Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:15]=[N:16][C:17]([CH:21]3[CH2:23][CH2:22]3)=[C:18]([Cl:20])[CH:19]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:24][C:25]1([F:33])[CH2:28][N:27]([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:26]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:15]=[N:16][C:17]([CH:21]3[CH2:23][CH2:22]3)=[C:18]([Cl:20])[CH:19]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:32][S:29]([N:27]1[CH2:28][C:25]([F:33])([F:24])[CH2:26]1)(=[O:31])=[O:30])=[O:9]
Reactant: O=C(O)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Reactant: NS(=O)(=O)N1CC(F)(F)C1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NS(=O)(=O)N1CC(F)(F)C1)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
To a solution of 5-chloro-4-(((5-chloro-6-cyclopropylpyridin-3-yl)oxy)methyl)-2-fluorobenzoic acid (Preparation 27, 100 mg, 0.28 mmol) and 3,3-difluoroazetidine-1-sulfonamide (Preparation 23, 75 mg, 0.42 mmol) in DCM (10 mL) was added diisopropylethylamine (73 mg, 0.56 mmol) followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (160 mg, 0.42 mmol). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in DMSO (2 mL) and purified by reverse phase chromatography (0-90% acetonitrile/water containing 0.1% formic acid) to give the title compound as colourless solid (51 mg, 36%).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:20])[C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[N:34]1[C:38]2C=[CH:40][CH:41]=[CH:42][C:37]=2N=N1.N1CCCCC1>CN(C)C=O.O>[C:1]([NH:4][CH:5]([CH3:20])[C:6]([NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([N:34]1[CH2:40][CH2:41][CH2:42][CH2:37][CH2:38]1)=[O:19])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(=O)NC(C)C(=O)NC(Cc1ccccc1)C(=O)N1CCCCC1
Temperature: 50 °C

Procedure:
N-[2-(Acetylamino)propionyl]phenylalanine obtained in Experimental Example 21 (10 mg, 0.036 mmol) is suspended in N,N-dimethylformamide (5 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14 mg, 0.073 mmol), 1-hydroxybenzotriazole (15 mg, 0.11 mmol) and piperidine (40 μl, 0.40 mmol) are added to the suspension at room temperature, followed by stirring at 50° C. Fog 24 hours. To the reaction mixture is added water, and the resulting mixture is extracted three times with chloroform. The organic layer is washed with 10% hydrochloric acid and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After the solvent is distilled away under reduced pressure, the residue is purified by silica gel column chromatography to obtain 1-{2-[N-(2-(acetylamino)propionyl)amino]-3-phenylpropionyl}piperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[Bi](Cl)(Cl)Cl.[BH4-].[Na+]>CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl[Bi](Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCc1ccc(OCc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
To a solution of methyl 4-[(4-nitrophenyl)methoxy]benzenepropanoate (0.55 g, 1.67 mmol) and bismuth (III) chloride (0.79 g, 2.5 mmol) in methanol (30 mL) was added sodium borohydride (0.51 g, 13 mmol), and the mixture was stirred at room temperature for 2 hrs. Insoluble material was filtered off, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5:1) to give the title compound (0.13 g, yield 25%) as a powder.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].O>C1C=CC(Cl)=C(Cl)C=1>[C:8]1(=[O:9])[O:7][C:5](=[O:6])[C:4]2=[CH:10][CH:11]=[CH:12][CH:2]=[C:3]12
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Solvent: Clc1ccccc1Cl
Solvent: O
Product: O=C1OC(=O)c2ccccc21

Procedure:
In the “In Situ ClPAMI” procedure, the five-necked flask setup described above was used. The ClPAMI was synthesized in the five-necked flask by reacting two moles of chlorophthalic anhydride with one mole of mPD using oDCB as solvent. The water formed was removed by distillation until a moisture content of less than 20 ppm in the distillate was obtained. Then, HEGCl , a phase transfer catalyst, was added in an amount of 0.6 weight %, based on the ClPAMI amount. More oDCB was distilled off to confirm that the moisture level was less than 20 ppm in the distillate. Then, a slurry of Na2BPA and NaPCP in oDCB in the second flask was transferred to the five-necked flask using the addition tube in communication with the second flask, and polymerization was conducted at 180° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][N:8]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture of 0.5 g (1.936 mmol) 4-tert-Butoxycarbonylamino-piperidine-4-carboxylic acid methyl ester, 0.387 g (2.03 mmol) p-toluenesulfonyl chloride and 0.587 g (5.8 mmol) NEt3 in 6 mL DCM was stirred at room temperature over night. DCM and NaHCO3 aq. was added and the organic layer was separated and dried with MgSO4. After evaporation the residue was dried under high vacuum and used without further purification. 0.796 g (95%) of the title compound was obtained as white foam. MS (m/e): 413.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[C:9](=O)[NH:8][C:5]2=[CH:6][CH:7]=1.[BH4-].[Na+].II>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)C(=O)Nc1ccc(Cl)cc12
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(Cl)cc32)C1
Temperature: 0 °C
Yield: 101.7 %

Procedure:
To a stirred solution of tert-butyl 5-chloro-2-oxospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (0.530 g, 1.64 mmol) in THF (5 mL) was added NaBH4 (0.311 g, 8.21 mmol). The reaction was cooled to about −20° C. to −10° C. A solution I2 (0.833 g, 3.28 mmol) in THF (3 mL) was added to the mixture dropwise. The reaction was stirred with warming to about room temperature overnight. The reaction was cooled to about 0° C. and quenched by the addition of saturated NH4Cl, and diluted with DCM. The organics were washed with Na2SO3 and brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography to yield tert-butyl 5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (0.515 g, 100%). LCMS (APCI+) m/z 209, 211 [M+H-Boc]+; Rt=3.67 min.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.C(N(C(C)C)CC)(C)C.[CH2:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:25]#[CH:26]>C(Cl)(Cl)Cl>[CH2:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:3][C:4]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[CH2:29][CH2:28]1)[C:25]#[CH:26]
Reactant: C#CCN1CCNCC1
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN1CCN(Cc2ccc(O)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a mixture of 5-chloromethyl-8-hydroxyquinoline hydrochloride (A2) (323 mg, 1.407 mmol) and diisopropylethylamine (0.26 ml, 1.477 mmol, 1.05 eq) in 6 ml CHCl3 at 0° C., N-propargylpiperazine obtained in step 2(iii) above was added (173 mg, 1.407 mmol, 1 eq). The mixture was stirred for 24 h at room temperature. 10 ml of CHCl3 was then added and the solution was washed with 5% NaHCO3 (3×50 ml), brine (2×50 ml), and then dried over Na2SO4. The crude product was purified by FC to give the title compound (HLA20) as a white solid. (337 mg, 86% yield). H1 NMR (250 MHz,CDCl3), 2.23 (m, 1H), 2.54 (s, 8H), 3.28 (d, J=2.44 Hz, 2H), 3.80 (s, 2H), 7.08 (m, 1H), 7.36 (d, J=10.59, 1H), 7.46 (dd, J=8.55, 4.18 Hz, 1H), 8.67 (dd, J=8.56, 1.55 Hz, 1H), 8.78 (dd, J=4.18. 1.51 Hz, 1H); 13C NMR (100 MHz, CDCl3) 46.77, 51.98, 52.87, 60.55, 73.05, 78.92, 108.60, 121.40, 124.58, 127.87, 128.87, 134.10, 138.68, 147.50, 151.78.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][O:31][C:32](=[O:40])[NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:34]1([NH:33][C:32]([O:31][CH2:30][C:10]2[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:21][C:22]=3[CH3:23])[CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]([OH:41])=[O:5])=[O:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(COC(=O)NC2CCCCC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)c(COC(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
