Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[K+].[C:12](=S)=[S:13]>CCO>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:12](=[S:13])[NH:1][C:2]=2[CH:7]=1
Reactant: S=C=S
Reactant: Nc1cc(Cl)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=c1[nH]c2cc(Cl)ccc2o1
Reaction time: 7 h
Yield: 89 %

Procedure:
2-Amino-4-chlorophenol (5.0 g, 35 mmol) and potassium hydroxide (2.34 g, 41.8 mmol) were dissolved in carbon disulfide (50 mL) and EtOH (75 mL), and the reaction mixture was heated to reflux. After 7 h, the reaction mixture was concentrated under reduced pressure. The material was taken up in EtOAc (100 mL) and 1M HCl (50 mL). The aqueous layer was separated, and the organic layer was washed with water (50 mL) and brine (50 mL). The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 5.71 g (89%) of the desired product as a brown solid. LC-MS: RT=7.60 min., [M+H]+=186.1.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([C:23](OC)=[O:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([CH2:23][OH:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:1]
Reactant: COC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(CO)ccc1OCC2
Yield: 82.9 %

Procedure:
To a solution of methyl 4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-13-carboxylate (1.70 g, 4.82 mmol) in THF (150 mL) was added LiAlH4 (732 mg, 19.3 mmol). The reaction mixture was heated to reflux for 2 hours. After cooling down, the reaction was quenched with a piece of ice cube at 0° C. The solid was filtered off and washed with ethyl acetate (3×30 mL). The combined filtrate was concentrate to give the crude product, which was purified by column chromatography on silica gel eluting with a 50% gradient of EtOAc in petroleum ether to afford {4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}methanol (1.30 g, 83% yield) as a pale yellow solid. LCMS (ESI) m/z: 326.2 [M+H+].
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([CH2:15][N:16]1[CH2:32][CH2:31][C:19]3([N:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:22][NH:21][C:20]3=[O:30])[CH2:18][CH2:17]1)[CH2:8][CH2:7]2.[BH4-].[Na+]>CO.O>[F:33][C:3]([F:2])([F:34])[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([OH:14])[CH:9]([CH2:15][N:16]1[CH2:32][CH2:31][C:19]3([N:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][NH:21][C:20]3=[O:30])[CH2:18][CH2:17]1)[CH2:8][CH2:7]2
Reactant: O=C1c2ccc(C(F)(F)F)cc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1NCN(c2ccccc2)C12CCN(CC1CCc3cc(C(F)(F)F)ccc3C1O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
8-[(6-(Trifluoromethyl)-1,2,3,4-tetrahydro-1-oxo-2-naphthal-enyl)methyl]-1-phenyl-1,3,8,-triazaspiro[4.5]decan-4-one, hydrochloride (1:1) (0.65 g, see example 184) is slurried in methanol (10 ml) and, with cooling, treated with a solution of sodium borohydride (0.27 g) in water (2 ml). The resulting mixture is stirred at room temperature under nitrogen for 16 hours, diluted with water (10 ml), and extracted with methylene chloride. Concentration of the dried organic solution followed by trituration with absolute ethanol yields the free base of the title alcohol as a tan powder (0.5 g), melting point 238°-240° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[N:23]=[CH:22][N:21]=2)=[C:17]([F:44])[CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:44][C:17]1[CH:16]=[C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[S:13])[CH:43]=[CH:42][C:18]=1[O:19][C:20]1[CH:25]=[C:24]([NH:26][C:27]([N:29]2[CH2:30][CH2:31][CH:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH2:33][CH2:34]2)=[O:28])[N:23]=[CH:22][N:21]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)ncn3)CC2)CC1
Reaction time: 3.5 h
Yield: 46 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 2.0 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-6-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyrimidine (98 mg) and (+)-10-camphorsulfonic acid (79 mg) in ethanol (2.0 ml) at room temperature, the mixture was stirred for 3.5 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3) to provide the title compound (65.2 mg, 46%) as white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:10]2[S:14][C:13]([N:15]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:16][C@@H:17]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[NH2:9].[C:44](N1C=CN=C1)(N1C=CN=C1)=[O:45]>C1COCC1>[CH3:1][N:2]1[C:3]2[CH:4]=[C:5]([C:10]3[S:14][C:13]([N:15]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:16][C@@H:17]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=4)=[N:12][N:11]=3)[CH:6]=[CH:7][C:8]=2[NH:9][C:44]1=[O:45]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNc1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1N
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2ccc(-c3nnc(N(C[C@H](Cc4ccc(C(F)(F)F)cc4)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s3)cc21
Temperature: 70 °C
Reaction time: 10 h

