Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl/[C:6](=[N:11]\[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[CH:21]1[CH2:23][CH2:22]1)/[C:7]([F:10])([F:9])[F:8]>C(#N)C>[CH:21]1([C:13]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[N:11]2[C:6]([C:7]([F:10])([F:9])[F:8])=[N:3][N:2]=[N:1]2)[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccc(C2CC2)c(/N=C(\Cl)C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C2CC2)c(-n2nnnc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of NaN3 (0.56 g, 8.57 mmol, 2.5 eq) and (Z)—N-(1-chloro-2,2,2-trifluoroethylidene)-2-cyclopropyl-5-nitrobenzenamine intermediate (1.0 g, 3.43 mmol, 1.0 eq) in 15 mL dry acetonitrile was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold aqueous Na2CO3 solution, extracted with ethyl acetate. The organic layer washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude mixture was purified by column chromatography, eluting with n-hexane: ethyl acetate (10-50% EtOAc in increments of 10% EtOAc)), giving the desired product in 37% overall yield (1.55 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]1[CH2:32][CH2:31][CH2:30][C@H:15]1[C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])(=[O:13])=[O:12])=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]1[CH2:32][CH2:31][CH2:30][C@H:15]1[C:16]([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])(=[O:13])=[O:12])([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1S(=O)(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product of Example 18 (56) (1.8 mmoles) was mixed with dioxane (25 mL) and 1N NaOH (1.8 mmoles) and the reaction was stirred at room temperature for 16 hours. 1N HCl (1.8 mmoles) was added and the water and dioxane were removed under reduced pressure. The product was extracted with 0.2 N NaOH (50 mL) and EtOAc (2×50 mL) and the recovered organic layer was dried over MgSO4, filtered, and concentrated to yield a colorless oil.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[O:5]1[C:9]2[CH:10]=[C:11]([CH2:14][C:15]#[N:16])[CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6]1.[OH-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH:2]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]2[CH:7]=[CH:6][O:5][C:9]=2[CH:10]=1)[C:15]#[N:16])([CH3:4])[CH3:3]
Reactant: CC(C)I
Reactant: N#CCc1ccc2ccoc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)C(C#N)c1ccc2ccoc2c1
Yield: 42.6 %

Procedure:
2-Iodopropane (6.5 g, 0.038 mol) was added to a well-stirred mixture of benzofuran-6-acetonitrile (3.0 g, 0.019 mol), tetrabutylammonium hydrogen sulphate (6.5 g, 0.019 mol), sodium hydroxide (47% w/w, 20 cm3, 0.037 mol), water (10 cm3) and dichloromethane (50 cm3), and the mixture was refluxed for 6 hr. with good stirring. The organic layer was washed with water, dried (Na2SO4), filtered and the solvent was removed. Toluene (15 cm3) was added to the residue, the mixture was filtered, and the solvent was removed. The residue was chromatographed on silica using toluene as eluant, to give α-isopropylbenzofuran-6-acetonitrile (1.62, 0.0081 mol, 42.6%) as an oil. (Found: C, 79.32; H, 6.22; N, 6.55. C13H13NO requires C, 78.36, H, 6.58; N, 7.03%) t.l.c./silica/toluene RF 0.38.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:7]([CH3:9])[CH3:8])(Cl)[Cl:5])[CH3:3].[C:10]([B-:12]([C:17]#[N:18])([C:15]#[N:16])[C:13]#[N:14])#[N:11].[K+]>O>[C:10]([B-:12]([C:17]#[N:18])([C:15]#[N:16])[C:13]#[N:14])#[N:11].[CH3:1][N:2]([C+:4]([N:7]([CH3:9])[CH3:8])[Cl:5])[CH3:3]
Reactant: CN(C)C(Cl)(Cl)N(C)C
Agent: N#C[B-](C#N)(C#N)C#N
Agent: [K+]
Solvent: O
Product: CN(C)[C+](Cl)N(C)C
Reaction time: 0.17 h