A 25 mL round bottomed flask was charged with 3-{2-cyclohexylcarbamoyloxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}-propionic acid tert-butyl ester (0.080 g, 0.14 mmol) and CH2Cl2 (2 mL). Trifluoroacetic acid (2 mL) was added, and the solution was stirred at ambient temperature under a nitrogen atmosphere for 1.5 h. The solution was concentrated to give a white solid (0.068 g, 94%). 1H NMR (400 MHz, CDCl3) 1.08-1.18 (m 3H), 1.21-1.42 (m, 2H), 1.57 (br s, 1H), 1.66-1.70 (m, 2H), 1.90 (br s, 2H), 2.40 (s, 3H), 2.61 (t, J=7.7 Hz, 2H), 2.94 (t, J=7.8 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 3.48 (br s, 1H), 4.22 (t, J=6.4 Hz, 2H), 4.74 (br s, 1H), 5.07 (s, 2H), 6.79-6.89 (m, 1H), 6.90 (s, 1H), 7.11 (d, J=8.3 Hz, 1H), 7.44-7.46 (m, 3H), 7.98 (dd, J=6.7, 2.8 Hz, 2H). MS (ES) m/e 507 (M+1).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-])=O)[CH3:6])(=[O:3])[CH3:2].[H][H]>[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-].CO>[NH2:17][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:7]=1[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:6])[C:11]([O:13][CH3:14])=[O:12]
Reactant: [H][H]
Reactant: COC(=O)c1ccc([C@@H](C)NC(C)=O)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(N)c1
Yield: 100.3 %

Procedure:
Methyl (R)-4-(1-acetamidoethyl)-3-nitrobenzoate (1 g) was stirred in a stream of hydrogen at room temperature for 3 hours using 10% palladium hydroxide carbon (0.3 g) in a methanol (20 ml) solution. After the reaction, the catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to give 0.89 g of methyl (R)-3-amino-4-(1-acetamidoethyl)benzoate.
Reaction SMILES: [Sm].ICCI.[I-].[I-].[Sm+2].[C:9]([C-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH-:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1.[Fe+2:27].C(Br)C=C>O1CCCC1>[C-:17]1([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:26][CH:22]=[CH2:23])[CH:21]=[CH:20][CH:19]=[CH:18]1.[CH-:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1.[Fe+2:27]
Reactant: O=C(c1ccccc1)[c-]1cccc1
Agent: [Fe+2]
Agent: ICCI
Agent: [I-]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CC=C(c1ccccc1)[c-]1cccc1
Yield: 99 %

Procedure:
In a nitrogen environment, about 330 mg (2.20 mmole) of samarium and about 500 mg (1.77 mmole) of 1,2-diiodoethane is disposed in a round-bottomed flask. About 20 ml of tetrahydrofuran is added into the round-bottomed flask. The mixture in the round-bottomed flask is stirred until a deep-blue samarium diiodide solution is obtained. Following the process flow described in Example 1, about 348 mg (1.20 mmole) of benzoylferrocene reacts with about 242 mg (2.0 mmole) of allyl bromide to produce oil-type 1-Ferrocenyl-1-phenyl-1,3-butadiene (3c) with a weight of about 373 mg (1.19 mmole) and a yield of about 99%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]([C:35]2[C:36]3[C:48]([NH2:49])=[N:47][CH:46]=[N:45][C:37]=3[N:38]3[C:43]=2[CH2:42][CH2:41][CH:40]([NH2:44])[CH2:39]3)[CH:26]=1.Cl.[CH3:51][N:52]([CH3:59])[CH2:53]/[CH:54]=[CH:55]/[C:56](O)=[O:57].C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:49][C:48]1[C:36]2[C:35]([C:27]3[CH:26]=[N:25][C:34]4[C:29]([CH:28]=3)=[CH:30][CH:31]=[CH:32][CH:33]=4)=[C:43]3[N:38]([C:37]=2[N:45]=[CH:46][N:47]=1)[CH2:39][CH:40]([NH:44][C:56](=[O:57])/[CH:55]=[CH:54]/[CH2:53][N:52]([CH3:59])[CH3:51])[CH2:41][CH2:42]3
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Nc1ncnc2c1c(-c1cnc3ccccc3c1)c1n2CC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)NC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
HATU (10.3 mg) and 5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizine-4,8-diamine (8.8 mg) obtained in Step 11 of Example 1 were added to a solution of trans-4-dimethylaminocrotonic acid hydrochloride (4.5 mg) in DMF (0.5 ml) at room temperature. After being stirred for 1 hour at the same temperature, the mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (produced by Wako, NH2 silica-gel 60 F254 plate, developing solvent: chloroform/methanol) to obtain the title compound as a light-yellow solid (6.4 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:37]([O:39]C)=[O:38])=[C:9]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:41]([CH:44]([CH3:46])[CH3:45])(=[O:43])=[O:42])[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:37]([OH:39])=[O:38])=[C:9]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:29][CH2:30]3)[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:41]([CH:44]([CH3:45])[CH3:46])(=[O:43])=[O:42])[CH3:2]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(=O)(=O)C(C)C