Procedure:
The above mentioned crude tert-butyl (S)-1-(5-(3-(methylamino)-4-aminophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate was dissolved in 150 mL THF in a round bottom flask. To this flask was added a 50 mL THF solution of 1,1′-carbonyldiimidazole (1.37 g, 8.45 mmol). The mixture was stirred at 70° C. for 10 hours. After removing the solvent under reduced pressure, the remaining residue was mixed with 200 mL EtOAc. The organic solution was washed with water, three times with saturated ammonium chloride, and dried over sodium sulfate. After removing the solvent, the remaining residue was subjected to silica gel column chromatograph separation using 40% EtOAc in hexane as the eluant. There were two very close major spots on TLC (Rf=0.16, 0.17). The pure fractions for the bottom spot were combined. After removing the solvent, tert-butyl (S)-1-(5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.36 g) was obtained as a tan solid. LCMS (API-ES) m/z (%): 649.3 (100%, M++H); 1H NMR (400 MHz, CDCl3) δ ppm 1.21 (s, 9H) 1.42 (s, 9H) 2.83 (m, 1H) 2.98 (m, 1H) 3.40 (s, 3H) 3.93-4.09 (m, 1H) 4.21-4.44 (m, 2H) 4.97-5.13 (m, 1H) 7.05 (d, J=8.02 Hz, 1H) 7.32 (d, J=7.82 Hz, 2H) 7.50 (m, 3H) 7.60 (s, 1H) 9.24 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]C)[CH:6]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH3:15]
Reactant: CCN(CC)C(=O)c1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Compound 15a (0.68 g; 3.28 mmol) in CH2Cl2 (50 mL) was added BBr3 (1.0M in CH2Cl2) (16 mL; 16 mmol) dropwise at 0° C. The reaction was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated to afford Compound 15b. The crude product was used in the next reaction without further purification. MS m/z 194.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@:7]23[CH2:14][C@H:13]([NH2:15])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[C:8]3=[O:25])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@:7]23[CH2:14][C@H:13]([NH:15][C:28](=[O:30])[CH3:29])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[C:8]3=[O:25])=[CH:26][CH:27]=1
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@@]2(Cc2ccc(Br)cc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@@]2(Cc2ccc(Br)cc2)C1
Reaction time: 5 h

Procedure:
To a solution of (5R,7S)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-7-amino-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.103 g) in THF (4 mL) was added acetic anhydride (0.031 mL). After 5 hours, the reaction mixture was concentrated and purified by chromatography (silica gel: CH2Cl2, Chromatotron) to afford the titled compound (0.125 g) MS (m/z) 510 (MH+). mp 140.7° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([O:8][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C(C)c1ccc(O)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 110.6 %

Procedure:
To a solution of compound (8) (3.69 g, 14.9 mmol) and triethylamine (4.13 mL, 29.7 mmol) in dry dichloromethane, (CF3SO2)2O (2.93 mL, 17.8 mmol) was added dropwise at 0° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 12 hours. The organic layer was washed sequentially with a 1M aqueous solution (90 mL) of hydrochloric acid, a 1M aqueous solution of sodium hydroxide (90 mL), and saline (90 mL), and dried (over sodium sulfate). The solvent was then distilled off. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (10:1) solution to give 5.44 g (96%) of compound (18) of interest as clear yellow liquid matter.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[NH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][S:16][CH2:17][CH2:18][NH:19][C:20]([NH:24][CH3:25])=[N:21][C:22]#[N:23])[N:14]=1>CN(C)C=O>[F:1][C:2]([F:8])([F:7])[CH2:3][NH:4][C:5](=[S:6])[NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][S:16][CH2:17][CH2:18][NH:19][C:20]([NH:24][CH3:25])=[N:21][C:22]#[N:23])[N:14]=1
Reactant: CNC(=NC#N)NCCSCc1csc(N)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CN(C)C=O
Product: CNC(=NC#N)NCCSCc1csc(NC(=S)NCC(F)(F)F)n1

Procedure:
A mixture of 2,2,2-trifluoroethyl isothiocyanate (0.68 g.) and 2-amino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole (1.08 g.) in dimethylformamide (5 ml.) was maintained at 60° for 4 hours and then evaporated to dryness. The residue was recrystallised from acetonitrile to give 2-[3-(2,2,2-trifluoroethyl)thioureido]-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole, m.p. 157°-158°.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[C:10]2[C@H:17]1[O:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][CH2:25][NH:26][CH3:27])[CH2:18]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[CH:37]=O.CC=C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[CH2:37][N:26]([CH3:27])[CH2:25][CH2:24][CH2:23][N:19]1[CH2:18][C@@H:17]([C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([O:6][CH3:5])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)[O:21][C:20]1=[O:22]
Reactant: CNCCCN1C[C@@H](c2ccnc3ccc(OC)cc23)OC1=O
Reactant: O=Cc1cc2ccccc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2nccc([C@@H]3CN(CCCN(C)Cc4cc5ccccc5[nH]4)C(=O)O3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.5 %

