Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3]>C1COCC1.CO.[OH-].[Na+].O>[CH2:22]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:23][CH3:24]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ccsc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ccsc2)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-[(dipropylamino)carbonyl]-5-(3-thienyl)benzoate (XLIX, step 3, 0.31 g, 0.88 mmol) in THF/methanol/sodium hydroxide (3/1/1, 5 mL) is stirred at 40 degrees C. for 2 hours. The reaction is cooled to 20-25 degrees C., diluted with water and extracted with ethyl acetate. The aqueous phase is acidified to pH=4 and extracted with ethyl acetate. The organic phase is washed with water and saline, dried over magnesium sulfate and concentrated under reduced pressure to give 3-[(dipropylamino)carbonyl]-5-(3-thienyl)benzoic acid (IX-L), ESI-MS (m/z) [M+H]+=332.
Reaction SMILES: [F:1][C:2]1[C:3]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].N#N.[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C.O>[CH2:31]([N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:11]=[C:2]([F:1])[C:3]([B:12]3[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]3)=[CH:4][C:5]1=2)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: CC1(C)OB(c2cc3c(cc2F)OCCN3)OC1(C)C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCOc2cc(F)c(B3OC(C)(C)C(C)(C)O3)cc21
Temperature: 70 °C
Yield: 74.8 %

Procedure:
A solution of 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.503 g, 1.802 mmol, Ref. WO20100130034) and K2CO3 (0.504 g, 3.65 mmol) in dry DMF (5 mL) was sparged with N2 for 5 min, then treated with allyl bromide (0.8 mL, 9.17 mmol). The reaction tube was sealed then heated (70° C.) for 22 h. The reaction was diluted with water (50 mL) and extracted into EtOAc (50 mL). The organic layer was washed with water, brine, and then dried (Na2SO4), filtered, and concentrated. The residue was purified by biotage (4 g SiO2, 5% (3 CV), 5-40% (15 CV), 40% (2 CV), EtOAc in hexanes), affording the desired product (0.430 g, 1.347 mmol, 74.8% yield) as a clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.03 (6, J=5.7 Hz, 1H), 6.51 (d, J=9.9 Hz, 1H), 5.84-5.94 (m, 1H), 5.26-5.31 (m, 1H), 5.24 (m, 1H), 4.25-4.32 (m, 2H), 3.87 (m, 2H), 3.19-3.25 (m, 2H), 1.34 (s, 12H). LCMS (M+H)=319.7.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]([CH:15]=[CH2:16])=O.ClC(Cl)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:35][C:36]([NH2:38])=[S:37])[CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1>>[C:1]([C:5]1[CH:11]=[CH:10][C:8]([CH2:12][C:13]2[S:37][C:36]([NH:35][C:25]3[CH:26]=[CH:27][C:28]([N:29]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]4)=[C:23]([O:22][CH3:21])[CH:24]=3)=[N:38][C:15]=2[CH3:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)=O
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: O=C(Cl)Cl
Product: COc1cc(Nc2nc(C)c(Cc3ccc(C(C)(C)C)cc3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 7 without purification of the intermediate from 149 mg (1 mmol) 4-tert-butylaniline and 421 mg (6 mmol) methyl vinylketone. The crude chloroketone was used without further purification in the next step with 53 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 45 mg (50%) of [5-(4-tert-butyl-benzyl)-4-methyl-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a brown solid. MS ISP (m/e): 447.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.12 (s, 1H), 7.63 (s, 1H), 7.53 (s, 1H), 7.32 (d, 2H), 7.22 (s, 2H), 7.15 (d, 2H), 7.01 (s, 1H), 3.92 (s, 2H), 3.77 (s, 3H), 2.24 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[C:6](Cl)=[N:7]2.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1.Cl.[O:33]1CCOCC1>C1COCC1>[Cl-:1].[F:17][C:15]1[CH:14]=[CH:13][C:5]2[C:6]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH2+:21][CH2:20]3)=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:2](=[O:33])[C:3]=3[C:4]=2[CH:16]=1
Reactant: C1COCCO1
Reactant: Fc1ccc2c(Cl)nc3ccnc(Cl)c3c2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]ccc2nc(N[C@@H]3CCC[NH2+]C3)c3ccc(F)cc3c12
Product: [Cl-]
Temperature: 125 °C

