Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][C@H:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29][CH2:28][C@@H:27]1[CH:40]=[O:41])=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:42][C:43]1[CH:48]=[C:47]([CH2:49][CH2:50][N+:51]([O-:53])=[O:52])[CH:46]=[C:45]([F:54])[CH:44]=1>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][C@H:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:29][CH2:28][C@@H:27]1[CH:40]([OH:41])[CH:50]([N+:51]([O-:53])=[O:52])[CH2:49][C:47]1[CH:48]=[C:43]([F:42])[CH:44]=[C:45]([F:54])[CH:46]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=[N+]([O-])CCc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC[C@@H]1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC[C@@H]1C(O)C(Cc1cc(F)cc(F)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add tetrabutylammonium fluoride (0.08 mL, 0.08 mmol, 1.0 M in tetrahydro-furan) to (2R, 5R)-5-Benzyloxy-2-formyl-piperidine-1-carboxylic acid tert-butyl ester (0.27 mg, 0.84 mmol) and 1,3-difluoro-5-(2-nitro-ethyl)-benzene (0.17 g, 0.93 mmol) in 5 mL tetrahydrofuran. Stir at room temperature overnight and concentrate. Subject the residue to silica gel chromatography, eluting with from 100% hexane to 90:10 hexane:ethyl acetate to provide the desired compound as a mixture of 3 isomers (0.286 g, 67%).
Reaction SMILES: [C:1]1([S:7]([CH3:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCCN(S(F)(F)[F:20])CCOC>C(Cl)Cl>[C:1]1([S:7][CH2:9][F:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CS(=O)c1ccccc1
Solvent: ClCCl
Product: FCSc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution of methyl phenyl sulfoxide (140 mg, 1 mmol) in CH2Cl2 (5.0 mL) was added to bis(methoxyethyl)aminosulfur trifluoride (332 mg, 1.5 mmol ) under N2 and stirred for 16 h at room temperature. After work-up as above fluoromethyl phenyl sulfide (70% yield as determined by NMR) was obtained. 1H NMR (CDCl3) d 7.5-7.0 (m, 5H), 3.3 (d, 2H). 19F
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:10]([I:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CI.[BH4-].[Na+].[C:26](=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15][C:16]3[CH2:17][CH2:18][N:19]([CH3:26])[CH2:20][CH:21]=3)=[C:10]([I:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(SCc3ccncc3)c(I)cc21
Reactant: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2cc(SCC3=CCN(C)CC3)c(I)cc21
Temperature: 0 °C

Procedure:
1-Acetyl-2,3-dihydro-6-iodo-5-(pyridin-4-ylmethylthio)-1H-indole (D50) (0.390 g, 0.951 mmol) was dissolved in dry DMF (5 ml) and was treated with methyl iodide (0.089 ml, 1.430 mmol) with stirring. After 24 hours the reaction mixture was evaporated under reduced pressure and was triturated with ethyl acetate (~20 ml). The resultant brown solid was then filtered off, washed with diethyl ether and dried in vacuo (0.513 g). The solid was then redissolved in a mixture of ethanol (20 ml) and water (10 ml) and was cooled to 0° C. Sodium borohydride (0.069 g, 1.824 mmol) was then added. After 0.5 h a further amount of sodium borohydride (0.035 g, 0.912 mmol) was added. The reaction mixture was then allowed to warm to room temperature. After 1.5 hours the reaction mixture was treated with sodium bicarbonate solution (~15 ml) and was partitioned between dichloromethane and water. The aqueous layer was then extracted with dichloromethane (1X) and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give a yellow solid which was purified by silica-gel chromatography (5% MeOH/CH2Cl2 as eluant) to give the title compound as an off white solid (0.208 g, 53%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:15]>[Pt]=O.CO>[ClH:15].[O:1]([CH2:8][CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCc2ccncc2)cc1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: c1ccc(OCC2CCNCC2)cc1
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of 18.5 g (0.1 mole) of 4-phenoxymethylpyridine, 250 ml of methanol, 250 ml of 3 N methanolic hydrogen chloride solution and 2 g of platinum oxide is shaken at ambient temperature under a hydrogen pressure of 1 atmosphere absolute. After the take up of the calculated amount of hydrogen, the catalyst is filtered off, the filtrate is evaporated in a vacuum and the residue is recrystallized from ethanol. There are obtained 12.0 g of 4-phenoxymethylpiperidine hydrochloride (53% of theory); m.p. 218°-219° C. The free base is obtained by treating the hydrochloride with an aqueous solution of sodium hydroxide.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH:9]([C:13]([O:15]CC)=[O:14])[CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CCOCC>[CH:1]1[C:6]2[CH2:7][CH2:8][CH:9]([C:13]([OH:15])=[O:14])[CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCc2ccccc2C(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C1CC(C(=O)O)CCc2ccccc21
Yield: 66.9 %

