Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([F:30])[CH:24]=1>>[F:30][C:25]1[CH:24]=[C:23]([O:22][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH:28]=[CH:27][C:26]=1[NH:29][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(OCc2ccccn2)cc1F
Product: O=[N+]([O-])c1ccc2ncnc(Nc3ccc(OCc4ccccn4)cc3F)c2c1
Yield: 98 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 42 which is concerned with the preparation of starting materials, 4-chloro-6-nitroquinazoline was reacted with 4-amino-3-fluorophenyl 2-pyridylmethyl ether to give 4-[2-fluoro-4-(2-pyridylmethoxy)anilino]-6-nitroquinazoline in 98% yield.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:16]3[C@@H:17]4[C@@H:22]([C:21]5[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:20]=5[CH2:19][CH2:18]4)[CH2:13][CH2:14][CH2:15]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: N#Cc1ccc2c(c1)[C@H]1CCCN[C@H]1CC2
Product: N#Cc1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 64 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-9-carbonitrile following a procedure analogous to that described in Example 1. Yield: 64% of theory; LC (method 1): tR=2.40 min; Mass spectrum (ESI+): m/z=357 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[C@@H:13]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>>[C@@H:13]1([NH:22][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: N[C@H]1CCc2ccccc21
Product: COc1ccc(C(=O)N[C@H]2CCc3ccccc32)cc1C
Yield: 63 %

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and (S)-2,3-dihydro-1H-inden-1-amine. Yield 63%. 1HNMR (500 MHz, dMSO): δ 1.94-1.99 (m, 1H), 2.17 (s, 3H), 2.41-2.46 (m, 1H), 2.82-2.87 (m, 1H), 2.96-3.01 (m, 1H), 3.83 (s, 3H), 5.53-5.57 (dd, 1H), 6.98-6.99 (d, 1H), 7.16-7.23 (m, 3H), 7.26-7.27 (m, 1H), 7.75-7.80 (m, 2H), 8.54-8.55 (d, 1H). MS (M+H, 282).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[NH:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:1][C:2]3[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=3)[N:28]=2)=[CH:19]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)c1
Yield: 45.5 %