Temperature: 25 °C
Yield: 102.1 %

Procedure:
A stirred suspension of methyl 7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.3 g, 1.959 mmol) and potassium hydroxide (0.879 g, 15.67 mmol) in methanol (15 mL) and water (3.75 mL) was heated to reflux for 20 h. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The resulting yellow oil was partitioned between water and methylene chloride and cooled in an ice bath. The pH was adjusted to ⅚ with 2N HCl and the organic phase was separated. The aqueous phase was extracted twice more with methylene chloride. The combined organic extracts were washed with brine, dried, and concentrated to afford 7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1.3 g, 97% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ8.81 (s, 1H), 8.01 (s, 1H), 7.86-7.94 (m, 2H), 7.75-7.82 (m, 1H), 7.67 (s, 1H), 4.37 (q, J=6.80 Hz, 2H), 4.10 (br. s., 2H), 3.84 (quin, J=6.80 Hz, 1H), 3.56 (br. s., 4H), 3.02 (d, J=11.08 Hz, 2H), 2.52-2.63 (m, 2H), 2.44 (br. s., 4H), 2.33 (br. s., 1H), 1.79 (d, J=12.34 Hz, 2H), 1.44 (t, J=6.92 Hz, 3H), 1.26-1.39 (m, 2H), 1.23 (s, 3H), 1.21 (s, 3H); MS (m/z) 650.2 (M+H+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][C:14]=1[OH:15]>Cl.[Cl-].[Cl-].[Zn+2]>[CH3:12][C:13]1[C:14]2[O:15][C:19]3[C:13]([CH3:12])=[C:14]([OH:15])[CH:16]=[CH:17][C:18]=3[C:4]3([O:6][C:1](=[O:11])[C:2]4[C:3]3=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:16]=2[CH:17]=[CH:18][C:19]=1[OH:20]
Reactant: Cc1c(O)cccc1O
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1c(O)ccc2c1Oc1c(ccc(O)c1C)C21OC(=O)c2ccccc21
Temperature: 230 °C

Procedure:
In a round bottom flask, phthalic anhydride (16.7 g, 113 mmol) and 2-methylresorcinol (24.9 g, 201 mmol) were combined and melted into a brown liquid at 150° C. Fused ZnCl2 (15 g, 110 mmol) was added over 40 min, and the temperature was slowly increased to 230° C. until all material solidified. The brick red solid was pulverized and boiled in 6M HCl for 30 min. The red solid was collected on a glass frit, washed with water, and dried in air over night (yield: 32.62 g, 91% of the theoretical yield).
Reaction SMILES: [Cl-].[NH4+].O.C(O)(=O)C.[C:8]([O:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:14][C:13]=1[NH:43][S:44]([C:47]1[CH:52]=[C:51]([N+:53]([O-])=O)[CH:50]=[CH:49][C:48]=1[N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)(=[O:46])=[O:45])(=[O:10])[CH3:9]>C(O)(C)C>[C:8]([O:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:15]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:14][C:13]=1[NH:43][S:44]([C:47]1[CH:52]=[C:51]([NH2:53])[CH:50]=[CH:49][C:48]=1[N:56]1[CH2:57][CH2:58][O:59][CH2:60][CH2:61]1)(=[O:45])=[O:46])(=[O:10])[CH3:9]
Reactant: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N2CCOCC2)c(OC(C)=O)cc1C(C)(C)CC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc(N)ccc2N2CCOCC2)c(OC(C)=O)cc1C(C)(C)CC(C)(C)C

Procedure:
26 g of reduced iron, 0.5 g of ammonium chloride, 7.2 ml of water and 7.2 ml of acetic acid were added to 100 ml of isopropyl alcohol and the mixture was refluxed with stirring. To the mixture was gradually added 17.5 g (0.0226 mol) of the compound obtained in Step (d) above and further refluxed with stirring for 20 minutes. After the reaction, the reaction solution was filtered with celite while hot. The filtrate was cooled and the crystals thus-precipitated were collected by filtration. Yield: 13.3 g (78%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:8]2)=[O:4].[BrH:24].CC(O)=O>>[BrH:24].[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CN(S(=O)(=O)c1ccc(C)cc1)C2
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)CNC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(Toluene-4-sulfonyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (5.00 g) are dissolved in 33% HBr/HOAc (39 mL) and stirred for 16 h at ambient temperature. The reaction mixture is evaporated and the residue is treated with MeOH (40 mL). The resulting solid is separated, washed and dried. 3.00 g of the title compound are obtained with MP of 243-246° C.