Procedure:
Acetic acid (30 ul, 0.475 mmol) was added to a solution of (R)-5-(6-methoxy-quinolin-4-yl)-3-(3-methylamino-propyl)-oxazolidin-2-one (150 mg, 0.475 mmol) and 1H-indole-2-carbaldehyde [19005-93-7] (72 mg, 0.475 mmol) in methylene chloride stabilized over amylene (4.5 ml) and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (230 mg, 1.01 mmol) was then added and stirring was maintained for 48 hours at room temperature. Then water (5 ml) was added, the organic phase was decanted, washed with water dried over magnesium sulfate and concentrated. The residue was chromatographed on silicagel eluting with methylene chloride-methanol (9-1) to give a first crop of pure (R)-3-{3-[(1H-indol-2-ylmethyl)-methyl-amino]-propyl}-5-(6-methoxy-quinolin-4-yl)-oxazolidin-2-one (18 mg) and a less pure fraction of 90 mg (estimated yield >50%).
Reaction SMILES: I[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].Cl[C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[N:10]=1>C1(C)C=CC=CC=1.CN(C)C(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:11]1[CH:12]=[C:13]([CH3:15])[N:14]=[C:9]([CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[N:10]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: COC(=O)CCI
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: COC(=O)CCc1nc(C)cc(C)n1
Temperature: 110 °C
Yield: 9.1 %

Procedure:
A suspension of Zn—Cu couple (3.45 g) in toluene/N,N-dimethylacetamide (14:1, 30 mL) was degassed by bubbling N2 through the suspension for 15 min. Then methyl 3-iodopropanoate (1.96 g, 9.14 mmol) was added to the suspension, and the resulting mixture was heated at 110° C. for 6 h. The reaction mixture was allowed to cool to 70° C., and 2-chloro-4,6-dimethylpyrimidine (961 mg, 6.77 mmol) and tetrakis(triphenylphosphine) palladium (235 mg, 0.203 mmol) were added. The reaction mixture was maintained at 70° C. for 22 h. Upon cooling to r.t., the mixture was filtered, and the filter cake was rinsed with ether (10 mL×3). The filtrate was extracted with 1 M hydrochloric acid (75 mL×2). The acidic extracts were basified with the addition of sodium bicarbonate, and the resulting solution was extracted with ether (75 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and the solution was concentrated to give a residue, which was purified by prep-TLC to afford methyl 3-(4,6-dimethylpyrimidin-2-yl)propanoate as a pale-yellow solid (120 mg). MS (ESI): m/z 195 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([C:21]3[N:29]4[C:24]([CH:25]=[CH:26][CH:27]=[CH:28]4)=[C:23]([C:30]4[CH:45]=[CH:44][C:33]([C:34]([O:36]CC5C=CC=CC=5)=[O:35])=[CH:32][CH:31]=4)[C:22]=3[CH3:46])=[O:20])=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:47])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CN(C=O)C.C(OC(C)C)(C)C>[C:1]([O:5][C:6](=[O:48])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([C:21]3[N:29]4[C:24]([CH:25]=[CH:26][CH:27]=[CH:28]4)=[C:23]([C:30]4[CH:45]=[CH:44][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=4)[C:22]=3[CH3:46])=[O:20])=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:47])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(-c2ccc(C(=O)OCc3ccccc3)cc2)c2ccccn2c1C(=O)c1ccc2c(=O)n(CC(=O)OC(C)(C)C)c(=O)[nH]c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: Cc1c(-c2ccc(C(=O)O)cc2)c2ccccn2c1C(=O)c1ccc2c(=O)n(CC(=O)OC(C)(C)C)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Palladium on carbon (10% active, 0.2 g) and benzyl 4-(3-{[3-(2-tert-butoxy-2-oxoethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl]carbonyl}-2-methylindolizin-1-yl)benzoate (1 g, 1.55 mmol) are added, under nitrogen, to ammonium formate (0.97 g, 15.54 mmol) in solution in 15 mL of DMF. The reaction mixture is stirred for 3 h at ambient temperature and filtered through Celite, and the filtrate is concentrated to dryness. The solid obtained is taken up in diisopropyl ether. After filtration and drying under vacuum, 732 mg (yield: 85%) of a green solid are obtained.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.Cl.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[C:5]([C:6]1[CH:14]=[CH:13][C:9]([C:10](=[O:11])[C:6]2[CH:14]=[CH:13][CH:9]=[CH:8][CH:7]=2)=[CH:8][CH:7]=1)(=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32 %

