Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[F:15][C:3]1[C:4]([CH:11]([CH3:13])[CH3:12])=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(C(C)C)c(C#N)c(=O)[nH]1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cc1[nH]c(=O)c(C#N)c(C(C)C)c1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
To a stirred solution of 6-methyl-2-oxo-4-(propan-2-yl)-1,2-dihydropyridine-3-carbonitrile (225 mg, 1.277 mmol) in MeCN (6 mL) was added Selectfluor (620 mg, 1.75 mmol). The reaction mixture was stirred at 50° C. for 3 h. Alter cooling to 23° C., the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (50% to 100% EtOAc-heptane to obtain the titled compound (90 mg, 36%). 1H NMR (400 MHz, CDCl3) δ ppm 3.39 (m, 1H), 2.44 (d, J=3.1 Hz, 3H), 1.41 (dd, J=7.0, 3.1 Hz, 6H); LCMS E-S (M+H)=195.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[O:19][CH:18]([CH2:20][OH:21])[CH2:17][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.O.S(=O)(=O)(O)[OH:24]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[CH3:1][C:2]1[C:3]2[O:19][CH:18]([C:20]([OH:24])=[O:21])[CH2:17][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1
Reactant: Cc1cc2c(-c3ccccc3)noc2c2c1OC(CO)C2
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc2c(-c3ccccc3)noc2c2c1OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A portion (4.5 g) of the 7,8-dihydro-5-methyl-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 9 was dissolved in 150 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (5.9 g), water (12 ml) and concentrated sulfuric acid (8.3 g) was added dropwise over time, and the resulting mixture was stirred for 2 hours at room temperature. After leaving the mixture to stand overnight, the insolubles were filtered off by suction. After distilling off the acetone, water was added and the mixture was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water to yield 2.9 g of 7,8-dihydro-5-methyl-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7carboxylic acid. m.p. 210°-213° C. This compound exhibited a mass spectrum haivng a molecular ion peak at m/e 295.
Reaction SMILES: O[CH:2]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4].S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:18][CH:2]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(O)c1cncnc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)C(Cl)c1cncnc1C(F)(F)F
Yield: 48.6 %

Procedure:
22 g (100 mmol) of 5-(1-hydroxy-2-methylpropyl)-4-trifluoromethylpyrimidine was dissolved in 150 ml of chloroform, and 25 ml (342 mmol) of thionyl chloride was added. The reaction mixture was heated and refluxed for 2 hours. The solvent and thionyl chloride was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent/n-hexane:ethyl acetate=6:1) to obtain 11.6 g (yield: 49%) of 5-(1-chloro-2-methylpropyl)-4-trifluoromethylpyrimidine as brown liquid (refractive index nD20: 1.4558).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[N+:18]([C:21]1[CH:37]=[CH:36][C:24]([CH2:25][C@@H:26]2[CH2:31][C@@H:30]([NH:32][C:33](=[O:35])[CH3:34])[CH2:29][CH2:28][NH:27]2)=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:27]1[CH2:28][CH2:29][C@H:30]([NH:32][C:33](=[O:35])[CH3:34])[CH2:31][C@H:26]1[CH2:25][C:24]1[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:37][CH:36]=1)=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)N[C@H]1CCN[C@H](Cc2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.49 g (9.0 mmol) of 3,5-bis-trifluoromethylbenzoyl chloride are added in the course of 1 hour at 0-5° C. to a stirred suspension of 2.50 g (9.0 mmol) of (2R*,4S*)-N-[2-(4-nitro-benzyl)-piperidin-4-yl]-acetamide in 20 ml of methylene chloride and 20 ml of a 10% aqueous sodium hydrogen carbonate solution. The mixture is then stirred for 1 hour at 25° C. The organic phase is dried over sodium sulfate, concentrated to dryness by evaporation and chromatographed on silica gel with methylene chloride/methanol. The title compound is obtained in the form of a yellowish resin. TLC: methylene chloride/methanol/conc. ammonia (90:9:0.5) Rf =0.45. 1H-NMR (200 MHz, D2O): rotameric mixture. δ 8.28-7.08 (m, 7H), 5.41 (br d, NH), 5.36-5.20 (m, 0.5H), 4.87-4.73 (m, 0.5H), 4.51-4.30 (m, 1H), 4.00-3.82 (m, 0.5H), 3.60-2.85 (m, 3.5H), 1.98 (s, 3H), 2.30-1.92 (m, 2H), 1.62-1.22 (m, 2H).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10](O)[CH3:11].O>CC(O)=O>[Br:1][CH:10]([C:4]1[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=1[Cl:2])[CH3:11]
Reactant: CC(O)c1ccc(Cl)cc1Cl
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(Br)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
15 ml of a 33% solution of HBr in AcOH are cooled to 0° C., 2 ml of 2,4-dichloro-1-(1-hydroxyethyl)benzene are added dropwise and the reaction mixture is stirred for 30 minutes at 0° C. and then for 3 hours at RT. It is poured into iced water and extracted with AcOEt, the organic phase is washed with saturated aqueous NaHCO3 solution, with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 3.4 g of the expected product.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH:12]1([CH:15]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:16][CH2:17][OH:18])[CH2:14][CH2:13]1>C(Cl)Cl.C(OCC)C>[CH:12]1([CH:15]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:16][CH:17]=[O:18])[CH2:14][CH2:13]1
Reactant: OCCC(c1ccc(Cl)cc1)C1CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCC(c1ccc(Cl)cc1)C1CC1
Yield: 24 %