Procedure:
A suspension of 0.7 g (3 mmol) of ethyl (±)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one-7-carboxylate (prepared as described in Bowman, Tetrahedron, 48, 4027, 1992) in 2 mL of 2N NaOH (4 mmol) was refluxed for 2 h, then cooled and extracted with Et2O. The aqueous layer was brought to acidic pH with 10% HCl, the precipitate formed was redissolved in Et2O and the organic phase was washed with water and dried. The solvent was removed in vacuo and the resulting residue was purified by flash chromatography, eluting with a mixture CH2Cl2/MeOH 9:1 respectively, yielding 0.41 g of the title compound. m.p.=134-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23]C)=[O:22])(=[O:14])=[O:13].[OH-].[Li+]>O1CCCC1.CO>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([S:12]([NH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([OH:23])=[O:22])(=[O:13])=[O:14])=[C:2]([Cl:1])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(Cl)c1
Temperature: 77.5 °C
Yield: 86.8 %

Procedure:
To a solution of 22 (272.0 mg; 0.73 mmol) in tetrahydrofuran (8 mL) and methanol (2 mL) was added aqueous lithium hydroxide (4 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a white solid (237 mg).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][P:6]([O-:9])([O-:8])=[O:7])#[N:2].[Ba+2].Cl>O>[C:1]([CH2:3][CH2:4][O:5][P:6](=[O:7])([OH:9])[OH:8])#[N:2]
Reactant: N#CCCOP(=O)([O-])[O-]
Agent: Cl
Agent: [Ba+2]
Solvent: O
Product: N#CCCOP(=O)(O)O

Procedure:
A 6.277 g portion of barium 2-cyanoethylphosphate was placed into an Erlenmeyer flask and slurried in deionized water. About 2 ml. of concentrated hydrochloric acid was added to form the compound 2-cyanoethylphosphoric acid. The flask was fitted with a Tuttle cover (Fisher Scientific Company Cat. No. 10-042) and the contents heated to boiling. To this was added 1.100 g of ZrOCl2.8H2O. A white precipitate formed immediately, and the mixture was heated and refluxed for about one day. The solution was inadvertently evaporated to dryness during this time.
Reaction SMILES: Br[C:2]1[N:6]=[C:5](/[C:7](/[CH3:20])=[CH:8]/[C:9]2[N:19]=[C:12]3[C:13]([CH3:18])=[N:14][CH:15]=[C:16]([CH3:17])[N:11]3[N:10]=2)[N:4]([CH3:21])[N:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:17][C:16]1[N:11]2[N:10]=[C:9](/[CH:8]=[C:7](/[C:5]3[N:4]([CH3:21])[N:3]=[C:2]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[N:6]=3)\[CH3:20])[N:19]=[C:12]2[C:13]([CH3:18])=[N:14][CH:15]=1
Reactant: C/C(=C\c1nc2c(C)ncc(C)n2n1)c1nc(Br)nn1C
Reactant: C1CCNC1
Product: C/C(=C\c1nc2c(C)ncc(C)n2n1)c1nc(N2CCCC2)nn1C
Yield: 25 %

