Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:30]=1B1OC(C)(C)C(C)(C)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:30]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[F:24])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(c2ccncc2F)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccncc4F)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine following a procedure analogous to that described in Example 28. LC (method 10): tR=1.71 min; Mass spectrum (ESI+): m/z=400 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1>C1C=CC=CC=1>[CH:11](=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1Cc2ccccc2N1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=Cc1ccccc1
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of oxindole (49.5 g, 0.37 mole), benzaldehyde (50 ml, 0.5 mole) and piperidine (2 ml) in 500 ml of benzene is heated at reflux temperature, with removal of water, for one hour. Benzene is removed in vacuo and the residue is crystallized from ethanol to give 69.6 g of 3-benzylidene indolin-2-one (m.p. 177°-179°).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[S:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.CC([O-])=O.[K+].CN(C)C(=O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:21]4[S:17][CH:18]=[N:19][CH:20]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1cscn1
Reactant: Brc1cnc2cc(-c3ccccc3)ccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1ccc(-c2ccn3c(-c4cncs4)cnc3c2)cc1
Temperature: 200 °C

Procedure:
A microwave vessel was charged with 3-bromo-7-phenylimidazo[1,2-a]pyridine (6-1, 0.050 g, 0.183 mmol), thiazole (0.065 ml, 0.92 mmol), tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.10 mmol) and KOAc (0.054 g, 0.55 mmol). N,N-dimethylacetamide, 1.5 ml, was added and the reaction was placed in the microwave reactor. The reaction was heated to 200° C. for 10 min. The reaction was diluted with water, and extracted 3× with DCM. The extracts were dried over Na2SO4, filtered and concentrated. The resulting residue was dissolved in DMSO and purified by reverse phase preparative HPLC. The resulting oil was triturated with ether, resulting in the rapid crystallization to a white solid. The solid was filtered and washed with ether. Afforded the pure title compound. 1H NMR (CDCl3) δ 9.11 (s, 1H), 8.47 (s, 1H), 8.37 (d, 1H, J=7.4 Hz), 8.20 (s, 1H), 8.00 (s, 1H), 7.73 (d, 2H, J=7.3 Hz), 7.57–7.52 (m, 4H). LCMS m/z (M+1) Calc: 278.1, found 278.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH2:12].[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][CH2:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: C=Cc1ccccn1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Brc1ccc2[nH]cc(CCc3ccccn3)c2c1

Procedure:
To 5-bromoindole (5.9 g) in acetic acid (10 ml) solution, 2-vinylpyridine (3.6 ml) was added and the mixture was heated and refluxed for 15 hours. The reaction solution was cooled, then was diluted with ethyl acetate, the aqueous layer was made alkaline with 4N-aqueous sodium hydroxide solution and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off in vacuo, and the residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to 17:33) to afford the above-identified compound (5.6 g).
Reaction SMILES: N#N.[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1)(=[O:5])[CH3:4].C([O-])=O.[NH4+]>CN(C=O)C.[Pd].CO>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Agent: N#N
Agent: O=C[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87.8 %

Procedure:
A N2 covered solution of 1.19 g (6.6 mmol) of the product from Step 1 in 24 ml of DMF was treated with 2.07 g (32.9 mmol) of ammonium formate followed by 0.36 g of palladium on carbon catalyst. After stirring vigorously at room temperature for 17 hours, the reaction was diluted with MeOH and the catalyst was removed by filtration through celite. The filtrate was concentrated in vacuo and the residue was chromatographed over silica gel (3% MeOH: 0.3% NH4OH: CH2Cl2) to yield 0.876 g, m.p. 152°-153.5° C. (88.2%) of the titled product.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].S=[C:7]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9][NH:8]1.C(OCC)C>CO>[OH:3][N:2]=[C:7]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCNC(=S)CC1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCNC(=NO)CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A solution of hydroxylamine hydrochloride (2 eq.) in methanol was added to an equimolar methanolic solution of potassium hydroxide. Potassium chloride was filtered off and the filtrate was added to a solution of the above tert-butyl 5-thioxo-1,4-diazepane-1-carboxylate (1 eq.) in methanol. The mixture was stirred at 55° C. overnight, then cooled to room temperature and the solvent was removed under reduced pressure. The residue was taken in chloroform, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give, after trituration with ethyl ether, the title amidoxime. 1H NMR (300 MHz, CDCl3) δ 6.4-6.1 (bs, 1H), 5.8 (broad triplet, 1H), 3.6-3.5 (m, 4H), 3.35-3.22 (m, 2H), 2.5-2.4 (m, 2H), 1.45 (s, 9H); MS (ES) C10H19N3O3 requires 229. Found: 230 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[F:16].[NH3:17]>O1CCCC1.CO>[NH2:17][C:11]1[CH:12]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([NH2:1])=[C:3]([F:16])[CH:4]=2)[N:8]=[CH:9][N:10]=1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1F
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(Oc2ccc(N)c(F)c2)ncn1
Temperature: 25 °C
Yield: 35 %

