Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[C:4](=[CH:23]\[C:24](\[CH3:39])=[CH:25]\[CH:26]([CH3:38])[CH2:27][CH:28]([CH3:37])[CH2:29][CH:30]([CH3:36])[CH2:31][CH:32]([CH3:35])[CH2:33][CH3:34])/[CH2:5][CH:6]([CH3:22])[C:7]([O:9][CH:10]1[C:14](=[O:15])[O:13][CH:12]([C:16]([OH:18])=[O:17])[CH:11]1[C:19]([OH:21])=[O:20])=[O:8])([OH:3])=[O:2].C1C[O:43]CC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1](/[C:4](=[CH:23]\[C:24](\[CH3:39])=[CH:25]\[CH:26]([CH3:38])[CH2:27][CH:28]([CH3:37])[CH2:29][CH:30]([CH3:36])[CH2:31][CH:32]([CH3:35])[CH2:33][CH3:34])/[CH2:5][CH:6]([CH3:22])[C:7]([O:9][CH:10]([C:14]([OH:43])=[O:15])[CH:11]([C:19]([OH:21])=[O:20])[CH:12]([OH:13])[C:16]([OH:18])=[O:17])=[O:8])([OH:3])=[O:2]
Reactant: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)OC1C(=O)OC(C(=O)O)C1C(=O)O)C(=O)O
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)OC(C(=O)O)C(C(=O)O)C(O)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Step 1) To Compound 1 (1.33 g, 2.41 mmol), THF (20 mL), water (20 mL), and sodium carbonate (1.02 g, 9.62 mmol) were added, and the resulting mixture was stirred at room temperature for 30 minutes. The solvent in the reaction mixture was evaporated under reduced pressure. The resulting residue was purified by Diaion (registered trademark) HP-20ss (Mitsubishi Chemical Corporation) column chromatography (water/methanol), and to the residue, water (20 mL) and Dowex 50 (registered trademark) (Muromachi Technos, 50WX8, 50-100 mesh, H+ form) (10 g) were added, and the resulting mixture was gently stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by high performance liquid chromatography (column: Waters SunFire (registered trademark) C18, 19×250 mm, Cat. No. 186002669; mobile phase: acetonitrile containing 0.1% TFA/water containing 0.1% TFA), whereby 1-{(4Z,6E)-4-carboxy-2,6,8,10,12,14-hexamethylhexadec-4,6-dienoyloxy}-3-hydroxypropane-1,2,3-tricarboxylic acid (174 mg) was obtained.
Reaction SMILES: [C:1]1([CH3:36])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][NH:26][C:27](=[O:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>CCO>[C:1]1([CH3:36])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][NH:26][C:27](=[O:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCC(=O)NCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCNC(=O)CCC(=O)O)CCC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 4-(2-(2,3-dip-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)ethylamino)-4-oxobutanoate (step 3)(168 mg, 0.345 mmol) was dissolved in EtOH (3 ml). 2M Sodium hydroxide (0.345 ml, 0.690 mmol) was added and the solution stirred for 30 minutes at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 0.1 M HCl solution. The organic layer was separated and washed with saturated brine, dried (MgSO4) and concentrated in vacuo to a volume of 5 ml. The suspension was filtered and washed with EtOAc to afford the title compound;
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@@H:9]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(O)=O.CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:21])[N:7]([CH3:8])[C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Temperature: 60 °C

Procedure:
To a solution of Example 1E (285 mg, 0.98 mmol) in 4.4% HCO2H/MeOH (20 mL) under a nitrogen atmosphere was added Pd(OH)2 on carbon (20%, 40 mg), and the resulting mixture was heated at 60° C. for 16 hours. The mixture was cooled to room temperature and filtered through a layer of diatomaceous earth, the filter pad was washed with extra MeOH (30 mL), and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (30 mL) and washed with 1 M NaOH, then the organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 4.57 (d, J=6 Hz, 1H), 3.03 (m, 2H), 2.87 (m, 1H), 2.79 (s, 3H), 2.76 (m, 1H), 1.99 (m, 1H), 1.79 (m, 1H), 1.46 (s, 9H). MS (DCI+) m/z 201 (M+H).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25]>CO>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH:25][C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COCCOCCCN