Procedure:
A mixture of 6.5 grams (0.03 mole) of pyridinium chlorochromate in 25 ml of methylene chloride was stirred, and a solution of 2.1 grams (0.03 mole) of 3-cyclopropyl-3-(4-chlorophenyl)propan-1-ol in 5 ml of methylene chloride was quickly added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for one hour. The reaction mixture was then diluted with 100 ml of diethyl ether, and this mixture was filtered through a pad of activated magnesium silicate. The filtrate was concentrated under reduced pressure, yielding 1.5 grams of 3-cyclopropyl-3-(4-chlorophenyl)propionaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20])[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:28])[C@@H:19]([NH:20][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:16]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 2.00 g, 10.2 mmol) in DMF (50 mL) was added L-phenylalanine ethyl ester hydrochloride (2.45 g, 10.7 mmol), HOBt (1.37 g, 10.2 mmol) and DIPEA (5.3 mL, 30.5 mmol). After 5 min, EDCI (2.54 g, 13.2 mmol) was added and the reaction mixture stirred at rt for 16 h. The solvent was removed in vacuo and the solid dissolved in ethyl acetate (150 mL) and washed with water (200 mL). The organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol/dichloromethane (3:97) to give the title compound as a pale yellow solid. δH (CD3OD): 1.21 (3H, t), 3.13 (1H, dd), 3.28 (1H, dd), 4.17 (2H, q), 4.86 (1H, m), 7.09 (1H, s), 7.16–7.26 (5H, m), 7.65 (1H, s), 8.55 (1H, s); m/z (ES+)=372 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=O)[CH:25]=[CH:26][CH:27]=1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][CH:10]2[CH:15]3[CH2:16][CH:12]([CH:13]=[CH:14]3)[CH:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)C1C2C=CC(C2)C1Nc1c(Cl)cnc2[nH]c(-c3cccc(F)c3)nc12
Yield: 56 %