Procedure:
After dissolving 4-(4-amino-3-fluorophenoxy)-6-chloropyrimidine (2.25 g) in tetrahydrofuran (25 ml) and a 7N ammonia solution in methanol (50 ml), the mixture was heated in a sealed tube for 3 days at 130° C. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and 1N aqueous sodium hydroxide. The separated organic layer was washed with brine. The aqueous layer was then re-extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:3, then ethyl acetate) to provide the title compound (0.73 g, 35%) as a purple solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][OH:35])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:35][CH2:2][C:3]2[N:4]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:5]=[C:6]([C:8]3[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:10][O:11][C:12]=3[CH3:13])[N:7]=2)=[CH:32][CH:31]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2ccc(Cl)cc2)n1
Yield: 22 %

Procedure:
As described for Example 153, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (100 mg, 0.25 mmol), using 4-chlorobenzyl alcohol instead of 4-methylbenzyl alcohol, was converted to the title compound (28 mg, 22%) which was obtained as a light yellow solid. MS: m/e=501.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:24]([O:31][CH3:32])(=[O:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27]>>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:23])[CH2:15][CH:16]([CH:25]([C:24]([O:31][CH3:32])=[O:30])[C:26]([O:28][CH3:29])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(C=Cc1ccccc1)c1ccc2c(c1)[nH]c1ccccc12
Reactant: COC(=O)CC(=O)OC
Product: COC(=O)C(C(=O)OC)C(CC(=O)c1ccc2c(c1)[nH]c1ccccc12)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(9H-carbazol-2-yl)-3-phenylprop-2-en-1-one and dimethyl malonate, dimethyl 2-(3-(9H-carbazol-2-yl)-3-oxo-1-phenylpropyl)malonate was obtained as colourless solid.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:14]1[CH2:16][CH:15]1[CH2:17]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[CH:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:17][CH:15]3[CH2:16][O:14]3)[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Reactant: C1CCC(CN2CCNCC2)CC1
Product: C1CCC(CN2CCN(CC3CO3)CC2)CC1
Yield: 92 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from 1-cyclohexylmethyl piperazine and (±)-3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after flash chromatography the title compound as a yellow oil in a 92% yield.
Reaction SMILES: [F:1][B-](F)(F)F.[CH2:6]([O:8][C:9]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[N:15][C:16]([O:24][CH3:25])=[C:17]([N+]#N)[CH:18]=2)[N:13]([CH2:26][CH3:27])[CH:12]=1)=[O:10])[CH3:7]>C1(C)C(C)=CC=CC=1>[CH2:26]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([F:1])=[C:16]([O:24][CH3:25])[N:15]=2)[C:20](=[O:21])[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])=[CH:12]1)[CH3:27]
Reactant: CCOC(=O)c1cn(CC)c2nc(OC)c([N+]#N)cc2c1=O
Reactant: F[B-](F)(F)F
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cn(CC)c2nc(OC)c(F)cc2c1=O
Yield: 47.7 %

Procedure:
A suspension of 10 g of 3-ethoxycarbonyl-1-ethyl-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-6-diazonium tetrafluoroborate in 300 ml of xylene was heated under reflux for 30 minutes. After evaporation of the xylene, the residue was taken up in chloroform. The chloroform solution was washed with water and the solvent was distilled off. The crude product was chromatographed on silica gel with chloroform as an eluent to give 3.6 g of ethyl 1-ethyl-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 181°-182° C.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C@H:17]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]C=1.ClC(OCC(C)C)=O>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][C@H:17]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH2:18][C:19]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCc1ccccc1
Agent: CC(C)COC(=O)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 63 %