Procedure:
Was prepared in the same manner as described in Example 87a) using (E)-2-(2-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)prop-1-enyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (448 mg, 1.29 mmol, Eq: 1.00) instead of 2-[(E)-2-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine and pyrrolidine (183 mg, 213 μl, 2.57 mmol, Eq: 2) instead of pyrrolidin-2-one affording 5,8-dimethyl-2-[(E)-2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-propenyl]-[1,2,4]triazolo[1,5-a]pyrazine (109 mg, 41.1%) as a white solid. MS: m/z=339.5 (M+H+)
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].I[CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[C:22]([C:18]1[N:17]([CH2:16][CH2:15][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:21]=[CH:20][CH:19]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(c1ccccc1)c1cccn1CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCn1cccc1C(=O)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of diethyl malonate (5.40 g, 33.8 mmol) in anhydrous N,N-dimethylformamide (50 mL) at 0° C. was added sodium hydride (60% in mineral oil, 1.35 g, 33.8 mmol). The reaction mixture was warmed and stirred at room temperature for 30 minutes. To this mixture was then added a solution of 1-(2-iodoethyl)-2-benzoylpyrrole (11.0 g, 33.8 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into water (1000 mL) and extracted with ethyl acetate (3×300 mL). The ethyl acetate extracts were combined, washed with water (2×200 mL) and saturated aqueous sodium chloride (300 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to provide 9.85 g (82%) of 2-benzoyl-1-[3,3-di(ethoxycarbonyl)propyl]pyrrole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:10]=1[C:11]1[CH:12]([CH2:30][O:31][CH3:32])[CH:13]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:14][CH:15](C(O)=O)[C:16]=1[NH:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C(C)=CC=CC=1>[CH2:28]([O:27][C:25]([CH:13]1[CH:12]([CH2:30][O:31][CH3:32])[C:11]2[C:10]3[C:18](=[CH:19][CH:20]=[CH:21][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH:17][C:16]=2[CH2:15][NH:14]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C1NC(C(=O)O)c2[nH]c3cccc(OCc4ccccc4)c3c2C1COC
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1NCc2[nH]c3cccc(OCc4ccccc4)c3c2C1COC
Yield: 98.2 %

Procedure:
10 g of crystalline 5-benzyloxy-3-ethoxycarbonyl-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-1-carboxylic acid is heated to boiling for 1 hour in 200 ml of xylene and the xylene is distilled off to dryness in vacuum. (decarboxylation) After crystallization from ethyl acetate, the residue yields 8.83 g of 5-benzyloxy-4-methoxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid ethyl ester with a melting point of 170°-171° C. (98.2% of theory).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:19][C:18]=2[O:28][CH3:29])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:29][O:28][C:18]1[CH:19]=[C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:21]=[CH:22][C:17]=1[S:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:16])=[O:15]
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCNCC2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of 4-(4-Acryloylamino-2-methoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 4.7 mmol) in DCM (20 ml) was added trifluoroacetic acid (5 ml) in one portion. The resulting mixture was then stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the reaction was concentrated under vacuum to afford the title compound (1.3 g, 93% yield) as an orange gum.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][N:12]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:14]Cl.O>CC(C)=O>[CH2:1]([N:8]1[CH2:10][CH2:11][N:12]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cccc(N(CCCl)CCCl)c1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cccc(N2CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 41 h
Yield: 51 %

