Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[C:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.ClC(Cl)(Cl)C(C(Cl)(Cl)Cl)=[O:38].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:26][C@H:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[C@H:24]4[C@@H:15]([CH2:16][C@@H:17]5[O:38][C@@:18]65[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]6)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: COc1ccc(C2=C3[C@H]4CCCCC4=CC[C@H]3[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)C2)cc1
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc([C@H]2C[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@@H]3C[C@@H]4O[C@@]45CCCC[C@@H]5[C@H]32)cc1
Temperature: 0 °C
Reaction time: 168 h

Procedure:
20 g of the diketal prepared in Example 1 c) are dissolved in 200 ml of methylene chloride. 0.1 ml of pyridine are added, the whole is cooled to 0° C., and 0.9 ml of hexachloroacetone is added. 9.2 ml of a 30% aqueous hydrogen peroxide solution are then added dropwise. The whole is stirred at room temperature for 7 days and then saturated sodium thiosulphate solution is cautiously added to the reaction solution with gentle cooling. The aqueous phase is removed and extracted repeatedly with methylene chloride and the organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The crude product is purified by chromatography on silica gel with a mixture of ethyl acetate and hexane. 16.6 g of 3,3;17,17-bis-(ethylenedioxy)-11β-(4-methoxyphenyl)-5α,6α-epoxy-oestrane are obtained in the form of a white foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:13]=2)=[N:4][C:3]=1[NH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].C(OCC)(=O)C.C(OC(C)C)(C)C>ClCCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]3[CH2:21][CH2:22][CH:23]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[CH2:24][CH2:25]3)[CH:13]=2)=[N:4][C:3]=1[NH:27][C@H:28]1[CH2:29][CH2:30][C@H:31]([OH:34])[CH2:32][CH2:33]1
Reactant: COc1ccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Cl)nc2C(N)=O)cc1N1CCC(=O)CC1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Cl)nc2C(N)=O)cc1N1CCC(N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide (Example 495) (0.346 mg), N-methylpiperazine (0.12 mL) and 1,2-dichloroethane (10 mL), sodium triacetoxyborohydride (225 mg) was added and stirred at room temperature for 5 hours. After addition of saturated aqueous sodium hydrogen carbonate, the reaction liquid was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=100:0:0 to 20:1:0.1) to give a crude product. The crude product was solidified with ethyl acetate-diisopropyl ether and then washed with ethyl acetate to give 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-methoxy-3-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (39 mg) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:22]=[CH:21][NH:20][C:19]3[C:18](=[O:23])[C:17]4[NH:16][C:15](=[O:24])[CH:14]=[C:13]([CH3:25])[C:12]=4[C:11](=[O:26])[C:10]2=3)=[CH:5][CH:4]=1>C1(C)C(C)=CC=CC=1>[CH3:27][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:22]=[CH:21][N:20]=[C:19]3[C:10]=2[C:11](=[O:26])[C:12]2[C:13]([CH3:25])=[CH:14][C:15](=[O:24])[NH:16][C:17]=2[C:18]3=[O:23])=[CH:5][CH:4]=1
Reactant: Cc1cc(=O)[nH]c2c1C(=O)C1=C(NC=CC1c1ccc(N(C)C)cc1)C2=O
Solvent: Cc1ccccc1C
Product: Cc1cc(=O)[nH]c2c1C(=O)c1c(-c3ccc(N(C)C)cc3)ccnc1C2=O
Yield: 79.5 %