Procedure:
To a solution of 1,6-dichloro-9-fluorobenzo[c]-1,6-naphthyridine (320 mg, 1.2 mmol) in dioxane (8 mL) was added tert-butyl (3R)-3-aminopiperidine-1-carboxylate (960 mg, 4.79 mmol) and heated in a microwave reactor for 1 hr at 125° C. The solution was concentrated to provide the crude solid. The crude material was dissolved in THF (5 mL) and 6 N HCl 5 mL) and heated to 85° C. for 2 hr. Upon cooling the solution solidifies and the reaction mixture was triturated with Et2O and filtered to afford (3R)-3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-6-yl)amino]piperidinium chloride. LRMS (ESI) calc'd for (C17H18FN4O) [M+H]+, 313.2; found 313.1.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:32])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[N:10]([CH2:24][C:25]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:26])[C:9]2=[O:31].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH:28]([NH:27][C:25]([CH2:24][N:10]1[C:9](=[O:31])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([O:5][CH2:4][C@@H:3]([CH3:32])[CH2:2][O:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:7]=2)[N:12]=[C:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[O:26])([CH3:29])[CH3:30]
Reactant: COc1cccc(-c2nc3ccc(OC[C@@H](C)CO)cc3c(=O)n2CC(=O)NC(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cccc(-c2nc3ccc(OC[C@@H](C)COS(C)(=O)=O)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: -78 °C

Procedure:
To a suspension of (S)-(+)-2-[6-(3-hydroxy-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (0.96 g, 2.18 mmol) in dichloromethane (100 mL) cooled to −78° C. under argon was added methanesulfonyl chloride (2.50 g, 1.7 mL, 21.90 mmol) dropwise over 5 min, followed by dropwise addition (10 min) of triethylamine (2.21 g, 3.10 mL, 21.9 mmol). The reaction mixture was warmed to −30° C. over 60 min followed by warming to room temperature over 15 min after which time the reaction was found to be complete (HPLC monitoring). The reaction mixture was diluted with ethyl acetate (300 mL), poured into ice water (100 mL) and the organic phase washed with 1N HCl (aq.) (2×200 mL), sat. NaHCO3 (aq.) (1×200 mL) and brine (1×200 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to afford (R)-(−)-methanesulfonic acid 3-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]-2-methylpropyl ester as a pale yellow solid (1.13 g, 2.18 mmol, 100%, 91% purity by LC-MS).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([C:14]2[N:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[N:5]=1)[CH3:2].C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>C1COCC1>[Cl:28][CH2:29][C:30]([NH:20][C:17]1[CH:18]=[N:19][C:14]([C:6]2[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[C:8]([C:10]([F:11])([F:13])[F:12])[N:7]=2)=[CH:15][CH:16]=1)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: CCOc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1cc(C(F)(F)F)nc(-c2ccc(NC(=O)CCl)cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cool (0° C.) solution of compound of example 58 (0.04 g, 0.14 mmol) in THF (3 mL) was added triethylamine (0.021 g, 0.21 mmol) and chloroacetylchloride (0.023 g, 0.21 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 50% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:42][CH:26]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](CCC(OCC)=O)=[CH:31][CH:30]=1.[OH-:43].[K+].Cl>O1CCOCC1.O>[OH:25][CH:26]([CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([O:43][CH2:4][C:1]([OH:3])=[O:2])=[CH:33][CH:34]=1)[CH2:42][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: [OH-]
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CCOC(=O)CCc1ccc(OCC2CO2)cc1
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)COc1ccc(OCC(O)CN2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(2-ethoxycarbonylethyl)-phenoxy]-propane are added in 80 ml of dioxane/60 ml of water and adjusted to pH 13 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted to pH 7 with 5N hydrochloric acid and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed-phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[Cl:10][CH2:11][CH2:12][CH2:13]I.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH:5][CH2:13][CH2:12][CH2:11][Cl:10]
Reactant: ClCCCI
Reactant: Cc1ccc(N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NCCCCl)cc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 60 %