Procedure:
Benzylamine (1.2 mL, 11 mmol), 120b (1.0 g, 3.6 mmol), water (50 mL), and acetone (50 mL) were heated at reflux for 28 h, then stirred at room temperature an additional 41 h. After evaporation of the acetone, the mixture was extracted with EtOAc (2×). The organic phase was extracted further with water and brine, then dried (Na2SO4), filtered and concentrated. The product was purified by chromatography on silica gel, eluting with 30% to 50% EtOAc in hexanes, then evaporated to yield a yellow oil (0.57 g). IR(neat): cm-1 1722. 1H NMR (300 MHz, CDCl3): 7.57-7.08 (m, 9H), 3.88 (s, 3H), 3.56 (s, 2H), 3.24 (m, 4H), 2.61 (m, 4H). HR-MS: Calc'd. 311.1760, Found 311.1764.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([NH2:21])[CH2:17][CH:18]([CH3:20])[CH3:19]>>[CH2:16]([NH:21][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=1)[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)CCN
Product: CC(C)CCNC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using Preparation Method 1, 4-phenylbenzoic acid was reacted with isoamylamine. The resulting reaction mixture was purified using SiO2 with CH2Cl2 100%. A white crystalline solid was obtained (29%). NMR 1H (ppm, CDCl3): 7.81 (d, J3=8.3 Hz, 2H), 7.65-7.58 (m, 4H), 7.47-7.34 (m, 3H), 6.06 (br. s., 1H), 3.53-3.36 (m, 2H), 1.74-1.65 (m, 1H), 1.52 (quart., J3=6.7 Hz, 2H), 0.96 (d, J3=6.6 Hz).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]ccc23)cc1
Temperature: 110 °C

Procedure:
To a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (3.1 g, 20 mmol) dissolved in DMF (60 ml) are added 4-nitrophenol (4.9 g, 35 mmol) and potassium carbonate (5.3 g, 38 mmol). The resulting solution is heated to 110° C. overnight. After the completion of reaction as indicated by disappearance of starting material, the reaction mixture is cooled to ambient temperature and poured into cold water. The resulting solids are collected by filtration and washed with water (3×100 ml). The crude product is purified by flash column chromatography using hexanes:ethyl acetate (1/1 v/v) as eluent to afford the title compound as a solid: 1H NMR 400 MHz (DMSO-d6) δ 12.34 (bs, 1H), 8.35 (m, 3H), 7.57 (m, 3H), 6.61 (m, 1H); HRMS (MALDI-FTMS) calculated for C12H9N4O3 [MH]+ 257.0669,found 257.0670.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][NH:6][C:5]([NH2:8])=[N:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[N:18][CH:17]=1>C(O)C>[F:1][C:2]1([F:9])[CH2:7][N:6]2[C:24](=[O:25])[CH:23]=[C:22]([C:19]3[CH:20]=[CH:21][N:16]=[CH:17][N:18]=3)[N:8]=[C:5]2[NH:4][CH2:3]1
Reactant: NC1=NCC(F)(F)CN1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncn2)nc2n1CC(F)(F)CN2

Procedure:
To a suspension of 2.17 g (16.12 mmol) of 5,5-difluoro-1,4,5,6-tetrahydro-2-pyrimidinamine and 1.81 g (16.12 g) of potassium carbonate in 30 ml of ethanol was treated with 2.55 g (13.13 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate. The reaction mixture was heated at reflux temperature during 32 h.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:24])[CH3:23])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])=[CH:8][CH:7]=1.C([O-])(=[S:28])C.[K+].O>CC(N(C)C)=O>[SH:28][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:24])[CH3:23])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])=[CH:8][CH:7]=1
Reactant: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCI)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCS)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6.6 g (0.015 mol) of 1-[4-(3-Iodopropylamino)phenyl]-2-dimethylamino-2-benzyl-propan-1-one are dissolved in 50 ml of dimethylacetamide. To the solution are added 2.42 g of potassium thioacetate and heated up to 50° C. After the reaction mixture is stirred at 50° C. for 2 h, it is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the ethyl acetate, the residue is dissolved in 70 ml of ethanol and the solution is bubbled by nitrogen for 30 min. to remove oxygen. To the solution are added 7 ml of 2 N sodium hydroxide solution and stirred at 0° C. for 30 min. After the reaction mixture is neutralized by adding 2 N hydrochloric acid solution, the resulting solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After ethyl acetate is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:2) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 1.14 (s, 3H), 1.43 (t, 1H), 1.97 (m, 2H), 2.33 (s, 6H), 2.68 (q, 2H), 2.96 (d, 1H), 3.34-3.39 (m, 2H), 3.42 (d, 1H), 4.18 (br, 1H), 6.57 (d, 2H), 6.89-6.92 (m, 2H), 7.10-7.12 (m, 3H), 8.46 (d, 2H).
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]1([CH:43]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:44](O)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:47]1([CH:43]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:44]([O:20][CH:5]([C:6]2[C:16](=[O:17])[C:15]3[C:10]([C:8](=[O:9])[CH:7]=2)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=3[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])=[O:45])[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
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: CC(C)=CCC(OC(=O)C(c1ccccc1)c1ccccc1)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 56 %

