Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22](=[O:57])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:29](=[O:48])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C@H:35]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:36]([O:38]C)=[O:37])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22](=[O:57])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:29](=[O:48])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C@H:35]([NH:40][C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[C:36]([OH:38])=[O:37])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](CCCCNC(=O)[C@H](CCCCNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
A solution of methyl ester 45 (2.00 g, 2.18 mmol) in MeOH/THF/H2O (60 mL/60 mL/20 mL) was charged with NaOH (436 mg, 10.9 mmol) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the pH of the solution was adjusted to 5 with 1 N HCl. The suspension was partitioned between CH2Cl2 (50 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to afford compound 46 (1.90 g, 97%) as a white solid, which was used directly in the next step: 1H NMR (400 MHz, CD3OD) δ 4.08-4.00 (m, 1H), 3.98-3.89 (m, 2H), 3.27-3.10 (m, 4H), 3.02 (t, J=6.6 Hz, 2H), 1.86-1.65 (m, 4H), 1.64-1.24 (m, 14H), 1.43 (s, 18H), 1.42 (s, 18H).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[C:28]1([CH:34]([CH3:38])[CH2:35][CH:36]=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.[OH-].[Li+]>C(Cl)Cl.CO.O>[CH3:26][C:23]1[C:22]([NH:27][CH2:36][CH2:35][CH:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:38])=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)=[CH:10][CH:11]=3)=[CH:20][CH:19]=2)[O:25][N:24]=1
Reactant: CC(CC=O)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NCCC(C)c1ccccc1
Reaction time: 8 h

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.1 g, 0.27 mmol), 3-phenyl-butyraldehyde (0.048 g, 0.33 mmol) and sodium triacetoxyborohydride (0.11 g, 0.54 mmol) were mixed in CH2Cl2 and stirred overnight. Lithium hydroxide monohydrate (0.100 g, 2.38 mmol) in MeOH/H2O was added and the reaction stirred at 60° C. for 1 hour. The reaction was submitted to standard aqueous workup to yield the title compound.
Reaction SMILES: [C:1]1([C:15]([OH:17])=O)[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C[N:19](C=O)C.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+]>C1COCC1>[C:1]1([C:15]([NH2:19])=[O:17])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2cc3ccccc3cc12
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2cc3ccccc3cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
To a solution of anthracene-1-carboxylic acid (2.5 g, 11.26 mmol) in THF (30 ml) was added DMF (1.75 ml, 22.52 mmol). The solution was cooled to 0° C. and oxalyl dichloride (2M in CH2Cl2, 22.5 ml, 45 mmol) was added dropwise. The reaction solution was stirred at room temperature for 2 hours and then was cannulated into a solution of concentrated ammonium hydroxide (25 ml) in a 3-necked flask cooled at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The white precipitate was filtered and washed with water to give anthracene-1-carboxylic acid amide as an off-white solid (2.58 g, 100% yield). LC/MS (m/z 222.15 (M+H)+); HPLC (Column: Shimadzu VP-0DS, C-18 Ballistic; 10-90% aq CH3OH/0.1% H3PO4, same for compounds hereafter unless noted) Rt: 2.872 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([N:31]([CH2:40][CH2:41][O:42][Si](C(C)(C)C)(C)C)[CH:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([C:29]([N:31]([CH2:40][CH2:41][OH:42])[CH:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(c1ccccc1)N(CCO)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reaction time: 6 h
Yield: 87.6 %

