids were isolated by filtration affording 6-bromo-2-trifluoromethyl-imidazo[1,2-a]pyridine p (3.0 g, yield=98%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:23]=2)[S:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])(=[O:11])=[O:10])=[CH:4][CH:3]=1.C[O:36][C:37](=[O:40])[CH:38]=[CH2:39].C(N(CC)CC)C.O>CN(C)C=O>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][N:8]([S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])(=[O:11])=[O:10])[C:5]1[CH:4]=[CH:3][C:2]([CH:39]=[CH:38][C:37]([OH:40])=[O:36])=[CH:7][CH:6]=1
Reactant: C=CC(=O)OC
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(I)cc2)c(C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(C=CC(=O)O)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of N-(4-iodo-phenyl)-2,4,6-trimethyl-N-[3-(tetrahydro-pyran-2yloxy)-benzyl]-benzenesulfonamide (1.06 g, 1.79 mmol) in dimethylformamide was added acrylic acid methyl ester (0.81 mL, 8.95 mmol), triethylamine (0.75 mL, 5.37 mmol), and palladium tetrakistriphenylphosphine (0.103 g, 0.09 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was allowed to cool to room temperature and was poured into water. The reaction mixture was extracted with ethyl acetate and the organic layer was dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography of the residue (1:1 hexanes:methylene chloride to methylene chloride to 20% ethyl acetate/methylene chloride) afforded 0.93 g (94%) of the title compound of Step A.