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5][C@@:6]1([CH3:45])[O:15][C:14]2[C:13]([CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[C:12]3[O:21][C@@:22]45[C@@:32]6([CH2:37]/[CH:38]=[C:39](\[C:41]([OH:43])=[O:42])/[CH3:40])[O:33][C:34]([CH3:36])([CH3:35])[C@@H:23]4[CH2:24][C@H:25]([C:30]6=[O:31])[CH:26]=[C:27]5[C:28](=[O:29])[C:11]3=[C:10]([OH:44])[C:9]=2[CH:8]=[CH:7]1.[CH2:47](Cl)CCl.CO.O>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5][C@@:6]1([CH3:45])[O:15][C:14]2[C:9](=[C:10]([OH:44])[C:11]3[C:28](=[O:29])[C:27]4[C@@:22]5([C@@:32]6([CH2:37]/[CH:38]=[C:39](\[C:41]([O:43][CH3:47])=[O:42])/[CH3:40])[O:33][C:34]([CH3:35])([CH3:36])[C@@H:23]5[CH2:24][C@H:25]([C:30]6=[O:31])[CH:26]=4)[O:21][C:12]=3[C:13]=2[CH2:16][CH:17]=[C:18]([CH3:19])[CH3:20])[CH:8]=[CH:7]1
Reactant: ClCCCl
Reactant: CC(C)=CCC[C@]1(C)C=Cc2c(O)c3c(c(CC=C(C)C)c2O1)O[C@]12C(=C[C@@H]4C[C@H]1C(C)(C)O[C@@]2(C/C=C(/C)C(=O)O)C4=O)C3=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)/C(C)=C\C[C@@]12OC(C)(C)[C@@H]3C[C@@H](C=C4C(=O)c5c(O)c6c(c(CC=C(C)C)c5O[C@]431)O[C@](C)(CCC=C(C)C)C=C6)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
A mixture of gambogic acid (200 mg, 0.32 mmol), DMAP (78 mg, 0.64 mmol), EDC (123 mg, 0.64 mmol) and methanol (102 mg, 3.2 mmol) in THF (5 mL) was stirred at room temperature for 3 h. The solution was poured into water (10 mL) and was extracted with ethyl acetate (3×10 mL). The combined organic layer was dried and concentrated to give the crude product, which was purified by chromatography (SiO2, EtOAc/Hexane 1:5) to give the title compound (196 mg, 95%). 1H NMR (CDCl3): 12.85 (s, 1H), 7.54 (d, J=6.9 Hz, 1H), 6.67 (d, J=10.5 Hz, 1H), 5.94 (t, J=6 Hz, 1H), 5.43 (d, J=10.2 Hz, 1H), 5.05 (m, 2H), 3.49 (m, 1H), 3.43 (s, 3H), 3.35-3.10 (s, 2H), 3.00 (t, J=7.2 Hz, 1H), 2.52 (d, J=10.2 Hz, 1H), 2.32 (quar, J1=4.8 Hz, 1H), 2.02 (m, 1H), 1.74 (s, 3H), 1.69 (s, 3H), 1.67-1.64 (m, 9H), 1.55 (s, 3H), 1.44 (s, 3H), 1.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:18])=[CH:14][CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N+:15]([O-:18])=[CH:14][CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1cc[n+]([O-])c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1cc[n+]([O-])c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Yield: 144.8 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-1-oxide (0.23 g) and aminoguanidine hydrochloride (100 mg) were added ethanol (6 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was refluxed for 3 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline-1-oxide hydrochloride (Compound 157) (220 mg) as colorless crystals.