Procedure:
To a stirred solution of 5-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(1-phenylethyl)pyrimidine-4-carboxamide (35) (220 mg, 314 μmol, Eq: 1.00) in tetrahydrofuran (5 ml) was added HCl (1N) (471 μl, 471 μmol, Eq: 1.5) at room temperature. The reaction mixture was stirred for 6 hrs, neutralized with 1N NaOH aq. solution, extracted with ethyl acetate, dried (MgSO4), concentrated and chromatographed (silica gel, gradient, 0 to 5% methanol-dichloromethane) to obtain 5-(benzyloxy)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)-N-(1-phenylethyl)pyrimidine-4-carboxamide (36) (white foam, 161.2 mg, 275 μmol, 87.6% yield).
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:37]([O:39]C)=[O:38])=[CH:16][C:17]=3[N:18]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH2:22][C:21]4[CH:33]=[CH:34][CH:35]=[CH:36][C:20]=4[C:19]=23)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(Cl)Cl>[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:37]([OH:39])=[O:38])=[CH:16][C:17]=3[N:18]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)[CH2:22][C:21]4[CH:33]=[CH:34][CH:35]=[CH:36][C:20]=4[C:19]=23)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(Cc1cnn(C)c1)Cc1ccccc1-3
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1cc(CN2CCn3c(c(C4CCCCC4)c4ccc(C(=O)O)cc43)-c3ccccc3C2)cn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 7 %

Procedure:
BBr3 (5 eq, 1 M sol. in CH2Cl2) was added to a solution of methyl 14-cyclohexyl-6-[(1-methyl-1H-pyrazol-4-yl)methyl]-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate in CH2Cl2 (0.06 M), and the mixture stirred at RT for 40 mins. The volatiles were removed in vacuo. The crude was then purified by prep RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×150 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder in a 7% yield (over two steps).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]3[CH2:24][C:20]4([CH2:23][CH2:22][CH2:21]4)[O:19][N:18]=3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.Cl.[F:26][C:27]1[C:28]([C@H:34]([NH2:36])[CH3:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:26][C:27]1[C:28]([C@H:34]([NH:36][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:17]3[CH2:24][C:20]4([CH2:21][CH2:22][CH2:23]4)[O:19][N:18]=3)[CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:9]=2)[CH3:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: C[C@@H](N)c1ncc(F)cc1F
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C3=NOC4(CCC4)C3)c2)nc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ncc(F)cc3F)cc(C3=NOC4(CCC4)C3)c2)nc1
Yield: 57.9 %

Procedure:
To a solution of 3-(5-methylpyridin-2-yl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)benzoic acid (0.20 g, 0.56 mmol) in N,N-dimethylformamide (2.5 mL) were added (1R)-1-(3,5-difluoropyridin-2-yl)ethanamine hydrochloride salt (0.13 g, 0.67 mmol), EDC (0.16 g, 0.70 mmol), HOAT (0.5 M in DMF; 0.56 mL, 0.28 mmol) and diisopropylethylamine (0.09 mL, 0.56 mmol). The reaction mixture was at ambient temperature and solid was filtered off. Purification by reverse phase HPLC(C-18, 95% water/acetonitrile 5% water/acetonitrile with 0.1% trifluoroacetic acid). Clean fractions were combined and saturated aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated gave the title compound (150 mg). HRMS 463.1948 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H); 8.44 (t, J=1.7 Hz, 1H); 8.38 (t, J=1.6 Hz, 1H); 8.29 (d, J=2.4 Hz, 1H); 8.14 (t, J=1.6 Hz, 1H); 7.71 (d, J=8.1 Hz, 1H); 7.63 (d, J=7.6 Hz, 1H); 7.58 (dd, J=8.1, 2.2 Hz, 1H); 7.24-7.16 (m, 1H); 5.71-5.61 (m, 1H); 3.51 (s, 2H); 2.62-2.50 (m, 2H); 2.37 (s, 3H); 2.26-2.18 (m, 2H); 1.90-1.79 (m, 1H); 1.68-161 (m, 1H); 1.54 (d, J=6.7 Hz, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C@@H:17]([O:23][C:24](=[O:27])[CH2:25]I)[CH2:16][C@@:15]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[CH2:29]([N:31]([CH2:25][C:24]([O:23][C@H:17]1[CH2:16][C@@:15]2([CH3:28])[C@@H:8]([CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[C@H:7]2[C@H:18]1[C@:19]1([CH3:22])[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@H:2]([OH:1])[CH2:21][CH2:20]1)=[O:27])[CH2:32][CH3:33])[CH3:30]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CI)C[C@]12C
Reactant: CCNCC
Product: CCN(CC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)CC[C@]3(C)[C@H]21