Procedure:
Aluminum trichloride (1.37 g, 10.33 mmol) was added to a solution of terephthaloyl dichloride (1.0 g, 4.42 mmol) in anhydrous dichloromethane and excess benzene. After stirring for 12 h at room temperature under an inert atmosphere of nitrogen gas, the reaction mixture treated with 10% HCl (50 mL) and the products were extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine and dried over sodium sulfate. After the organic layer was concentrated under reduced pressure, purification using flash chromatography (silica gel, hexanes:ethyl acetate, 80:20) afforded 1,4-dibenzoyl benzene 1 (0.405 g, 1.41 mmol) in a 32% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[SH:18][C:19]1[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][S:18][C:19]1[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=1)[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: Cn1ccnc1S
Solvent: C1COCCO1
Product: Cn1ccnc1SCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 65.6 %

Procedure:
2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-oxirane (0.27 g, 0.001 m), and 2-mercapto-1-methylimidazole (0.228 g, 0.002 m) were heated under reflux in dioxan for 72 hours. The dioxan was then evaporated and the residue was dissolved in ethyl acetate (70 ml). This solution was washed sequentially with dilute potassium carbonate solution, dilute sodium hydroxide solution, and water dried (MgSO4) and evaporated to give an oil which crystallized on standing. Recrystallization from ethyl acetate/hexane gave the title compound 0.252 g (66%); m.p. 159°-161° C.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6]3=[C:7]([C:12]([C:14]4[C:15](=[O:29])[NH:16][C:17](=[O:28])[C:18]=4[C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][CH:20]=4)=[CH:13][N:5]3[CH2:4][CH2:3]1)[CH:8]=[CH:9][CH:10]=2.[Mg]>CO>[OH:1][CH:2]1[C:11]2[C:6]3=[C:7]([C:12]([C@H:14]4[C@H:18]([C:19]5[C:27]6[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=6)[NH:21][CH:20]=5)[C:17](=[O:28])[NH:16][C:15]4=[O:29])=[CH:13][N:5]3[CH2:4][CH2:3]1)[CH:8]=[CH:9][CH:10]=2
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)C(O)CC3)=C1c1c[nH]c2ccccc12
Agent: [Mg]
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)C(O)CC3)[C@@H]1c1c[nH]c2ccccc12
Temperature: 80 °C
Yield: 14.3 %

Procedure:
To a solution of 3-(6-hydroxy-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione (293 mg, 0.76 mmol) in anhydrous methanol (15 mL) in a 40 mL reaction vial was added magnesium turnings (300 mg, 15.2 mmol). The mixture was capped and heated at 80° C. in an oil bath. After 4 hr the reaction was cooled to room temperature and the methanol removed under reduced pressure. The mixture was diluted with dichloromethane (20 mL) and washed with 10% HCl (20 mL). The aqueous layer was extracted with dichloromethane (3×20 mL), washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel chromatography, eluting with a methanol/dichloromethane (1-5%) to afford (rac)-trans-3-(6-hydroxy-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione as a off-white solid (42 mg, 14%). Mp: 153-155° C.; 1H NMR (DMSO-d6) 400 MHz δ: 11.54 (bs, 1H), 11.04 (bs, 1H), 7.42-7.35 (m, 4H), 7.26 (d, J=7.8 Hz, 1H), 7.04-7.08 (m, 2H), 6.98-6.93 (m, 2H), 5.34 (brs, 1H), 4.88 (brs, 1H), 4.55 (d, J=6.6 Hz, 1H), 4.49 (d, J=6.6 Hz, 1H), 4.13 (s, 2H), 2.10 (s, 2H); LCMS [M+H]: 386.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=O)N.[NH2:10][C@H:11](C(O)=O)[CH2:12]C1C=CC=CC=1.N[C@H](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:12][CH2:11][NH2:10]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
Asn⇄Gln; and Phe⇄Trp⇄Tyr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[CH:7][C:6]2=[S:15].Br[C:17]1[S:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][N:21]=1.C(OCC)(=O)C.[OH-].[Na+]>CN(C)C=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:17]1[S:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][N:21]=1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: COc1cc2[nH]ccc(=S)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc2nccc(Sc3ncc([N+](=O)[O-])s3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
After suspending 6,7-dimethoxy-1H-quinoline-4-thione (2.21 g, 10.0 mmol) in dimethylformamide (30 ml), 2-bromo-5-nitrothiazole (2.30 g, 11.0 mmol) was added at 0° C., and then the mixture was stirred at room temperature for 1 hour. The reaction solution was distributed between ethyl acetate and 1N aqueous sodium hydroxide, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:hexane=3:1), and the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, after which the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (1.70 g, 4.87 mmol, 49%) as light yellow crystals.