Procedure:
In a similar fashion compound to CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 3-FC6H4CHO (23.2 mg, 0.187 mmol) and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to yield 37.94 mg (56%) of the title compound. (300 MHz, DMSO-d6) 13.40 (s, 1H), 7.99 (m, 2H), 7.91 (s, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 7.29 (m, 3H), 6.39 (s, 2H), 5.15 (m, 1H), 2.90 (s, 1H), 2.80 (s, 1H), 2.62 (s, 1H), 2.26 (s, 1H), 1.38 (s, 1H). MS=398 (M+H), HPLC: 2.55 min. (G Method)
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH:8]2[CH2:9][C:10](=[N:16]O)[CH2:11]3)=[CH:4][CH:3]=1.[Na].Cl>C(O)CCCC.CCOCC>[NH2:16][CH:10]1[CH2:9][CH:8]2[N:7]([CH2:6][C:5]3[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:12]([CH2:13][CH2:14][CH2:15]2)[CH2:11]1
Reactant: Cc1ccc(CN2C3CCCC2CC(=NO)C3)cc1
Agent: Cl
Agent: [Na]
Solvent: CCCCCO
Solvent: CCOCC
Product: Cc1ccc(CN2C3CCCC2CC(N)C3)cc1
Yield: 95.1 %

Procedure:
9-(4-Methylbenzyl)-9-aza-bicyclo-[3.3.1]-nonan-3-one oxime (4 g) was dissolved in amyl alcohol (100 ml) and heated to reflux. Sodium (2 g) was added portionwise whilst the solution was stirred. After all the sodium had dissolved, the solution was cooled, diluted with ether and acidified with dilute hydrochloric acid. The acid extract was washed with ether and then basified with excess potassium carbonate. Extraction with ethyl acetate followed by evaporation of solvent afforded crude 3-amino-9-(4-methylbenzyl)-9-azabicyclo[3.3.1]-nonane (3.6 g, 95%) used in the next procedure without purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[N:6]2[CH2:11][CH2:12]O.O=S(Cl)[Cl:23]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[N:6]2[CH2:11][CH2:12][Cl:23]
Reactant: O=S(Cl)Cl
Reactant: Nc1ncnc2c1nc(Nc1cccnc1)n2CCO
Product: Nc1ncnc2c1nc(Nc1cccnc1)n2CCCl
Reaction time: 12 h
Yield: 27 %

Procedure:
0.11 g of 2-(6-amino-8-(pyridin-3-ylamino)-purin-9-yl)ethanol were cooled to −20° C. and 2 ml of SOCl2 were added. The temperature was gradually risen to 50° C. and the mixture was stirred at this temperature for 12 hours. The excess of SOCl2 was evaporated and aqueous ammonia was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was separated and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate:MeOH 20:1) to give 30 mg (27%) of the desired product. 1H-NMR (DMSO-d6): 9.10 (s, 1H); 9.0 (s, 1H); 8.35 (d, 1H); 8.20 (d, 1H); 8.05 (s, 1H); 7.30 (m, 1H); 6.65 (s, 2H, —NH2); 4.55 (t, 2H); 4.0 (t, 2H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>>[ClH:1].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH2:11])=[CH:15][CH:14]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1

Procedure:
4-Methoxyphenylhydrazine hydrochloride is reacted with 4-bromobenzyl bromide in the presence of a base to provide N-(4-bromo-benzyl)-N-(4-methoxy-phenyl)-hydrazine hydrochloride. N-(4-bromo-benzyl)-N-(4-methoxy-phenyl)-hydrazine hydrochloride is reacted with 5-tert-butylsulfanyl-2,2-dimethyl-4-oxo-pentanoic acid alkyl esters of structure 2-4 (where R1 is C1-C6 alkyl) to provide 3-[1-(4-bromo-benzyl)-3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl]-2,2-dimethyl-propionic acid alkyl esters of structure 3-1. In one aspect, R1 is selected from methyl, ethyl, propyl, isopropyl, and butyl. In another aspect, R1 is methyl or ethyl. In another aspect, R1 is ethyl.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:34](Br)[C:35]#[CH:36].O>CN(C=O)C>[CH2:36]([CH:14]([C:12](/[CH:11]=[CH:10]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=1)=[O:13])[C:15](=[O:16])/[CH:17]=[CH:18]/[C:19]1[CH:27]=[C:24]([C:22]([OH:23])=[CH:21][CH:20]=1)[O:25][CH3:26])[C:35]#[CH:34]
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC(C(=O)/C=C/c1ccc(O)c(OC)c1)C(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 49 h
Yield: 47 %