Procedure:
A mixture of 3-chloro-4-methylaniline (7.79 g, 55 mmol), 1-chloro-3-iodopropane (5.91 ml, 55 mmol), cesium carbonate (35.84 g, 110 mmol) and DMF (15 ml) was stirred at room temperature for 19 hours. To the mixture was added water (75 ml), and the mixture was extracted with hexane (60 ml, 30 ml×2). The organic layer was washed with water (10 ml), dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 200 g, hexane/ethyl acetate=1/0 to 19/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (7.30 g, 33 mmol, Yield 61%) as a pale brown oily substance.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:43][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[CH:18][C:17]([CH2:22][NH:23][C@H:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:25][CH2:26][NH:27][C:28]1([C:33]([O:35]C)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:16]3.O([Si](C)(C)C)[K:45]>C1COCC1>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:43][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[CH:18][C:17]([CH2:22][NH:23][C@H:24]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH2:25][CH2:26][NH:27][C:28]1([C:33]([O-:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]1)=[CH:16]3.[K+:45]
Reactant: C[Si](C)(C)O[K]
Reactant: COC(=O)C1(NCC[C@H](NCc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)c2ccccc2)CCCC1
Solvent: C1CCOC1
Product: O=C([O-])C1(NCC[C@H](NCc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)c2ccccc2)CCCC1
Product: [K+]
Temperature: 50 °C

Procedure:
To a solution of methyl 1-{[(3S)-3-({[(7S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclo-penta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-3-yl]methyl}amino)-3-phenylpropyl]amino}cyclopentanecarboxylate from Step A (50. mg, 0.087 mmol) in a minimal amount of THF (5 mL) was added KOTMS (22 mg, 0.17 mmol), prior to heating to 50° C. Additional KOTMS was added as needed (˜2 equiv) until very little starting material was detected in solution. The reaction was allowed to cool to ambient temperature before the THF solution was separated from the precipitated solids. Analysis of the remaining solids indicated it was 87% title compound and 13% starting material. This mixture was used without further purification in the next step. MS: m/z=562 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[C:13]1(=O)[NH:17][C:16](=O)C2=CC=CC=C12.[C:24](Cl)(=[O:28])[C:25](Cl)=[O:26].CNC.C1COCC1>CCOCC>[CH3:16][N:17]([CH3:13])[C:24](=[O:28])[C:25]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)=[O:26]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Agent: CNC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)C(=O)C(=O)c1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 147.3 %

Procedure:
To a stirred mixture of 5-nitroindole (5.00 g, 30.8 mmol) and phtalimide (2.00 g, 40% by weight) in anhydrous ether (125 mL) was added oxalyl chloride (8.09 mL, 95.6 mmol). The resulting mixture was stirred at room temperature for 24 h. The solids were filtered off, rinsed with several portions of ether and air-dried for 15 min. This intermediate was suspended in 100 mL anhydrous ether and cooled to 0° C. To this mixture was 2M dimethylamine in THF (154 mL, 0.308 mol) added in small increments. After the addition was complete the reaction was stirred for an additional 1 h at room temperature. The volatiles were evaporated and the crude re-crystallized in refluxing MeOH afforded N,N-dimethyl-2-(5-nitro-1H-indol-3-yl)-2-oxoacetamide (5.2 g, 20.02 mmol, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][CH:12]([CH3:15])[CH2:13][OH:14].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[N:11]/[CH:12]([CH3:15])[CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(N)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=N/C(C)CO)cc1