Procedure:
Using the procedure of example 1, m-toluidine (87 mg) was reacted with compound 1f (100 mg) to provide compound 9 (37 mg, 46%). 1H NMR (400 MHz, CD3OD) δ 8.90 (d, J=8;0 Hz, 1H), 8.30 (m, 2H), 8.18 (s, 1H), 7.63 (s, 1H), 7.43(d, J=8.0 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.22 (m, 1H), 7.17 (d, J=5.2 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 2.42 (s, 3H). MS (ESI) m/z: 302 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[F:34][CH2:35][CH2:36][NH2:37]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[NH:37][CH2:36][CH2:35][F:34])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCF
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)NCCF
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-tert-Butoxycarbonylamino-propionic acid (2.16 g, 11.4 mmol)) was dissolved in dichloromethane (80 ml) and cooled to 0° C. in an ice bath. [3-(Dimethylamino)propyl]ethylcarbodiimide hydrochloride (2.84 g, 14.8 mmol), hydroxybenzatriazole (1.54 g, 11.4 mmol) and triethylamine (7.9 ml, 57 mmol) were added and the reaction mixture stirred for 15 minutes. 2-fluoroethylamine hydrochloride (1.134 g, 11.4 mmol) was added in a single portion and then left to stir for 2 hours. The reaction mixture was partitioned between dichloromethane and water. The organic phase was dried over magnesium sulphate and evaporated. The crude product was purified by chromatography on silica using 2:3 iso-hexane:ethylacetate as eluant to afford the product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(COC)OC>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:11]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][N:6]=3)=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=2)[C:7]=1[CH3:8]
Reactant: Cc1nc(N)ccc1I
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1nc2ccc(I)c(C)n2c1-c1ccccn1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a suspension of 2 g of 5-iodo-6-methylpyridine-2-amine in 15 mL of dimethoxyethane are added 1.3 mL of ethyl bromopyruvate. The reaction mixture is stirred at 20° C. for 16 hours and then concentrated to dryness, taken up in 15 mL of ethanol, refluxed for 2.5 hours and finally concentrated under reduced pressure. The residue is taken up in a mixture of dichloromethane and saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure to give 2.77 g of ethyl 6-iodo-5-methyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate in the form of a beige-coloured solid.
Reaction SMILES: C(OC([N:6]=[C:7]=[S:8])=O)C.C[O:10][C:11](=[O:20])[CH2:12][CH2:13][C:14]1[S:15][C:16]([NH2:19])=[N:17][N:18]=1>ClCCl>[NH:19]([C:16]1[S:15][C:14]([CH2:13][CH2:12][C:11]([OH:10])=[O:20])=[N:18][N:17]=1)[C:7]([NH2:6])=[S:8]
Reactant: CCOC(=O)N=C=S
Reactant: COC(=O)CCc1nnc(N)s1
Solvent: ClCCl
Product: NC(=S)Nc1nnc(CCC(=O)O)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethoxycarbonyl isothiocyanate (0.656 ml, 5.61 mmol) is added dropwise to a stirred suspension of 3-(5-amino-[1,3,4]thiadiazol-2-yl)-propionic acid methyl ester (56a) in dichloromethane (30 ml). The reaction is at room temperature for 18 hours. After removing the solvent, aqueous sodium hydroxide (2M, 10 ml) is added and the stirred mixture is heated at reflux for 3 hours. The solution is allowed to cool to room temperature and brought to pH 3 by the addition of 6M aqueous HCl. The titled compound which precipitates is removed by filtration, washed with ethyl acetate and dried in vacuo.
Reaction SMILES: Cl.C([N:9]1[CH2:15][CH:14]2[N:16]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:11]([CH2:12][CH2:13]2)[CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:21][C:18]([F:19])([F:20])[C:17]([N:16]1[CH:11]2[CH2:12][CH2:13][CH:14]1[CH2:15][NH:9][CH2:10]2)=[O:22]
Reactant: O=C(N1C2CCC1CN(Cc1ccccc1)C2)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(N1C2CCC1CNC2)C(F)(F)F

Procedure:
A solution of the 3-benzyl-8-trifluoroacetyl-3,8-diazabicyclo-(3.2.1)octane hydrochloride in 50 mL of methanol was hydrogenated at atmospheric pressure in the presence of 10% Pd/C (0.5 g) until the theoretical quantity of hydrogen was absorbed. The mixture was filtered and the filtrate was evaporated to dryness to yield 1.08 g of titled compound as a white solid. MP 224° C. (dec).
Reaction SMILES: [CH:1](=[N:8][CH2:9][P:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:25]>O1CCCC1>[CH:1](=[N:8][CH:9]([P:10]([O:13][CH3:14])([O:11][CH3:12])=[O:15])[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)Cl)cc1
Reactant: COP(=O)(CN=Cc1ccccc1)OC
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)C(N=Cc2ccccc2)P(=O)(OC)OC)cc1

Procedure:
Dimethyl N-benzylidene-aminomethylphosphonate (22.72 g) is dissolved in anhydrous tetrahydrofuran (500 ml) under nitrogen. The solution is cooled to -78°, and phenyllithium (45 ml of a 2.3 M solution in benzene-ether) is added with stirring. The solution is stirred an additional 15 minutes at -78°. and then treated dropwise over 45 minutes with p-methoxybenzyl chloroformate (10.03 g) in tetrahydrofuran (100 ml). After stirring for 2 hours at -78°, the reaction mixture is allowed to warm to 0° over 30 minutes. The solvent is evaporated in vacuo and the residue is partitioned between ether (500 ml) and 0.5 M pH 3 phosphate buffer (100 ml). The ether portion is washed with water and saturated brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to dryness. Chromatography of the residue on silica gel affords p-methoxybenzyl N-benzylidene-α-amino-dimethylphosphonoacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.CC(N)CC1C=CC=CC=1.OP(O)(O)=O.C([O-])(=O)C.[K+]>O.CCO>[F:10][C:11]1[C:16]([C:6]2[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: OB(O)c1cccnc1F
Reactant: Cc1nc(N)cc(Cl)n1
Agent: CC(=O)[O-]
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCO
Product: Cc1nc(N)cc(-c2cccnc2F)n1
Temperature: 100 °C
Yield: 84.4 %