Procedure:
Curcumin (5 g, 13.57 mmol) and K2CO3 (1.88 g, 13.62 mmol) were dissolved in 60 mL DMF, and 1.62 g (13.61 mmol) of propargyl bromide was added. The mixture was stirred at room temperature under Ar for 49 h. H2O was added to the mixture and solvent was removed under vacuum. The product was purified on column chromatography, eluting with CH2Cl2: hexane 50:50—CH2Cl2. Yield 47%. NMR 1H (CDCl3), δ (ppm): 2.54 (s, 1H); 3.94 (d, 6H); 4.81 (d, 2H); 5.82 (s, 1H); 5.93 (s, 1H); 6.47-6.52 (t, 2H); 6.93-7.15 (m, 6H); 7.59-7.61 (dd, 2H). MS (ESI) calcd. for C24H22O6: 406.43. found: 407.2 [M+H]+, 445.2 [M++K].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[CH:5][CH:4]=1.[Cl:16][C:17]([Cl:21])([Cl:20])[C:18]#[N:19]>N12CCCN=C1CCCCC2>[Cl:16][C:17]([Cl:21])([Cl:20])[C:18](=[NH:19])[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][CH:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[CH:7][CH:8]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: O=C1OCCC1Sc1ccc(CO)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: N=C(OCc1ccc(SC2CCOC2=O)cc1)C(Cl)(Cl)Cl
Reaction time: 1 h
Yield: 96.4 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (34 mg, 0.22 mmol) was added to a 0° C. solution of 3-(4-(hydroxymethyl)phenylthio)dihydrofuran-2(3H)-one (1.0 g, 4.5 mmol) and 2,2,2-trichloroacetonitrile (3.2 g, 22 mmol). The reaction was stirred for 1 hour, then directly chromatographed (3:7 ethyl acetate/hexanes) to provide the product as a viscous oil (1.6 g, 31%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:35][CH3:36])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([C:43]([CH:45]2[CH2:49][CH2:48][CH2:47][O:46]2)=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH2:35][CH3:36])[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:40]3[CH2:41][CH2:42][N:37]([C:43]([CH:45]4[CH2:49][CH2:48][CH2:47][O:46]4)=[O:44])[CH2:38][CH2:39]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC1(c2ccc(Cl)cc2)N=C(c2ccc(OC)cc2OC(C)C)N(C(=O)Cl)C1c1ccc(Cl)cc1
Reactant: O=C(C1CCCO1)N1CCNCC1
Product: CC[C@@]1(c2ccc(Cl)cc2)N=C(c2ccc(OC)cc2OC(C)C)N(C(=O)N2CCN(C(=O)C3CCCO3)CC2)[C@@H]1c1ccc(Cl)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4-ethyl-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazin-1-yl-(tetrahydro-furan-2-yl)-methanone (Aldrich) to give the title compound. LC-MS: 693.3 [(M+H)+]
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:39])[CH3:38].CCCCCC>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:39])[CH3:38]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 74.8 %

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 60 mg (1 mmole) of acetic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. 20 ml of n-hexane was added to the reaction solution. The mixture was filtered to remove the insoluble materials. The filtrate was dried and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (n-hexane: ethylacetate=20:1-5:1) to obtain 247 mg (Yield: 75%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2(O)[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7][CH2:6]1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:9]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(C2(O)ON=C(c3ccc(OC)cc3)C2c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2onc(-c3ccc(OC)cc3)c2-c2ccccc2)CC1
Temperature: 64 °C
Reaction time: 6.5 h
Yield: 39.7 %