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-methoxybenzaldehyde (54.4 g, 400.00 mmol, 1.00 equiv), 2-aminopropan-1-ol (30 g, 400.00 mmol, 1.00 equiv), 4-methylbenzenesulfonic acid (3.84 g, 20.21 mmol, 0.05 equiv), toluene (300 mL). The resulting solution was heated to reflux for overnight in an oil bath. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 3×50 mL of hexane. The resulting solids were collected by filtration. This resulted in 63 g (82%) of (E)-2-(4-methoxybenzylideneamino)propan-1-ol as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[CH:42]=[C:41]2[C:36]([C:37]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:38][C:39]([NH2:43])=[N:40]2)=[CH:35][CH:34]=1>>[NH2:43][C:39]1[CH:38]=[C:37]([N:44]2[CH2:49][CH2:48][N:47]([C:11]([NH:1][C:2]3[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:12])[CH2:46][CH2:45]2)[C:36]2[C:41](=[CH:42][C:33]([Cl:32])=[CH:34][CH:35]=2)[N:40]=1
Reactant: COc1ncccc1N
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1NC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described for example 78, 3-amino-2-methoxypyridine, 4-nitrophenyl chloroformate, diisopropyl(ethyl)amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 413 (M++1). 1H NMR (CDCl3) δ 8.40 (d, 1H), 7.80 (m, 1H), 7.75 (d, 1H), 7.64 (d, 1H), 7.20 (dd, 1H), 7.05 (s, 1H), 6.90 (m, 1H), 6.20 (s, 1H), 4.80 (s, 1H), 4.00 (s, 3H), 3.80 (m, 4H), 3.25 (m, 4H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[CH3:19].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC.C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[CH3:19][C:3]1[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:7][C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1-c1ccccn1
Temperature: 116 °C

Procedure:
To a reaction vessel under argon containing 2-(6-bromo-5-methylpyridin-2-yl)isoindoline-1,3-dione (85 mg, 0.27 mmol), 2-(tributylstannyl)pyridine (123 mg, 0.32 mmol), Pd(PPh3)4(31 mg, 0.027 mmol) is added anhydrous toluene (0.7 ml). The mixture is heated to 116° C. with an oil bath for 18 hours, cooled to room temperature, diluted with ethyl acetate and filtered through a celite pad to remove any solids. The filtrate is concentrated to afford 2-(3-methyl-2,2′-bipyridin-6-yl)isoindoline-1,3-dione as a brown solid (LC-MS m/z: 316.1 (M+1)) which is used without further purification in the next step.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].Cl[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=1)(=[O:26])=[O:25]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10]([C:11]1[CH:16]=[CH:15][C:14]([O:17][S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=2)(=[O:26])=[O:25])=[CH:13][CH:12]=1)=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Yield: 11 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using commercial 2-n-butyl-3-(4-hydroxybenzoyl)benzofuran (1.00 g, 3.40 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.61 g, 6.79 mmol). Purification on 2% H3PO4 /MeOH treated silica gel, eluting with EtOAc/hexane gave 0.185 g (11%) of the title compound as an off white solid, mp 143-145° C. 1H NMR (DMSO-d6) δ 0.76 (t, 3 H), 1.12-1.22 (m, 2 H), 1.60 (quintet, 2 H), 2.69 (t, 2 H), 7.21-7.38 (m, 7 H), 7.61 (d, 1 H), 7.76 (d, 2 H), 7.98 (d, 1 H). IR (KBr) 2950, 1690, 1600, 1380 and 1150 cm-1. mass spectrum (+ESI) m/z 495 (M+H). Anal. Calcd. for C26H22O8S.0.2H2O: C, 62.24; H, 4.58; N, 0.00. Found: C, 62.38; H, 4.59; N, 0.13.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+].[OH2:20]>>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][C:1]([C:13]([OH:15])=[O:20])=[CH:2][CH:3]=1
Reactant: Cc1ccc(-c2ccccn2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Product: O=C(O)c1ccc(-c2ccccn2)cc1

Procedure:
2-(p-Toluyl)pyridine (17.2 g) was suspended in water (200 ml), and to the suspension potassium permanganate (21.0 g) was added. The mixture was heated under reflux for 18 hours. After the reaction mixture was allowed to cool, and insoluble matter was removed by filtration, dichloromethane was added to the filtrate, and the resultant water layer was separated and acidified with 2N hydrochloric acid. The solution was concentrated, and precipitate was collected by filtration to obtain the title compound (7.07 g) as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2ccccn2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccn4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.1 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(2-pyridyl)thiazole (316 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography and ethyl 3-[4-phenyl-1-[4-[2-(2-pyridyl)-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (590 mg, yield: 75%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 81–82° 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])[CH:38]([CH3:40])[CH3:39]>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])[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)C(=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: CC(C)=CCC(OC(=O)C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 44.9 %

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 isobutanoic 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 161 mg (Yield: 45%) of the title compound having the following structure as a red oil.