Procedure:
Condensation of ZPheOH (11.7 g.) and HPheOMe (9.0 g.) by the mixed anhydride method using isobutyl chloroformate gave ZPhe-PheOMe in 82% yield. Debenzyloxycarbonylation of ZPhe-PheOMe (13.0 g.) by hydrogenation with palladium catalyst gave HPhe-PheOMe in 86% yield. Condensation of BocProOH (5.04 g.) and HPhe-PheOMe (8.5 g.) by the mixed anhydride method using isobutyl chloroformate gave BocPro-Phe-PheOMe in 63% yield. Hydrazinolysis of BocPro-Phe-PheOMe (4.5 g.) gave BocPro-Phe-PheNHNH2 in 93% yield.
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH:19][CH:20]([CH3:22])[CH3:21])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=O)C.FC(F)(F)C(O)=O.O.[OH-].[Na+]>C(Cl)Cl>[CH3:22][CH:20]([NH:19][C:18]1[C:13]([N:10]2[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]2)=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:21]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)Nc1cccnc1N1CCNCC1

Procedure:
1-[1,1-Dimethylethoxycarbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine (PREPARATION 3) is dissolved in methylene chloride (56 ml) and cooled to 0°. Then trifluoroacetic acid is added dropwise. The reaction is warmed to 20°-25° and additional trifluoroacetic acid is added (26.6 g). When the reaction is complete by TLC, it is poured into 200 ml of water and ice, basified to pH 12 with 2N aqueous sodium hydroxide, and extracted with 10% tetrahydrofuran/chloroform (2 l) followed by 10% methanol/chloroform (1 l). The organic layers are dried over anhydrous sodium sulfate, concentrated in vacuo, and used without further purification, NMR (300 MHz, CDCl3) 7.65, 6.85, 6.76, 4.16, 3.50, 2.98 and 1.20 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][NH2:23])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:23][CH2:22][CH2:21][N:20]([CH2:24][CH3:25])[CH2:18][CH3:19])=[N:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC1=Nc2cc(Cl)ccc2Nc2ccccc21
Yield: 11.4 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and N,N-diethylethylenediamine (58 mg, 0.5 mmol) were reacted according to GP4 to give 3.9 mg of the title compound (160FE16E). MS (ESI) 343 (MH+). Purity for MH+ (UV/MS) 99/94.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.[H-].[Na+:12].Br>O1CCCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([O-:10])=[CH:4][C:3]=2[O:2]1.[Na+:12]
Reactant: Oc1ccc2c(c1)OCO2
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: [O-]c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium 3,4-methylenedioxy-phenoxide was prepared by adding slowly with stirring and under nitrogen a solution of 3,4-methylenedioxy phenol (59.66 g, 0.432 mole) in 250 ml of tetrahydrofuran (THF) (distilled from lithium aluminum hydride) to a mixture of sodium hydride (50%) (20.74 g, 0.432 mole), (previously washed with hexane and dried) in 250 ml of THF. After stirring for 30 min at room temperature, all evolution of hydrogen ceased and 1-(2'-pyridyl)-2-bromoethanol* hydrobromide (30.56 g, 0.108 mole) was added as a solid over a 5 min period. The reaction was heated at reflux overnight under nitrogen. The THF was removed in vacuo, and the resulting dark brown oil was partitioned between water and methylene chloride. The methylene chloride layer was extracted with 10% sodium hydroxide and was dried over sodium sulfate. The solvent was removed in vacuo to give a brown solid (21.95 g). This material was dissolved in methanol and converted to the hydrochloride salt with ethereal hydrogen chloride. This salt was recrystallized from methanol-diethyl ether to give 18.29 g (57.3%) of a brown solid, m.p. 165.6°-167.0° C. with decomposition.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7]C1C=C2C(=CC=1)N=CN=C2NC1C=CC(OCC2C=CC=C(F)C=2)=C(Cl)C=1)=[O:6].C(OC(=O)NCCCC([C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][CH:56]=1)[N:53]=[CH:52][N:51]=[C:50]2[NH:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65]2[CH:66]=[N:67][C:68]([CH3:71])=[CH:69][CH:70]=2)=[C:60]([CH3:72])[CH:59]=1)=O)(C)(C)C>>[NH2:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][CH:56]=1)[N:53]=[CH:52][N:51]=[C:50]2[NH:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65]2[CH:66]=[N:67][C:68]([CH3:71])=[CH:69][CH:70]=2)=[C:60]([CH3:72])[CH:59]=1)=[O:6]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C(=O)CCCNC(=O)OC(C)(C)C)cc34)cc2C)cn1
Reactant: NCCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCCN)cc34)cc2C)cn1
Yield: 98 %