Procedure:
A solution of 25 mg (0.07 mmol) of 3 in xylene (60 ml) was refluxed for 16 hours while air was bubbling through the solution. After evaporation of the solvent, the residue was purified by silica gel chromatography, using ethyl acetate as eluent to yield 20 mg (80%) of 6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([NH2:15])=[C:6]2[C:10]=1[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7]2.[N:17]([O-])=O.[Na+].Cl[Sn]Cl.O.[OH-].[Na+]>O.OS(O)(=O)=O.Cl>[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7][C:6]=2[C:5]([NH:15][NH2:17])=[C:4]([F:16])[CH:3]=1
Reactant: CCN1c2c(Cl)cc(F)c(N)c2CS1(=O)=O
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCN1c2c(Cl)cc(F)c(NN)c2CS1(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 7-chloro-1-ethyl-5-fluoro-1,3-dihydro-2,1-benzisothiazol-4-amine 2,2-dioxide (0.5 g, 1.89 mmol) in water (3.1 mL) and H2SO4 (1.65 mL) at 0° was added NaNO2 (0.13 g, 1.89 mmol) in water (0.5 mL). The reaction mixture was stirred at 0° C for 1 h. A solution of SnCl2.H2O (0.85 g, 3.78 mmol) in conc. HCl (3.1 mL) was then added dropwise and the reaction mixture was stirred at room temperature for 12 h. Then 50% aqueous NaOH solution was added until the reaction mixture reached pH 13. The reaction mixture was extracted with ethyl acetate (200 mL) and the organic layer was washed with brine (3×50 mL) and dried (MgSO4). The solvent was removed and the title compound of Step A was isolated by flash chromatography. 1H NMR (CDCl3, 300 MHz): δ7.04 (d,1H), 5.62 (br s,1H), 4.62 (s,2H), 3.86 (m,2H), 1.26 (t,3H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH:7]1[C:8]2[C:4](=[C:3]([CH2:1][NH2:2])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: N#Cc1cccc2[nH]ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a solution of 4-cyanoindole (7.5 g, 53 mmol) in THF (100 ml) was added at rt a 1.0M solution of lithium aluminum hydride in THF (100 ml, 100 mmol). The mixture was refluxed for 30 min then cooled to rt. The reaction mixture was quenched with 1N NaOH and filtered. The filtrate was acidified with 1N HCl and stirred at rt for 10 min. The pH was adjusted to ˜8 by adding sat NaHCO3 and extracted with n-butanol. The layers were separated and the organic layer was concentrated to dryness. The residue was triturated with methanol. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to afford the desired product as a solid that was further dried under high vacuum at 50° C. (7.27 g, 94% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1.CC(=O)OCC>C(#N)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:15]1[CH2:16][CH2:17][N:12]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:13][CH2:14]1
Reactant: ClCc1nc2cccnc2s1
Reactant: c1ccc(C2CCNCC2)nc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc(C2CCN(Cc3nc4cccnc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 38A (50 mg, 0.11 mmol), 2-(4-piperidinyl)pyridine (25 mg, 0.13 mmol), and D1 EA (340 μL, 2.1 mmol) were combined in acetonitrile (1 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was treated with hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.13 (m, 4H), 3.13 (m, 4H), 3.61 (m, 3H), 7.38 (d, J=4.75 Hz, 1H), 7.76 (dd, J=8.3 Hz, 4.6 Hz, 1H), 7.91 (m, 1H), 8.31 (m, 1H), 8.54 (m, 2H), 8.72 (dd, J=4.6 hz, 1.53 Hz, 1H); (ESI) nil/z 311 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[F:28])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH3:9])=[CH:4][N:3]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]2[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:11](=[O:12])[N:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[F:28])[CH:8]([CH3:9])[C:5]2=[CH:6][N:7]=1
Reactant: COc1ccc(N(C(=O)Nc2ccccc2)C(C)c2cnc(Cl)nc2)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Cl)ncc3C2C)c(F)c1
Reaction time: 0.25 h

Procedure:
This urea was suspended in freshly distilled tetrahydrofuran (3 mL) and cooled in an ice-brine bath. Potassium tert-butoxide (1.0 M in tetrahydrofuran; 0.64 mL; 0.64 mmol) (Aldrich) was added dropwise to the suspension over 5 minutes. The solid went into solution as the potassium tert-butoxide was added. After stirring for an additional 15 minutes in the cold, the reaction mixture was filtered through a bed of silica gel (1.75 g), eluting with 1:1 ethyl acetate-hexanes and then ethyl acetate. Purification by flash chromatography (Biotage 40S; 40:60 to 50:50 ethyl acetate-hexanes) gave (±)-7-chloro-3-(2-fluoro-4-methoxy-phenyl)-4-methyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.22 g; 38% overall for two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.C(#N)C>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cc(C(C)Nc2cc(N3CCNCC3)ccc2S(C)(=O)=O)c1OC
Temperature: 67 °C
Yield: 22 %