Procedure:
3α-Hydroxy-11β-iodoacetoxy-5α-pregnan-20-one (50 mg) in the appropriate solvent (see Table 4) was treated with diethylamine (0.2 ml) and the resulting mixture was kept at room temperature.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@H:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=C(C4C=CC(C(F)(F)F)=CC=4)C=CC=3)=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=[O:10])=[N:5][N:4]=[N:3]1.[CH3:36]COC(C)=O>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:7]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH2:8][C:9]([O:11][CH3:36])=[O:10])=[CH:13][CH:14]=1
Reactant: CCOC(C)=O
Reactant: Cn1nnnc1[C@@H](CC(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Product: COC(=O)C[C@@H](c1ccc(O)cc1)c1nnnn1C
Reaction time: 8 h

Procedure:
Methyltetrazole 7 (413 mg, 0.833 mmol) was dissolved in 5 mL of EtOAc and nitrogen was bubbled through the solution for 5 minutes. Palladium on carbon (200 mg, 5 wt. %, wet contains 50% water) was added, and a hydrogen balloon was attached. After 8 hours, the mixture was filtered through a plug of silica with 10% MeOH in EtOAc. The organic layer was concentrated under reduced pressure and partitioned between acetonitrile (10 mL) and hexane (5 mL). The acetonitrile layer was washed with hexane (4×5 mL). The acetonitrile layer was concentrated under reduced pressure to afford (s)-methyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-tetrazol-5-yl)propanoate (8.1) (203 mg, 0.775 mmol) as a colorless oil.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1SC(Cc2ccc(OCCN3CCc4ccccc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Cc2ccc(OCCN3CCc4ccccc43)cc2)S1
Yield: 60 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 470 mg of 5-{4-[2-(indolin-1-yl)ethoxy]benzyl}-3-triphenylmethyithiazolidine-2,4-dione (prepared as described in Preparation 10) and 3 ml of trifluoroacetic acid were used, to give 170 mg of the title compound, melting at 132.8-135.6° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+].O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(F)cc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Yield: 74 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.23 mmol) and (4-fluorophenyl)boronic acid (47.3 mg, 0.34 mmol) in dioxane/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 adduct (9.2 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (56.8 mg, 0.68 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 100° C. for 20 min. Upon cooling down, water was added, and solids that crashed out were filtered. DCM/MeOH (1:1) was added, the contents pre-absorbed on silica gel and purified by SiO2 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH). The collected product was suspended in EtOAc along with some hexanes. The mixture was sonicated, and the solids that precipitated were filtered and dried to afford the title compound as a light grey solid (78 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.64 (t, J=4.80 Hz, 1H) 8.37 (s, 1H) 8.13 (s, 1H) 7.89-7.94 (m, 2H) 7.85 (s, 1H) 7.35 (t, J=8.97 Hz, 2H) 5.89 (s, 1H) 5.34 (quin, J=7.14 Hz, 1H) 4.40 (br. s., 1H) 4.38 (br. s., 1H) 2.22 (s, 3H) 2.11-2.18 (m, 5H) 1.98-2.06 (m, 2H) 1.86-1.94 (m, 2H) 1.66-1.75 (m, 2H). LC-MS (ES) m/z=459.1
Reaction SMILES: [CH2:1]([C:4]([OH:24])([CH2:21][CH:22]=[CH2:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18])[CH:2]=[CH2:3].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>O1CCCC1>[CH2:1]([C:4]([OH:24])([CH2:21][CH:22]=[CH2:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:19])([CH3:20])[CH2:17][OH:18])[CH:2]=[CH2:3]
Reactant: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C=O
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)CO