Procedure:
13.4 g (78.3 mmol) of bis(dimethylamino)dichloromethane are added at room temperature with stirring to a solution of 12.0 g (77.9 mmol) of potassium tetracyanoborate in 200 ml of water. The reaction mixture is stirred for 10 minutes and cooled with the aid of an ice bath. The precipitate is subsequently filtered off and washed a number of times with 30 ml of ice-water. The combined filtrates were dried for 3 hours under reduced pressure at 7 Pa and 60° C. in an oil bath, giving 13.4 g of bis(dimethylamino)chlorocarbenium tetracyanoborate as an oil, corresponding to a yield of 68.7%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](OC(C)(C)C)=O)[CH2:11][CH2:10]1)[CH3:8].[Br:22][C:23]1C(Cl)=[C:25]([N+:30]([O-:32])=[O:31])[C:26]([NH2:29])=[N:27][CH:28]=1.NC1C([N+]([O-])=O)=C(N2CCN(CC(NC3SC=CN=3)=O)CC2)C(Br)=CN=1>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC(O)C.CCN(C(C)C)C(C)C>[Br:22][C:23]1[C:15]([N:12]2[CH2:11][CH2:10][N:9]([CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH3:8])[CH2:14][CH2:13]2)=[C:25]([N+:30]([O-:32])=[O:31])[C:26]([NH2:29])=[N:27][CH:28]=1
Reactant: CC(c1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Agent: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reaction time: 18 h

Procedure:
A solution of tert-butyl 4-(1-(pyridin-2-yl)ethyl)piperazine-1-carboxylate (1.1 eq, 1.10 mmol, 321 mg) in TFA (4 mL) and CH2Cl2 (4 mL) at 0° C. was stirred for 30 minutes and concentrated in vacuo. The remaining TFA was removed by azeotroping with toluene (3×10 mL) and drying at high vacuum for 2 h. Then the residue was reacted with 5-bromo-4-chloro-3-nitropyridin-2-amine (253 mg, 1.00 mmol) in iPrOH (5 mL) and DIPEA (2 mL) using the same procedure described for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide. After 18 h, the precipitate was filtered and washed with cold water (2×3 mL) and hexane (3 mL) to give the product (313 mg, 70% for two steps) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.33 (d, J=6.7 Hz, 3H, CH3), 2.48-2.62 (2 m, 4H, piperazine N(CH2)2), 3.04-3.13 (m, 4H, piperazine N(CH2)2), 3.63-3.69 (m, 1H, CH), 6.95 (br s, 2H, NH2), 7.25 (dd, br, J=6.8, 5.2 Hz, 1H, pyridine H-5), 7.44 (d, J=7.8 Hz, 1H, pyridine H-3), 7.77 (td, J=7.7, 1.6 Hz, 1H, pyridine H-4), 8.13 (s, 1H, bromopyridine H-6), 8.50 (d, br, J=4.2 Hz, 1H, pyridine H-6);
Reaction SMILES: [CH:1]1([CH2:4][C:5]([C:7]2[N:11]([CH3:12])[C:10]([S:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[N:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([CH2:4][CH:5]([C:7]2[N:11]([CH3:12])[C:10]([S:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[N:9][N:8]=2)[OH:6])[CH2:2][CH2:3]1
Reactant: Cn1c(SCC2CC2)nnc1C(=O)CC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(SCC2CC2)nnc1C(O)CC1CC1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
The crude 2-cyclopropyl-1-{5-[(cyclopropylmethyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}ethanone (817 mg, 3.25 mmol) was dissolved in methanol (20 mL) and the mixture cooled in an ice bath (4° C.). Sodium borohydride (285 mg, 7.5 mmol) was added portionwise and the reaction mixture stirred at 4° C. for 30 min and then at room temperature for 2 h. Solvent was removed in vacuo and the residue purified by chromatography on silica eluting with ethyl acetate to give the title compound (578 mg, 24% yield over 2 steps). 1H NMR (500 MHz, CDCl3) δ (ppm) 4.91 (1H, s), 3.75 (1H, s), 3.65 (3H, s), 3.11 (2H, d, J=7.3 Hz), 1.98-1.90 (1H, m), 1.84-1.78 (1H, m), 1.20-1.12 (1H, m), 0.88-0.80 (1H, m), 0.62-0.58 (2H, m), 0.53-0.43 (2H, m), 0.29-0.26 (2H, m), 0.18-0.12 (1H, m), 0.08-0.04 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH:23]C(C)(C)C)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[CH:4][CH:3]=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[CH:4][CH:3]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ccc(N)nc2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2ccc(-c3ccccc3S(N)(=O)=O)cc2F)cn1
Temperature: 50 °C