Procedure:
To a 20 mL microwave vials was added 4-Amino-6-chloro-2-methylpyrimidine (SynChem) (0.500 g, 3.48 mmol), 2-fluoro-3-pyridineboronic acid (Aldrich) (0.687 g, 4.88 mmol), Amphos (Aldrich) (0.123 g, 0.174 mmol), potassium acetate (Aldrich) (0.653 mL, 10.45 mmol), EtOH (12 mL), and water (1.2 mL). The vial was degassed by bubbling N2 for 5 min then sealed off and microwave heated at 100° C. for 20 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (80 g, 20% to 40% acetone in hexanes) to afford the desired product as a yellow solid (600 mg). MS (ESI pos. ion) m/z: 205.1. 1H NMR (300 MHz, CDCl3) δ ppm 2.59 (s, 3H) 4.96 (br. s., 2H) 6.89 (s, 1H) 7.34 (ddd, J=7.34, 4.93, 1.90 Hz, 1H) 8.27 (dd, J=3.00, 1.53 Hz, 1H) 8.66 (ddd, J=9.76, 7.64, 2.05 Hz, 1H).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:15]=[CH:14][C:13]2[N:12]3[CH2:16][CH2:17][CH2:18][N:19]=[C:11]3[C:10]3(OCCC[O:20]3)[C:9]=2[CH:8]=1>>[Br:6][C:7]1[CH:15]=[CH:14][C:13]2[N:12]3[CH2:16][CH2:17][CH2:18][N:19]=[C:11]3[C:10](=[O:20])[C:9]=2[CH:8]=1
Reactant: Brc1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Agent: O=S(=O)(O)O
Product: O=C1C2=NCCCN2c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
To cold concentrated H2SO4 (4.2 mL) was added 8′-bromo-3′,4′-dihydrospiro[1,3-dioxane-2,10′(2′H)-pyrimido[1,2-a]indole] (0.400 g, 1.24 mmol) in four portions with cooling in an ice bath. The reaction was stirred at room temperature for one hr, poured onto ice and basified with the careful addition of NE4OH keeping the temp cold with an external ice bath. The reaction mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give the title compound as a red solid (0.332 g, 100% ). Anal: Calc'd for C11H9BrN2O: C, 49.84; H, 3.42; N, 10.7. Found: C, 49.86; H, 3.37; N, 10.51. NMR (300 Mz, DMSO-d6): consistent. MS: (ESI+) m/z 265 [M+H], one bromine pattern observed. m.p. 166-168° C., black melt.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>ClCCl>[CH2:26]([N:28]([CH2:29][CH3:30])[C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)[CH3:27]
Reactant: CCNCC
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(N(CC)CC)ncc2c(=O)[nH]1

Procedure:
A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (229 mg) and diethylamine (420 mg) in dichloromethane (8 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was eluted from a silica column with diethyl ether:chloroform (4:1) and the combined fractions containing product were evaporated under reduced pressure to yield an oil which on trituration with 40-60° petroleum ether yielded the title compound, 85.5 mg, m.p. 116-7° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[O:7].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C(O)(=O)C.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[OH:7][CH:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)c2nccs2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(O)c2nccs2)C1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Under a nitrogen atmosphere, 0.5 g (1.69 mmol) of tert-butyl (S)-3-(thiazole-2-carbonyl)-piperidine-1-carboxylate were dissolved in 20 ml of tetrahydrofuran, and 3.374 ml (3.374 mmol) of lithium tri-sec-butylborohydride (1.0 M solution in tetrahydrofuran) were subsequently added dropwise at room temperature. After 60 minutes, 20 ml of acetic acid (10%) were added. Water, saturated sodium chloride solution and ethyl acetate were then added successively. The organic phase was separated off, the aqueous phase was post-extracted with ethyl acetate, and the combined organic phases were subsequently dried over sodium sulfate, filtered off and evaporated, giving 0.5 g of tert-butyl (S)-3-(hydroxythiazol-2-yl-methyl)piperidine-1-carboxylate as diastereomer mixture of the S-piperidine in the ratio 70:30 (polar:nonpolar); HPLC/MS (M+H)+=299.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=O.O.O.[OH-].C[N+:14]([CH3:17])(C)C>C(#N)C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[N:14][C:17]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)[O-:3]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: C[N+](C)(C)C
Agent: [OH-]
Solvent: N#Cc1ccccc1
Solvent: O
Product: [O-][N+](=Nc1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 45 %