Procedure:
[1-(5-Chloro-2,3-dimethoxy-phenyl)-ethyl]-(5-fluoro-2-methanesulfonyl-phenyl)-amine (100 g, 0.26 mol), piperazine (444 g, 5.16 mol), Hunig's base (0.45 L, 2.6 mol) and ACN (0.75 L) were heated at 80° C. for 13.5 hours (a solution formed upon heating to 67° C.). Upon cooling, a large amount of solids precipitated. Filtration, washing of the filter cake with ACN, and concentration afforded a solid which was treated with 1 L EtOAc. The EtOAc layers were combined and washed with 3×1 L water, dried over sodium sulfate, and concentrated to give 26 g of product. The solid collected by filtration was suspended in 0.5 L DCM and washed with 0.5 L water. The water was back-extracted with 0.25 L DCM. The DCM layers were combined, washed with 7×0.5 L water, dried over sodium sulfate and concentrated. 65 g of the resulting white solid were suspended in TBME and left o/n. The mixture was filtered, re-triturated in 210 mL TBME, filtered, washed with 70 mL TBME and air-dried to afford 59.4 g (50.7%) of product as a white solid.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:4]=1[C:16]1[C:17]([CH3:25])=[C:18](C(O)=O)[O:19][C:20]=1[CH3:21])=[O:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>N1C2C(=CC=CC=2)C=CC=1.CN1C(=O)CCC1>[CH3:21][C:20]1[O:19][CH:18]=[C:17]([CH3:25])[C:16]=1[C:4]1[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][N:7]([CH3:8])[C:3]=1[CH:1]=[O:2]
Reactant: Cc1oc(C(=O)O)c(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1C=O
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CN1CCCC1=O
Solvent: c1ccc2ncccc2c1
Product: Cc1coc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1C=O
Yield: 51.9 %

Procedure:
A mixture of 4-(5-formyl-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazol-4-yl)-3,5-dimethylfuran-2-carboxylic acid (45 mg, 0.13 mmol), phenantroline (9.53 mg, 0.05 mmol) and Cu2O (3.78 mg, 0.026 mmol) in quinoline (0.73 ml) and NMP (2.19 mL) was flushed with N2 and irradiated in the microwave at 190° C. for 15 min. HCl (1M) and CH2Cl2 were added and the phases were separated. The crude product was purified on preparative IIPLC to give 4-(2,4-dimethylfuran-3-yl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (20.0 mg, 51%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH3:26][O:27][C:28](=[O:36])[C@H:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[NH2:30].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH:29]([NH:30][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=2)=[CH:20][CH:19]=1)[C:28]([O:27][CH3:26])=[O:36]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC(NC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1)C(=O)OC

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 4-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[C:19]3[CH:20]=[CH:21][O:22][C:18]=3[CH:17]=[CH:16][C:15]=2[F:23])[CH:10]([CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCC(OC(=O)C(C)=O)(C2C3C=COC=3C=CC=2F)C(C)C1)C1C=CC=CC=1.C([SnH](CCCC)CCCC)CCC>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:19]3[CH:20]=[CH:21][O:22][C:18]=3[CH:17]=[CH:16][C:15]=2[F:23])[C@H:10]([CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1(O)c1c(F)ccc2occc12
Agent: CC(=O)C(=O)OC1(c2c(F)ccc3occc23)CCN(Cc2ccccc2)CC1C
Agent: CCCC[SnH](CCCC)CCCC
Product: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1c1c(F)ccc2occc12
Yield: 90.4 %

Procedure:
Beginning with 0.50 gm (1.47 mMol) 1-benzyl-3-methyl-4-hydroxy-4-(5-fluorobenzofur-4-yl)piperidine, 1-benzyl-3-methyl-4-(methyl oxoacetoxy)-4-(5-fluorobenzofur-4-yl)piperidine was prepared essentially as described in EXAMPLE 16. This material was treated with tri(n-butyl)tin hydride essentially as described in EXAMPLE 16 to prepare 0.43 gm (80%) of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]#[N:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)CC)C.[N-:40]=[N+:41]=[N-:42].[Na+].O>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:24]3[NH:42][N:41]=[N:40][N:25]=3)[CH:16]=2)[C:11](=[O:26])[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:9]=1[CH2:8][NH:7][C:6](=[O:31])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C#N)cc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nnn[nH]3)cc12
Yield: 53.1 %