Procedure:
A mixture of 4′-(6-aminopyridin-3-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide (55 mg, 0.14 mmol) and TFA (1 mL) was heated to 50° Celsius for 1.5 h.
Reaction SMILES: [NH3:1].F[CH:3]1[N:8]=[C:7]([F:9])[N:6]=[C:5]([Cl:10])[N:4]1[O:11][CH:12]([F:14])[F:13]>O1CCCC1>[NH2:1][CH:3]1[N:8]=[C:7]([F:9])[N:6]=[C:5]([Cl:10])[N:4]1[O:11][CH:12]([F:14])[F:13]
Reactant: FC1=NC(F)N(OC(F)F)C(Cl)=N1
Reactant: N
Solvent: C1CCOC1
Product: NC1N=C(F)N=C(Cl)N1OC(F)F
Temperature: 22 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
7.8 g (0.46 mol) of ammonia were passed into a mixture of 50.0 g (0.23 mol) of 2,4-difluoro-6-chlorodifluoromethoxy-1,3,5-triazine in 150 ml of tetrahydrofuran in the course of 45 minutes at -70° C. while stirring. Stirring was carried out for 2 hours at -70° C. and overnight while the mixture warmed up to 22° C. The reaction mixture was evaporated down under reduced pressure and the residue was washed with water and dried. The reaction product was then suspended in methylene chloride, the suspension was applied to a silica gel column and elution was carried out with the same solvent. 21.5 g (43.6% of theory) of 2-amino-4-fluoro-6-chlorodifluoromethoxy-1,3,5-triazine of melting point 131°-133° C. were obtained in fractions 1 to 8. By further eluting with ethyl acetate, the more sparingly soluble 2,4-diamino-6-chlorodifluoromethoxy-1,3,5-triazine (11.2 g, 23% of theory) of melting point 114° C. was then isolated in fractions 9 to 14.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32]O)=[CH:31][C:26]=2[O:25][CH2:24]1>>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32][O:22][C:19]3[CH:18]=[CH:17][C:16]([C:13]4[N:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][N:14]=4)=[CH:21][CH:20]=3)=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: OCc1ccc2c(c1)OCO2
Product: CCCCCCCCOc1cnc(-c2ccc(OCc3ccc4c(c3)OCO4)cc2)nc1

Procedure:
By Mitsunobu etherification of 4-(5-octyloxypyrimidin-2-yl)phenol using benzo[1,3]dioxol-5-ylmethanol analogously to Example 208.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:5]([Cl:23])=[O:6]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Reaction time: 8 h
Yield: 109.3 %