Procedure:
A solution containing 10 g of nitrobenzene, 1.27 g of tetramethylammonium hydroxide dihydrate and 1 g of benzonitrile was stirred at 60° C. with nitrogen bubbled into the solution via a syringe needle for 1 hour. Analysis of a sample of the reaction product by HPLC revealed N-(4-nitrophenyl)-benzamide was produced in 45% yield and azoxybenzene was generated in 22% yield based on tetramethylammonium hydroxide.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.C(N(CC)CC)C>C1COCC1.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.[Cu](I)I>[Cl:12][C:9]1[CH:10]=[C:11]([C:3]#[C:2][CH2:1][OH:4])[CH:6]=[CH:7][C:8]=1[Cl:13]
Reactant: Clc1ccc(I)cc1Cl
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCC#Cc1ccc(Cl)c(Cl)c1
Temperature: 35 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (120 mg; 0.171 mmol) was added to a stirred solution of propargyl alcohol (5.24 g; 93.4 mmol; 1.02 eq), 1-iodo-3,4-dichlorobenzene (25.0 g; 91.6 mmol, 1 eq), triethylamine (18.5 g; 183.2 mmol, 2 eq), and copper iodide (60 mg; 0.32 mmol) in THF (50 mL). The mixture was stirred at 35° C. for 12 h under a nitrogen atmosphere. The mixture was then filtered through a bed of celite and the filtrate was washed with ethyl acetate. The filtrate was then concentrated at 35° C. (vac.=28 in Hg) using a rotary evaporator. The residue was purified using a silica gel column (4:1 heptane/ethyl acetate→2:1 heptane/ethyl acetate) to give the desired product as a light yellow solid (17.10 g; 85.2 mmol; 93%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.53 (s, 2H) 7.19 (d, 1H) 7.29 (d, 1H) 7.49 (s, 1H).
Reaction SMILES: [CH:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(N(CC)CC)C.[CH2:25]([O:29][C:30](Cl)=[O:31])[CH2:26][CH2:27][CH3:28]>CC(N(C)C)=O.C(O)C>[CH2:25]([O:29][C:30]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)=[O:31])[CH2:26][CH2:27][CH3:28]
Reactant: Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
To a solution of 4.0 g of arabinofuranosylcytosine dissolved in 50 ml of dimethylacetamide, there are added 5.0 g of triethylamine and 3.37 g of butyloxycarbonyl chloride. The reaction is carried out by stirring the mixture at room temperature for 3 hours. After completion of the reaction, the solvent is evaoprated under reduced pressure. The residue is diluted with 20 ml of ethanol, followed by addition of 150 ml of petroleum ether. After the mixture is stirred at 0° to 5° C. for one hour, the resultant precipitates are collected by filtration. The precipitates are dissolved in 15 ml of methanol and then 100 ml of water is added to the resultant solution. The mixture is left to stand in a refrigerator and the precipitated crystals are filtered to give 2.8 g of N4 -butyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:50%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][CH:6]=1.C1C(=O)N([Br:24])C(=O)C1>>[Br:24][C:6]1[NH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]([C:13]([O:15][CH3:16])=[O:14])[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)c[nH]c1-c1ccccc1
Product: COC(=O)c1c(-c2ccccc2)[nH]c(Br)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
To a solution of methyl 4-methyl-2-phenylpyrrole-3-carboxylate (74 mg, 0.341 mmol) in TEF (1.5 mL) was added NBS (67 mg, 0.375 mmol) at −78° C. After being stirred for 0.25 hour at the same temperature, the mixture was allowed to warm to room temperature. The mixture was poured into ice-water (5 mL). The whole was extracted with ethyl acetate (20 mL), dried over Na2SO4 and concentrated in vacuo. The residual oil was purified by flash chromatography eluting with ethyl acetate-hexane (1:8) to afford the subtitle compound (97 mg, 96% yield) as crystals.
Reaction SMILES: O1CCOCC1.CCCCCC.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[CH2:28][CH2:27][C:26]([C:32]([OH:34])=[O:33])([C:29]([OH:31])=[O:30])[CH2:25][CH:24]=2)=[C:15]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)C>[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]2[CH2:28][CH2:27][C:26]([C:32]([OH:34])=[O:33])([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)=[C:15]1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cn1c(-c2ccccc2)c(C2=CCC(C(=O)O)(C(=O)O)CC2)c2ccccc21
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Cn1c(-c2ccccc2)c(C2CCC(C(=O)O)(C(=O)O)CC2)c2ccccc21
Yield: 50.3 %