Procedure:
A solution of tert-butyl(4-butoxy-6-cyano-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.85 g, 2 mmol), triethylamine hydrochloride (0.34 g, 2.5 mmol) and sodium azide (0.16 g, 2.5 mmol) in toluene (20 ml) was stirred at 90° C. for 24 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl [4-butoxy-2-isobutyl-1-oxo-6-(1H-tetrazol-5-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.50 g, 53.2%) as crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1>[CH2:24]([O:23][C:21](=[O:22])[C:17]1[CH:18]=[C:19]([Cl:20])[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][CH:16]=1)[CH3:25]
Reactant: CCOC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N2CCNCC2)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Dissolve a solution of 4-(3-chloro-5-ethoxycarbonyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (7.78 g, 0.021 mol) in dioxane, and then add a solution of 4M HCl/dioxane (12 mL). Stir at 50° C. for 2 h, and then add additional 4M HCl/dioxane (5 mL) and stir for an additional 1 h. Cool the mixture in ice, collect the precipitate and wash with ether. Prepare the freebase by partitioning between EtOAc and 10% NaOH solution. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: Br[CH:2]1[CH2:19][CH2:18][C:5]2=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH2:10][CH2:11][CH3:12])=[C:4]2[C:3]1=O.[C:21]([NH2:29])(=[S:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C>O>[C:22]1([C:21]2[S:28][C:2]3[CH2:19][CH2:18][C:5]4=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH2:10][CH2:11][CH3:12])=[C:4]4[C:3]=3[N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCSc1sc(C(=O)OCC)c2c1C(=O)C(Br)CC2
Reactant: NC(=S)c1ccccc1
Solvent: O
Solvent: CCO
Product: CCCSc1sc(C(=O)OCC)c2c1-c1nc(-c3ccccc3)sc1CC2
Yield: 34.9 %

Procedure:
A mixture of ethyl 5-bromo-4,5,6,7-tetrahydro-4-oxo-3-propylthiobenzo[c]thiophene-1-carboxylate (9.43 g), thiobenzamide (6.86 g) and ethanol (190 ml) was refluxed under heating for 4 hours, after which it was poured over water (600 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:10, v/v) to yield ethyl 4,5-dihydro-2-phenyl-8-propylthiothieno[3,4-e]-benzothiazole-6-carboxylate (3.63 g, 34.9%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 125-126° 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:42])[CH2:38][CH2:39][CH2:40][CH3:41]>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:42])[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCC(=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: CCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 59.9 %

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 102 mg (1 mmole) of n-pentanoic 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 223 mg (Yield: 60%) of the title compound having the following structure as a red oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][C:6]=1[CH3:11]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1Br
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of methyl-4-bromo-3-methylbenzoate (4.31 g) in dry tetrahydrofuran (20 ml) was stirred and cooled to 0° C. under nitrogen gas. A solution of 1.5M diisobutylaluminium hydride in toluene (44 ml) was added slowly and the reaction stirred for 2.5 hours, then quenched with methanol and allowed to warm to 21° C. Silica was added and the reaction concentrated in vacuo and purified using SPE (Si cartridge) using cyclohexane:ethyl acetate (3:1) as an eluent which furnished the title compound as a brown oil.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:3][CH:2]=1.I[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>[Cu].ClC1C=CC=CC=1Cl>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=[CH:5][C:4]([N:7]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:11]=[CH:10][C:9]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:3][CH:2]=1
Reactant: COc1ccc(I)cc1
Reactant: c1ccc(-c2ccc(Nc3c(-c4ccccc4)cccc3-c3ccccc3)cc2)cc1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: COc1ccc(N(c2ccc(-c3ccccc3)cc2)c2c(-c3ccccc3)cccc2-c2ccccc2)cc1
Yield: 51.1 %

Procedure:
N-([1,1′-biphenyl]-4-yl)[1,1′:3′,1″-terphenyl]-2′-amine (15.9 g, 40.0 mmol), 4-iodoanisole (37.4 g, 160.0 mmol), potassium carbonate (22.1 g, 160.0 mmol), copper powder (5.1 g, 80.0 mmol), 18-crown-6 ether (21.1 g, 80.0 mmol) and 1,2-dichlorobenzene (200 mL) were bubbled with nitrogen for 30 min. The mixture was refluxed for 72 h. After cooling, the reaction mixture was filtered through a silica pad and washed with toluene (containing 0.5% triethylamine). The solvent was removed in vacuo and the residue was purified by flash chromatography using 40-50% toluene/hexane (containing 0.5% triethylamine) to afford N-([1,1′-biphenyl]-4-yl)-N-(4-methoxyphenyl)-[1,1′:3′,1″-terphenyl]-2′-amine (10.3 g, 51% yield) as a white solid.