Reactant: COC(=O)c1cc2cc(S(N)(=O)=O)sc2s1
Solvent: CO
Product: COCCOCCCNC(=O)c1cc2cc(S(N)(=O)=O)sc2s1
Yield: 64.7 %

Procedure:
5-Methoxycarbonylthieno[2,3-b]thiophene-2-sulfonamide (0.55 g., 2 mmoles) and 3-(methoxyethoxy)propylamine (0.80 g., 6 mmoles) were refluxed in methanol (5 mL) for 96 hours. The solution was cooled and evaporated in vacuo to remove most of the methanol. Ether was added and the resulting product was recrystallized from 1,2-dichloroethane to give 0.49 g of 5-(N-methoxyethoxypropylcarbamoyl)thieno[2,3-b]thiophene-2-sulfonamide, m.p. 154°-155° C.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([O:19]C(=O)C)[C@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C.C(OCC)(=O)C>O1CCCC1.O>[Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([OH:19])[C@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O[C@@H]1[C@@H](O)[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)OC[C@H]1O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To 2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole (0.083 g, 0.16 mmol) magnetically stirring in 7 ml of tetrahydrofuran was added sodium carbonate (0.13 g, 1.2 mmol) in 1 ml of water. The mixture was allowed to stir at rt for 7 days, then heated at reflux for 2 h. The mixture was cooled to rt, neutralized with acetic acid (0.059 ml, 1.0 mmol) and stirred for an additional 0.5 h at rt. The product, 2-Bromo-5,6-dichloro-1-beta-D-xylopyranosyl-1H-benzimidazole, was purified on a silica gel column (2.5×10 cm, 230-400 mesh) eluting with ethyl acetate (0.40 g, 0.10 mmol, 63%); m.p. 149.6° C. (decomposes); 1H NMR (DMSO-d6) δ7.95 (s,1H), 7.90-7.80 (bs, 1H), 5.48-5.46 (d, J=5.2 Hz), 5.40-5.30 (bs, 1H), 5.23-5.19 (m, 2H), 3.96-3.90 (m, 1H), 3.85-3.50 (2 overlapping bs, 2H), 3.43-3.20 (m, 2H obscured by HOD peak).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[F:23])C1C=CC=CC=1>Br.CC(O)=O.O.C(=O)(O)[O-].[Na+]>[F:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8])=[O:24]
Reactant: O=C(Nc1ccccc1OCc1ccccc1)c1ccncc1F
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1O)c1ccncc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
Title compound 24 (4.40 g, 13.6 mmol) was dissolved in 33% HBr in AcOH (30 mL) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and solid sodium bicarbonate (until alkaline) then extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude was triturated in 30% ethyl acetate in hexanes to afford the title compound 25 (2.36 g, 75%) as a beige solid. LRMS (ESI): (calc) 232.06. (found) 233.1 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:21]2[N:22]([CH3:23])[C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Reaction time: 16 h
Yield: 15 %

Procedure:
According to general procedure B, 4-bromo-N-(tert-butyl)benzenesulfonamide (117 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. N-(tert-butyl)-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)benzenesulfonamide (19 mg, 15%) was provided after purification. MS (ESI) m/z 317. HPLC purity 100.0% at 210-370 nm, 10.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][Cl:13].O>O1CCCC1>[Cl:13][CH2:12][CH2:11][CH2:10][N:5]1[CH:6]=[C:2]([I:1])[N:3]=[CH:4]1
Reactant: Ic1c[nH]cn1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: ClCCCn1cnc(I)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
To a stirred solution of 4-iodo-1H-imidazole (291, 2 g, 10.3 mmol) La) Y. He et al., Tet. Lett. 45, 2004, 5529-5532, b) Panosyan, F. B., Still, I. W. J., Can. J. Chem. 79, 2001, 1110-1114.] in dry tetrahydrofuran (40 mL) at 0° C. under nitrogen was added sodium hydride (60% in oil, 0.91 g, 22.7 mmol). The mixture was stirred for 20 min. at 0° C., 1-bromo-3-chloropropane (1.2 mL, 12.4 mmol) was added and stirring was continued for 24 h at room temperature. Water was added and the aqueous solution was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent ethyl acetate-dichloromethane, 4:96) to afford 292 (1.35 g, 5.0 mmol, 49% yield) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.63 (d, J=1.2 Hz, 1H), 7.42 (d, J=1.2 Hz, 1H), 4.08 (t, J=6.8 Hz, 2H), 3.55 (d, J=6.8 Hz, 2H), 2.16 (q, J=6.8 Hz, 2H). MS (m/z): 271.0 (M+H, 100%), 273.0 (M+H, 32%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1C=CC=[CH:4][CH:3]=1.NCC#N.BrBr.[C:16]([NH:24][CH2:25][C:26]#[N:27])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)C#CC>C(OCC)(=O)C.C(N(CC)CC)C>[C:16]([NH:24][CH2:25][C:26]#[N:27])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:16]([NH:24][CH:25]([O:8][CH2:1][C:2]#[C:3][CH3:4])[C:26]#[N:27])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Agent: BrBr