Procedure:
To a solution of the product of Step C, 1-[5-hydroxy-3-(4-methoxy-phenyl)-4-phenyl-4,5-dihydro-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester, (2354 g) in toluene (8 L) is added p-toluenesulfonic acid monohydrate (40.8 g.) The mixture is stirred at 64° C. for 6.5 hours and is subsequently filtered over Celite filter aid. The Celite cake is washed with toluene (2×1 L) and the filtrate is diluted with a mixture of isopropanol (6 L) and heptane (6 L) to form a precipitate. The precipitate is triturated to afford a solid. The solid is triturated in a mixture of isopropanol (6 L) and heptane (2 L) for 3.5 hours and is subsequently collected by filtration. The solid is dried to afford the synthetic intermediate 1-[3-(4-methoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester (889 g.)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:10]=[C:9]([Cl:25])[CH:8]=2)=[O:4].C1C(=O)N([Br:33])C(=O)C1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[Br:33])=[C:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:10]=[C:9]([Cl:25])[CH:8]=2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2c(CCC=CC(=O)OC(C)(C)C)cc(Cl)cc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c2cc(Cl)cc(CCC=CC(=O)OC(C)(C)C)c2c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 6-chloro-4-(4-tert-butoxycarbonyl-3-butenyl)indole-2-carboxylic acid methyl ester (12.0 g, 33 mmol) in DMF (120 mL) was added slowly a solution of NBS (5.87 g, 33 mmol) in DMF (60 mL) at 0° C. The mixture was stirred for 1 h at 0° C., diluted with aqueous NaHCO3, and extracted with 2:1 ethyl acetate/toluene. The extract was washed with water and brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 8:1 to 5:1 hexane/ethyl acetate to give 13.3 g of the title compound (91%): 1H NMR (CDCl3) δ9.15 (bs, 1H), 7.28 (d, 1H, J=1.8 Hz), 6.97 (dt, 1H, J=15.8, 6.9 Hz), 6.93 (d, 1H, J=1.8 Hz), 5.83 (dt, 1H, J=15.8, 1.7 Hz), 3.99 (s, 3H), 3.32 (dd, 2H, J=8.3, 7.9 Hz), 2.57 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[F:15][C:12]([F:13])([F:14])[C:8]1[N:7]=[C:6]2[C:11]([C:2]([OH:1])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cnc2nc(C(F)(F)F)ccc2c1O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccnc2nc(C(F)(F)F)ccc12
Temperature: 25 °C

Procedure:
4-Hydroxy-7-trifluoromethyl[1,8]-naphthyridine-3-carboxylic acid (14.0 g, 54.2 mmol) was added in portions to refluxing Dowtherm A (250 mL)—Care! Effervescence!—and the mixture was stirred at reflux for 80 min. The mixture was allowed to cool to room temperature, and a buff coloured solid precipitated from solution. The slurry was diluted with diethyl ether (250 mL) and the solid was separated by filtration, was washed with plenty of diethyl ether and was dried. This was 7-trifluoromethyl[1,8]naphthyridin-4-ol (11.6 g, 100%). δH (360 MHz, d6-DMSO) 6.15 (1H, d, J 7.4), 7.76 (1H, d, J 8.1), 8.06 (1H, d, J 7.4), 8.70 (1H, d, J 8.1). m/z (ES+) 215 [MH]+.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=1>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH:15][C:2]([NH2:3])=[O:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(NN)cc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc(NNC(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Under ice-bath cooling, potassium cyanate (1.71 g, 21.1 mmol) was added to a suspension of 4-methoxyphenylhydrazine hydrochloride (3.35 g, 19.2 mmol) in water (40 mL). The mixture was stirred for 1 hour at the same temperature. And then the mixture was warmed to room temperature and stirred for 12 hours. An insoluble material was isolated by filtration, washed with water, and dried in vacuo to give 2-(4-methoxyphenyl)hydrazinecarboxamide (2.45 g, 70.5% yield).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:21]([NH:23][CH3:24])=[O:22]>>[CH3:27][CH:26]([CH3:28])[CH2:25][C@H:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:21](=[O:22])[NH:23][CH3:24]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CNC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and (2S)-2-amino-N,4-dimethyl-pentanamide monohydrochloride (CAN 99145-71-8) as starting materials, and isolated (67 mg, 87%) as off-white solid; LC-MS (UV peak area, ESI) 100%, 361.2232 (M+H).