Procedure:
To a solution of 2-(methyloxy)-4,6-bis(trifluoromethyl)benzoic acid (20.2 g; 70.14 mmol) in dry DCM (400 mL), at 0° C., was added dropwise oxalyl chloride (13.4 mL; 154.31 mmol) followed by dry DMF (5 drops). The reaction was allowed to reach room temperature. After overnight stirring the solvent was evaporated in vacuo to get the title product (23.5 g) as a yellow slurry used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Cl)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[N+](C1C=CC=CC=1)([O-])=O.C(=O)([O-])[O-].[Na+].[Na+].N[C:39]1[C:52]2[C:51](=[O:53])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44](=[O:54])[C:43]=2[CH:42]=[C:41](Cl)[CH:40]=1>>[CH:10]1[CH:9]=[C:8]2[C:7]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][C:42]4[C:43]5[C:44]([C:45]6[C:50]([C:51](=[O:53])[C:52]=5[CH:39]=[CH:40][CH:41]=4)=[CH:49][CH:48]=[CH:47][CH:46]=6)=[O:54])[C:15]=3[C:14](=[O:16])[C:13]2=[CH:12][CH:11]=1)=[O:17]
Reactant: Nc1cc(Cl)cc2c1C(=O)c1ccccc1C2=O
Reactant: Nc1ccc(Cl)c2c1C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Nc3cccc4c3C(=O)c3ccccc3C4=O)cccc21

Procedure:
21 g of 6-chloro-2-(4-diphenyl)-anthrapyrimidine (obtained by reacting 1-amino-4-chloroanthraquinone with diphenyl-4-carboxylic acid N-methylamide in the presence of thionyl chloride (in accordance with D.R.P. 566,474)) are condensed, in accordance with Example 1, in 250 parts of nitrobenzene in the presence of 7.5 parts of sodium carbonate and 0.25 part of copper-1 chloride with 13.5 parts of 1-amino-3-chloroanthraquinone. 28 parts are obtained of the anthrimide of the formula ##SPC9##
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[N:6]([CH2:13][C:14]3[N:15]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:16]4[C:21]([C:22]=3[C:23]([O:25]CC)=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:5]2=[O:33])[CH2:3][CH2:2]1.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([N:4]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[N:6]([CH2:13][C:14]3[N:15]([CH2:28][CH2:29][CH:30]([CH3:31])[CH3:32])[C:16]4[C:21]([C:22]=3[C:23]([OH:25])=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:5]2=[O:33])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(Cn2c(=O)n(C3CC3)c3ccncc32)n(CCC(C)C)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)c(C(=O)O)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
Compound 18 (0.5 g, 1 mmol) was dissolved in THF (25 mL), lithium hydroxide (48 mg, 2 mmol) dissolved in water (5 mL) was added. The resulting mixture was stirred at 60° C. overnight. The reaction mixture was allowed to cool down to room temperature then poured in water. The pH of the resulting mixture was adjusted to pH=4 by addition of a 1 M solution of hydrochloric acid. Then the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography using dichloromethane and methanol. The title compound 17 (400 mg, 94%) was isolated as a white powder. m/z=419 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[C:23]=1[O:24]C)[C:8]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[CH2:11]1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[C:23]=1[OH:24])[C:8]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[CH2:11]1)=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C(C)(C)C)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1S(C)(=O)=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(S(C)(=O)=O)c1O
Temperature: 130 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
3-(3-t-butyl-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (232 mg) was dissolved in N,N-dimethylformamide (5 mL), and lithium chloride (225 mg) was added to the solution, and then the mixture was stirred at 130° C. for 2 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (201 mg) as a colorless amorphous product.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[I:9][C:10]1[CH:11]=[N:12][NH:13][CH:14]=1.Cl[CH2:16][CH:17]1[O:21][C:20](=[O:22])[NH:19][CH2:18]1>O1CCOCC1.O.ClCCl>[I:9][C:10]1[CH:11]=[N:12][N:13]([CH2:16][CH:17]2[O:21][C:20](=[O:22])[NH:19][CH2:18]2)[CH:14]=1
Reactant: O=C1NCC(CCl)O1
Reactant: Ic1cn[nH]c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=C1NCC(Cn2cc(I)cn2)O1
Temperature: 110 °C