Agent: CC#CCO
Agent: N#CCN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC#CCOC(C#N)NC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
Benzoylaminoacetonitrile was synthesized in a conventional manner from benzoyl chloride and aminoacetonitrile. Bromine (40 g) was added at a time to a solution of 4.0 g of the benzoylaminoacetonitrile in 200 ml of ethyl acetate at room temperature. When the color of bromine in the reaction solution disappeared, the reaction solution was cooled to 0° to 5° C. 2-Butyn-1-ol (2.1 g) and 5.6 g of triethylamine were dissolved in 10 ml of ethyl acetate, and the solution was added dropwise to the ethyl acetate solution previously cooled. After the addition, the reaction was continued for 30 minutes at room temperature. Triethylamine hydrobromide was separated by filtration, and the filtrate was distilled under reduced pressure to evaporate the solvent. The residue was purified by silica gel column chromatography. By elution with hexane-ethyl acetate, 3.8 g of alpha-benzoylamino-(2-butynyloxy)acetonitrile was obtained as a solid. The yield was 65.5%, and the melting point of the product was 84° to 85.5° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)C.O.[OH-].[Li+]>O1CCCC1CO.O>[F:19][C:17]([F:18])([F:20])[C:14]1[CH:13]=[CH:12][C:11]([C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([OH:21])=[O:3])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cccnc1-c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: OCC1CCCO1
Solvent: O
Product: O=C(O)c1cccnc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
2-(4-Trifluoromethyl-phenyl)-nicotinic acid ethyl ester (2.33 g, 7.9 mmol) was dissolved in 40 ml of a 3:1:1 mixture of tetrahydrofuran-methanol-water, and lithium hydroxide monohydrate (828 mg, 19.8 mmol) was added. After stirring overnight at room temperature, the volatiles were removed under vacuum and 75 ml of water was added to the mixture, which was brought to pH 2 with 1N HCl. The resulting slurry was extracted with 2×100 ml of ethyl acetate, the combined organic layers were washed with brine, dried (magnesium sulfate), filtered and concentrated under vacuum to provide 2.15 g of the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](O)([CH3:19])[CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:19])=[CH:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(O)(CC(=O)O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=CC(=O)O)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 105.5 g 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutyric acid and 5.3 g p-toluenesulfonic acid in 1500 ml of toluene is heated for 2,5 hours and worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-2-butenoic acid, m.p. 58° - 60°.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH:17]1([CH2:20][O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:17]1([CH2:20][O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:15])[CH2:24][CH2:23]2)[CH2:18][CH2:19]1
Reactant: C1CC(OCC2CC2)CCN1
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](CN1CCC(OCC2CC2)CC1)CN1C(=O)COc2ccccc21
Reaction time: 72 h
Yield: 64.2 %

Procedure:
A reaction flask was charged with (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (0.199 g, 0.6 mmol), 4-cyclopropylmethoxypiperidine (0.093 g, 0.6 mmol), and K2CO3 (0.124 g, 0.9 mmol) in MeCN (2 mL) and stirred at 50° for 3 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography followed by flash column chromatography (SiO2; EtOAc) to give the title compound (0.138 g, 64%). 1H NMR (CDCl3) d 6.99-6.97 (m, 1H), 6.85-6.79 (m, 3H), 4.47-4.35 (m, 2H), 3.85-3.74 (m, 2H), 3.14-3.08 (m, 1H), 3.11 (d, J=6.8 Hz, 2H), 2.64-2.61 (m, 1H), 2.49-2.46 (m, 1H), 2.10-2.04 (m, 2H), 2.00-1.68 (m, 6H), 1.47-1.38 (m, 2H), 0.90-0.84 (m, 1H), 0.71 (d, J=6.6 Hz, 3H), 0.37-0.33 (m, 2H), 0.04-0.00 (m, 2H); 13C NMR (CDCl3) d 164.6, 145.4, 128.5 123.4, 122.4, 116.9, 115.3, 75.0, 72.5, 67.5, 63.3, 52.6, 51.6, 45.0, 31.6, 31.5, 29.1, 16.7, 10.9, 2.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:19][CH2:18][CH2:17][O:16][C:4]=2[N:5]=[C:6](/[CH:8]=C/C2C=CC=CC=2)[N:7]=1.[O:20]1CCOCC1.O>O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[C:3]2[CH2:19][CH2:18][CH2:17][O:16][C:4]=2[N:5]=[C:6]([CH:8]=[O:20])[N:7]=1
Reactant: Clc1nc(/C=C/c2ccccc2)nc2c1CCCO2
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=Cc1nc(Cl)c2c(n1)OCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To 4-chloro-2-[(E)-2-phenylethenyl]-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine (0.21 g, 0.79 mmol) was dissolved in a 2:1 solution of 1,4-dioxane/water (6 mL) and cooled to 0° C. NaIO4 (0.50 g, 2.4 mmol) and catalytic OsO4 (0.25 mL, 4% aq. solution) were added and the solution was then stirred at ambient temperature for 2 h. The reaction solution was diluted with water (10 mL) and extracted with EtOAc (4×). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was then purified by column chromatography (silica gel) using a DCM-MeOH (90:10) to yield the desired compound as an off-white solid (0.055 g, 36%).
Reaction SMILES: [C:1]1([CH3:49])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[C:22](C4C=CC(C)=CC=4)=[C:21]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]([NH:36][CH2:37][C:38]([O:40]C)=[O:39])=[O:35])[N:20](C4C=CC(C)=CC=4)[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([CH3:49])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:22]=[C:21]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]([NH:36][CH2:37][C:38]([OH:40])=[O:39])=[O:35])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)CNC(=O)CCCCc1c(-c2ccc(C)cc2)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2n1-c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc3cc(CCCCC(=O)NCC(=O)O)[nH]c3nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 2-(5-(2,3-di-p-tolyldi-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pentanamido)acetate (step 1) (17 mg, 0.036 mmol) in THF (1 ml) and water (0.5 ml) was treated with LiOH. monohydrate (8.12 mg, 0.108 mmol). After stirring at room temperature for 3 hours, the reaction mixture was treated with water (20 ml) and the pH adjusted to pH 2 using 2M HCl. The aqueous portion was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure. Purification by reverse phase (C18) chromatograpy eluting with 0-30% MeCN in water (0.1% TFA) afforded the titled compound;
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[C:8]([OH:10])[CH:9]=1.CN(C)C=O.[Br:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[C:27](=[O:33])[NH:26][C:25](=[O:34])/[C:24]/2=[CH:35]/OC>C(N(CC)CC)C>[Br:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[C:27](=[O:33])[NH:26][C:25](=[O:34])[C:24]2=[CH:35][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[C:8]([OH:10])[CH:9]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2cc(OC)c(Br)cc21
Reactant: CCCOc1ccc(CN)cc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCOc1ccc(CNC=C2C(=O)NC(=O)c3cc(OC)c(Br)cc32)cc1O
Reaction time: 0.25 h

Procedure:
A mixture of 5-Aminomethyl-2-propoxy-phenol hydrochloride (109 mg, 0.50 mmole), 4 mL of N,N-dimethylformamide and triethylamine (75 μL, x mmole) were stirred for 15 minutes. Then (4E)-6-bromo-7-methoxy-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (156 mg, 0.50 mmole) is added and the reaction mixture stirred for one hour. The product is isolated as before, to give an off-white solid, 119 mg, (51%), mp 212-214° C. dec; MS (ESI): m/z 459.1, 461.2 (M−H).