Procedure:
Using the method of Example 11, except that dioxane replaced ethanol as solvent and product was recrystallized from acetone:hexane one time, 7.5 g (0.020 mol) of 4-(1-methyl-2-phenyl-1H-indol-3-yl)-3-cyclohexene-1,1-dicarboxylic acid (Example 3) was hydrogenated to give 3.8 g (51%) of 4-(1-methyl-2-phenyl-1H-indol-3-yl)cyclohexane-1,1-dicarboxylic acid, m.p. 230° C.(decompn.).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:21]3[CH2:25][C:24]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=4[Cl:35])=[CH:23][C:22]3=[O:36])[CH2:16][C:17]([F:20])([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl.O[C@@H](CO)CN1C=CC(NC(=O)C(N2CC(OC3C=CC=C(OCC)C=3Cl)=CC2=O)CC(F)(C)C)=N1>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:21]2[CH2:25][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=3[Cl:35])=[CH:23][C:22]2=[O:36])[CH2:16][C:17]([F:20])([CH3:19])[CH3:18])=[N:9]1
Reactant: COc1cccc(OC2=CC(=O)N(C(CC(C)(C)F)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1Cl
Agent: CCOc1cccc(OC2=CC(=O)N(C(CC(C)(C)F)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(OC2=CC(=O)N(C(CC(C)(C)F)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-fluoro-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (390 mg, 0.71 mmol) in tetrahydrofuran (10 mL) was treated with 2N aqueous hydrochloric acid solution (10 mL). The reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated to afford, 2-[4-(2-chloro-3-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-fluoro-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (300 mg, 83%) as a white solid: LR-ES-MS m/z calculated for C23H28ClFN4O6 [M]+ 510, observed 511 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.27, 1.32 (2×d, J=3.0 Hz, 3H), 1.36, 1.39 (2×d, J=3.0 Hz, 3H), 1.99-2.34 (m, 2H), 3.19-3.33 (m, 2H), 3.69-3.89 (m, 2H), 3.90 (s, 3H), 4.09 (dd, J=13.6, 3.6 Hz, 1H), 4.26 (d, J=18.4 Hz, 1H), 4.37-4.58 (m, 1H), 4.71 (t, J=5.6 Hz, 1H), 4.77, 4.80 (2×s, 1H), 4.94 (d, J=5.1 Hz, 1H), 5.08 (dd, J=9.5, 4.4 Hz, 1H), 6.41 (d, J=2.1 Hz, 1H), 7.00, 7.06 (2×d, J=8.2 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 10.68, 10.79 (2×s, 1H)
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)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:37]([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])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=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: CCCCCCCC/C=C\CCCCCCCCOC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 49.2 %

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 282 mg (1 mmole) of oleic 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 265 mg (Yield: 48%) of the title compound having the following structure as a red oil.