Procedure:
A mixture of potassium phosphate tribasic (6.57 g, 30.9 mmol), 4-iodo pyrazole (2.00 g, 10.3 mmol), and 5-(chloromethyl)-1,3-oxazolidin-2-one (2.80 g, 20.6 mmol) in 1,4-dioxane (103 mL) was sealed in a pressure vessel and heated for 72 hours at 110° C. Upon cooling to room temperature, the mixture was diluted with water and dichloromethane. The organic layer was separated, washed with water, and concentrated under reduced pressure. The residue was triturated with a mixture of methanol and hexanes for several hours at room temperature, and then the precipitate was collected by filtration to afford 5-[(4-iodo-1H-pyrazol-1-yl)methyl]-1,3-oxazolidin-2-one. MS ESI calc'd. for C2H8IN3O2 [M+H]+ 294. found 294. The enantiomers were separated by chiral SFC (supercritical fluid chromatography), IC column with 20% isopropyl alcohol in CO2 to give isomer 1 (faster eluting) and isomer 2 (slower eluting).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[NH2:28][C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(Br)c1
Reactant: C#Cc1cccc(N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cccc(N)c2)c1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 26.6 %

Procedure:
Into the reaction flask were added tert-butyl (5-bromopyridin-3-yl)carbamate (2.00 g, 7.32 mmol), copper(I) iodide (56 mg, 0.29 mmol), bis(triphenylphosphine)palladium(II) chloride (0.20 g, 0.29 mmol), tetrahydrofuran (20 mL) and triethylamine (1.1 mL, 8.0 mmol). The reaction mixture was stirred under N2 bubbling for 5 min. 3-Ethynylaniline (0.849 g, 7.3 mmol) was then added. The reaction mixture was heated at 50° C. overnight. After removal of the solvent, the residue was treated with EtOAc and water. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude was purified by silica gel column chromatography to give the desired product as a yellow gel (0.60 g, 49%). LCMS for C14H12N3O2 ([M-(tBu)+H]+H)+: m/z=254.0.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][N:4]=[C:3]1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([OH:20])(=O)=[O:18])=[CH:9]1.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[NH:2]1[CH2:6][CH2:5][N:4]=[C:3]1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([Cl:24])(=[O:20])=[O:18])=[CH:9]1
Reactant: O=S(=O)(O)c1cn(CC2=NCCN2)c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cn(CC2=NCCN2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-1H-indole-3-sulfonic acid hydrochloride (1.52 g, 4.814 mmol) from Step 3 was dissolved/suspended in methylene chloride (25 mL) and stirred at room temperature. Oxalyl chloride (2 mL) was added dropwise to the mixture, after which stirring was continued for 3 hours. The mixture was then evaporated to dryness, and excess oxyalyl chloride was azeotroped off with methylene chloride (3×) to provide 1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-1H-indole-3-sulfonyl chloride as a hydrochloride salt.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cn2)C2CCCCC2)oc2ccc(F)cc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a mixture of 6-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridine-3-carboxylic acid (300 mg) synthesized above, β-alanine ethyl ester hydrochloride (181 mg), 1-hydroxybenzotriazole monohydrate (181 mg), triethylamine (328 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg), and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (366 mg, 97%) as a pale-brown oil
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 116 mg (1 mmole) of n-hexanoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 150 mg (Yield: 39%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:36][C:11]3[C:12](=[O:35])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][Si](C(C)C)(C(C)C)C(C)C)=[C:18]([O:33][CH3:34])[CH:17]=4)[CH2:14][CH2:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:36][C:11]3[C:12](=[O:35])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:33][CH3:34])[CH:17]=4)[CH2:14][CH2:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-6-(3-methoxy-4-triisopropylsilanyloxy-phenyl)-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (1.68 g, 3.1 mmol) in THF (20 mL) and add 1.0 M solution of tetrabutyl ammonium fluoride in THF (3.1 mL, 3.1 mmol). Stir at RT for 1 h. Slowly add 1N HCl until pH is approximately 1. A precipitate begins to form. Allow to sit at RT for 2-3 h. Filter the resulting solid to yield 850 mg (71% yield) of the desired product. MS/ES m/z (35Cl) 386.0 [M+H]+.