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].C(N(C(C)C)C(C)C)C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: C[C@@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C[C@H](CO)NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
(2R)-2-Aminopropan-1-ol (2.0 g, 26.7 mmol) and N-ethyl-N,N-diisopropylamine (8.5 mL, 48.9 mmol) was added dropwise over 20 min to a cooled (0° C.) solution of 4-bromobenzenesulfonyl chloride (6.12 g, 24 mmol) in methylene chloride (20 mL). The reaction mixture was allowed to stir for 1 h. Water was added and the mixture was washed, twice, with HCl (aq, 1 M) and one time with saturated aqueous sodium hydrogen carbonate. The organic phase was dried over sodium sulfate and evaporated to give 6.8 g, (96% yield) of the title compound: 1H NMR (CD3OD, 400 MHz) δ 7.82 (d, J=8 Hz, 2H), 7.76 (d, J=8 Hz, 2H), 3.44 (m, 1H), 3.34 (m, 3H), 1.03 (d, J=7 Hz, 3H); MS (ESI) m/z (M++1); 13C NMR (CD3OD, 100 MHz) 142.42, 133.36, 129.74, 127.90, 66.81, 52.49, 17.94
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Br:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:20]1[S:21][C:22]([CH:25]=O)=[CH:23][N:24]=1)([CH3:19])[CH3:18].[OH-].[Na+].O>C1COCC1>[NH2:9][C:8]1[C:7]2[C:10]([Br:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])/[CH:2]=[CH:25]/[C:22]1[S:21][C:20]([CH:17]([CH3:19])[CH3:18])=[N:24][CH:23]=1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Br
Reactant: CC(C)c1ncc(C=O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2oc(C(=O)/C=C/c3cnc(C(C)C)s3)c(N)c2c1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A mixture of 12G (1.5 g, 5.2 mmol), 2-isopropyl-thiazole-5-carbaldehyde (1.2 g, 7.7 mmol) in THF (20 mL) was cooled to 0° C. To the mixture was added NaOH (1.5 g), then stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 14A (1.4 g, 62.9% yield).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1[C:16]#[N:17].O(Cl)[Cl:19].[P+5]>>[Cl:19][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1[C:16]#[N:17]
Reactant: N#Cc1c(O)ccn2c(CC(F)(F)F)cnc12
Reactant: ClOCl
Agent: [P+5]
Product: N#Cc1c(Cl)ccn2c(CC(F)(F)F)cnc12
Temperature: 130 °C
Yield: 56 %

Procedure:
A mixture of compound D5 (1 g, 4.148 mmol) and phosphorus (V) oxychloride (2 ml) was subjected to microwave heating at 130° C. for 15 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue was then treated with NaHCO3 (aqueous sat. solution) and extracted with DCM. The organic layer was separated, dried (MgSO4) and evaporated in vacuo. The crude product was purified by column chromatography (silica gel; Et2O as eluent). The desired fractions were collected and evaporated in vacuo to yield compound D6 (0.6 g, 56%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:18][C:19]1[C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(O)c1cccnc1Cl
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccnc4Cl)cc3c2C1

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 15.9 mg (0.101 mMol) 2-chloro-3-pyridinecarboxylic acid, the title compound was recovered as a white solid.