Procedure:
The procedure of (87-1) of Example 87 was repeated except for using 1.51 g of the compound obtained in Example 99 instead of the compound obtained in example 86 to obtain the title compound (1.21 g, 98%).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:20])[C:8]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:28][C:29]([N:31]([CH3:42])[CH2:32][CH2:33][CH2:34][CH2:35][N:36]([CH3:41])[S:37](=[O:40])(=[O:39])[NH2:38])=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C3C(=CC(C(O)=O)=CC=3)N(C)C=2C2C=CC=CC=2OCC(N(C)CCOCCN(C)S(=O)(=O)N)=O)CCCCC1>>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:20])[C:8]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:28][C:29]([N:31]([CH3:42])[CH2:32][CH2:33][CH2:34][CH2:35][N:36]([CH3:41])[S:37](=[O:39])(=[O:40])[NH2:38])=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCC(=O)N(C)CCCCN(C)S(N)(=O)=O)n(C)c2c1
Agent: CN(CCOCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)O)cc2n1C
Product: CN(CCCCN(C)S(N)(=O)=O)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)O)cc2n1C
Yield: 78 %

Procedure:
3-cyclohexyl-1-methyl-2-{2-[2-(methyl {4-[methyl(sulfamoyl)amino]butyl}amino)-2-oxoethoxy]phenyl}-1H-indole-6-carboxylic acid 13 was synthesized in 78% yield from intermediate 12 following the procedure reported for the synthesis of intermediate 8: m/z=585 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:21][CH2:22][OH:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)(Cl)Cl>[Br:1][C:2]1[N:3]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCO)c2c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCOS(C)(=O)=O)c2c1

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1-(2-hydroxyethyl)-1H-indole-6-carboxylate (3.43 g, 9.01 mmol) in chloroform (30 ml) were added triethylamine (1.40 ml, 10.0 mmol) and methanesulfonyl chloride (0.77 ml, 9.90 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 30 min. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was successively washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-bromo-3-cyclohexyl-1-(2-methanesulfonyloxyethyl)-1H-indole-6-carboxylate as a crude product. The obtained crude product was used for Step 4 without purification.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.[NH:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[N:20]1([C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: C1CCCNCC1
Solvent: ClCCl
Product: CC(C)C[C@H](CC(=O)N1CCCCCC1)C(=O)OCc1ccccc1
Yield: 93.5 %

Procedure:
Benzyl (2R)-2-carboxymethyl-4-methylvalerate (1.35 g), hexahydro-1H-azepine (0.610 g) and WSCD·HCl (1.18 g) were reacted in methylene chloride (30 ml) in a similar manner to that of Preparation 1-1) to give benzyl (2R)-2-(hexahydro-1H-azepin-1-ylcarbonylmethyl)-4-methylvalerate (1.65 g).
Reaction SMILES: [CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][C:2]=1[C:14](Cl)=[O:15].[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>ClCCl>[CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][C:2]=1[C:14]([O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:15]
Reactant: OCCN1CCOCC1
Reactant: O=C(Cl)c1cn2c(n1)COc1ccccc1-2
Solvent: ClCCl
Product: O=C(OCCN1CCOCC1)c1cn2c(n1)COc1ccccc1-2
Temperature: 50 °C
Yield: 42.4 %

Procedure:
1.0 g (0.0043 mole) of 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carbonyl chloride was suspended in dry dichloromethane and 1.31 g (0.01 mole) of N-(2-hydroxyethyl)-morpholine was added thereto. The mixture was warmed at 50° C. for two hours and thin layer chromatography then indicated only a small quantity of starting material remained. The mixture was then washed with water, dried and evaporated. The residue was chromatographed on a silica column using ethyl acetate as eluant. The product thus obtained was finally crystallized from ether to obtain 0.6 g (43% yield) of 2-morpholinoethyl 4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate with a melting point of 142°-3° C.
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:41])[CH2:38][CH2:39][CH3:40]>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:41])[CH2:38][CH2:39][CH3:40]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 51.9 %

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 88 mg (1 mmole) of n-butanoic 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 186 mg (Yield: 52%) of the title compound having the following structure as a red oil.