Procedure:
A solution of 1.01 g (3.0 mmol) of the title compound of Example 7 and 2.5 g (10 mmol) of lithium tris-t-butoxyaluminum hydride in 250 mL of tetrahydrofuran under N2 was stirred overnight at room temperature. After dilution with ether the mixture was washed sequentially with saturated solutions of Na-K tartrate, NaCl, then dried and the solvents removed. The residue was dissolved in 100 mL of Skellysolve A, decolorized with activated charcoal, the mixture filtered and the filtrate evaporated. The residue was dried at 40°/3 mm to yield 0.92 g of a cloudy oil.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2]>C(O)C>[P:1]([O:4][P:1]([OH:4])([OH:3])=[O:2])([OH:3])([OH:2])=[O:5]
Reactant: O=P(O)(O)O
Solvent: CCO
Product: O=P(O)(O)OP(=O)(O)O

Procedure:
An ethanol solution of the same free base is treated with phosphoric acid, yielding a colorless needle (diphosphoric acid). m.p. 212.0° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1.O1CCCC1.C([Li])CCC.[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:32]=[C:31]([C:39]([CH3:43])([CH3:44])[C:40]([N:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])=[O:41])[CH:30]=[C:29]([C:28]([F:45])([F:27])[F:46])[CH:34]=1
Reactant: CNc1cnc(Cl)cc1-c1cccnc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution of 2.77 g (11.9 mmol) (6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-methyl-amine in 120 ml tetrahydrofuran 7.8 ml (12 mmol) of a 1.6 M solution of n-butyllithium in hexanes was added dropwise at −78° C. After 30 min. 4.2 g (13 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added. The reaction mixture was stirred at −78° C. for 5 min. and allowed to warm to room temperature during a period of 1 h. Dilution with 2 M aqueous sodium carbonate solution was followed by extraction with three portions of tert-butyl methyl ether. The combined organic layers were washed with 2 M aqueous sodium carbonate solution and brine, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 4.8 g (78%) of the title compound as an off-white solid.
Reaction SMILES: [C:1]([N:4]([CH2:13][CH2:14][C:15]([OH:17])=O)[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])(=[O:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:22][CH:21]=1>>[C:1]([N:4]([CH2:13][CH2:14][C:15]([N:26]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)=[O:17])[C:5]1[C:6]([CH3:12])=[CH:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCC(=O)O)c1c(C)cccc1C
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Product: COC(=O)CCCN(C(=O)CCN(C(C)=O)c1c(C)cccc1C)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-acetyl-3-(2,6-dimethylanilino)propionic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-acetyl-3-(2,6-dimethylanilino)propionyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-acetyl-3-(2,6-dimethylanilino)propionyl]-4-(p-anisidino)butyric acid (M.P. 90° to 92°).
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.[Cl:37][C:38]([Cl:43])([Cl:42])[C:39](O)=[O:40]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:37][C:38]([Cl:43])([Cl:42])[C:39]([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:40]
Reactant: O=C(O)C(Cl)(Cl)Cl
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(Cl)(Cl)Cl)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 91.8 %

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 163 mg (1 mmole) of trichloroacetic 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 398 mg (Yield: 92%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C1(S([N:21]2[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[C:23]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=3)=[CH:22]2)(=O)=O)C=CC=CC=1>>[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:10][CH:11]=3)[N:31]=2)=[CH:22]1
Reactant: Nc1ccc(OCCO)cc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: OCCOc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 70.5 %

Procedure:
Using the procedure of example 1, 2-(4-aminophenoxy)-ethanol (265 mg) was reacted with compound 1f (200 mg) to provide compound 4 (132 mg, 71%). 1H NMR (400 MHz, CD3OD) δ 8.85 (d, J=8.0 Hz, 1H), 8.25 (d, J=4.8 Hz, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.22 (s, 1H), 7.54 (d, J=9.0 Hz, 2H), 7.18 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.16 (d, J=5.2 Hz, 1H), 6.98 (d, J=9.0 Hz, 2H). MS (ESI) m/z: 348 (M+H)+.