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 212 mg (1 mmole) of diphenylacetic 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 270 mg (Yield: 59%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:14])[CH:12]=[CH2:13]>>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)Nc1ccc(C(=O)O)cc1

Procedure:
The monomer was prepared from p-aminobenzoic acid reaction with acryloyl chloride, per Example 1. The monomer was recrystallized from an ethanol-water mixture and dried to produce a crystalline solid with a melting point of 249°-253° C.
Reaction SMILES: [O-2].[Ca+2:2].[OH-].[Ca+2].[OH-].[OH:6][P:7]([OH:10])([OH:9])=[O:8]>O>[P:7]([O-:10])([O-:9])([O-:8])=[O:6].[Ca+2:2].[Ca+2:2].[Ca+2:2].[P:7]([O-:10])([O-:9])([O-:8])=[O:6]
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Agent: [O-2]
Agent: [OH-]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
1,000 ml. of distilled water were placed in a 2 liter Erlenmeyer flask. 243 gms. of calcium oxide were added with stirring. A great amount of heat accompanied the formation of calcium hydroxide. 500 gms of 85% H3PO4 were added slowly. Heat was also evolved. The suspension was stirred for 1/2 hour and then allowed to settle. The white tricalcium phosphate formed was filtered and placed in an oven at 100° C. overnight to dry.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[C:23]1([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]3)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(Br)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(-c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
Ethyl 6-bromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (0.185 g, 0.500 mmol), phenylboronic acid (0.76 g, 0.625 mmol, 1.2 equiv.) and potassium phosphate trihydrate (0.200 g, 0.750 mmol, 1.5 equiv.) were mixed together in a 10 ml microwave vial. The vial was purged with Argon and trans-dichlorobis(triphenylphosphine)-palladium (II) (0.0105 g, 0.015 mmol, 3 mol %) and 5 ml of dry dioxane were added to the mixture. The microwave vial was capped and irradiated at 100 watt, 150° C., under pressure up to 10 bars. Then it was allowed to cool down to rt, and toluene was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography using 20% of ethyl acetate/cyclohexane as eluent to yield a light-beige-colored solid in 70-80%. 1H-NMR (DMSO-d6) δ 1.11, 1.35 (each t, 3H, 3J=7.1 Hz, CH3); 2.60 (m, 2H, 2′-H); 3.31 (m, 2H, 1′-H); 3.99, 4.35 (each q, 2H, 4J=7.1 Hz, CH2); 7.35 (m, 2H, 4-H, 5-H); 7.46 (m, 2H, 2″-H, 6″-H); 7.62 (dd, 1H, 4″-H); 7.65 (m, 2H, 3″-H, 5″-H); 7.75 (dd, 1H, 7-H); 11.63 (s, 1H, NH). 13C-NMR (DMSO-d6) δ 14.9, 15.1 (2CH3, each C═OOCH2CH3); 20.90 (C-2′); 35.9 (C-1′); 60.7, 61.2 (2CH2, each C═OOCH2CH3); 111.0 (C-7); 120.1 (C-4); 121.8 (C-3); 122.3 (C-3a), 124.8 (C-5) 127.2 (C-2″, C-6″); 127.7 (C-4″); 128.0 (C-3″, C-5″); 129.8 (C-2); 137.7 (C-7a); 138.2 (C-6); 141.9 (C-1″); 162.3 (2′-CO2Et); 173.1 (2-CO2Et). LC-MS (m/z): 383 [M-NH4+]+, 366 [M]+, 364 [M]−. Purity LC-MS: 96%.