Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(OC(C)C)(C)C.C([Li])CCC.COB(OC)OC.Br[C:34]([C:36]([F:39])([F:38])[F:37])=[CH2:35].C(=O)([O-])[O-].[K+].[K+]>CCCCCC.O1CCCC1.CC(C1C=CC=C(C(C)C)C=1N1C(=[Pd])N(C2C(C(C)C)=CC=CC=2C(C)C)C=C1)C.CC(C1C=CC=C(C(C)C)C=1N1C(=[Pd])N(C2C(C(C)C)=CC=CC=2C(C)C)C=C1)C.C1C=C2C(C(C=CC2=O)=O)=CC=1.C1C=C2C(C(C=CC2=O)=O)=CC=1.C(OCC)(=O)C.O>[Cl:13][C:4]1[CH:3]=[C:2]([C:34]([C:36]([F:39])([F:38])[F:37])=[CH2:35])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]=1[Cl:12]
Reactant: C=C(Br)C(F)(F)F
Reactant: FC(F)(F)c1cc(Br)cc(Cl)c1Cl
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd]
Agent: COB(OC)OC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: C=C(c1cc(Cl)c(Cl)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a stirred solution of 5-bromo-2,3-dichlorobenzotrifluoride (26.2 g) and diisopropyl ether (9.1 g) in hexane (250 mL) at −10° C. was added dropwise 1.55M n-butyllithium in hexane (57.5 mL). After stirring at same temperature for 0.5 hour, trimethoxyborane (9.26 g) in tetrahydrofuran (30 mL) was added dropwise. After a further 10 minutes, water (150 mL), 2-bromo-3,3,3-trifluoropropene (23.4 g), potassium carbonate (36.9 g) and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium(0) dimer (0.131 g) were added to the reaction mixture, which was stirred at 60° C. for 4 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice-water (50 mL) and ethyl acetate (75 mL) and filtered. The filtrate was separated, and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with hexane to afford the title compound as a colorless oil (21.8 g).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([NH:14][NH2:15])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:17](N)(=[NH:19])[CH3:18].[OH-].[Na+].O>C1COCC1>[CH3:18][C:17]1[NH:15][N:14]=[C:12]([C:10]2[O:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[N:19]=1
Reactant: NNC(=O)c1ccc(-c2ccccc2)o1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(-c3ccccc3)o2)n[nH]1
Yield: 13.3 %

Procedure:
To a suspension of 5-phenylfuran-2-carbohydrazide (100 mg, 0.5 mmol) and acetamidine hydrochloride (141 mg, 1.49 mmol) in THF (20 mL), NaOH (59 mg, 1.49 mmol) was added. The mixture was refluxed overnight, cooled, then treated with H2O (30 ml) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with H2O (1×10 mL) and brine (1×10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc:Petroleum ether=1:1) to afford 5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazole as a white solid (15 mg, 13%). MS (ES+) C13H11N3O requires: 225. found: 226 [M+H]+.
Reaction SMILES: [Cl-].[CH2:2]([Si@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][Zn+])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4].[F:20][C:21]1[C:26]([F:27])=[C:25]([O:28][CH2:29][CH2:30]I)[CH:24]=[CH:23][CH:22]=1>[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.O1CCCC1>[CH2:2]([Si@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[C:26]([F:27])[C:21]=3[F:20])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4]
Reactant: CCC[Si@H]1CC[C@H](c2ccc(CC[Zn+])cc2)CC1
Reactant: Fc1cccc(OCCI)c1F
Agent: [Pd]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](c2ccc(C#Cc3ccc(OCC)c(F)c3F)cc2)CC1

Procedure:
10.0 ml (10.0 mmol) of a tetrahydrofuran solution of 1.0M 4-(trans-4-n-propyl-4-silacyclohexyl) phenylethyl zinc chloride was dripped into a mixture of 4.20 g (14.8 mmol) of 2,3-difluoro-4-iodoethoxybenzene, 70 mg of tetrakis (triphenylphosphine) palladium (0) and 15 ml of tetrahydrofuran. The reaction mixture was reacted for 2 hours at 50° C. After a conventional after treatment, purification was conducted by means of silica-gel column chromatography to obtain 3.25 g (yield 88%) of the target product.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:30]=2[N:31]=[CH:32][N:33]=1)[C@@H:15]1[O:29][C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]1[CH:57]=[CH:56][C:39]([C:40](Cl)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:30]=2[N:31]=[CH:32][N:33]=1)[C@@H:15]1[O:29][C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23])[C@@H:17]([O:18][C:40]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:39]2[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:57][CH:56]=2)[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(O[C@H]2C[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)O[C@@H]2CO[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 45 °C
Yield: 63.1 %

Procedure:
N6-bezoyl-5′-O-(tert-butyldimethylsilyl)-2′-deoxyadenosine (16.1 g) was dissolved in 100 ml of anhydrous pyridine. 4,4′-dimethoxytrityl chloride (12.8 g) and anhydrous pyridine (140 ml) were further added, follow by stirring at 45° C. After the reaction completed, the reaction mixture was neutralized by sodium hydrogen carbonate, and pyridine was distilled off. Extraction using chloroform was carried out and the extract was washed by a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. The extract was concentrated and then purified by column chromatography (ethyl acetate/hexane) to obtain 16.7 g of the titled compound (yield: 63%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([C:31]5[CH:32]=[CH:33][C:28]([C:37]6[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=6)=[CH:29][CH:30]=5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound, white solid (117 mg, 92%), MS (ISP) m/z=511.6 [(M+H)+], mp 220.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and biphenyl-4-carboxylic acid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[CH3:31][N:32]1[C:37]([CH3:38])=[CH:36][C:35](=[O:39])[C:34]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:33]1[CH2:48]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:31][N:32]1[C:37]([CH3:38])=[CH:36][C:35](=[O:39])[C:34]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:33]1[CH2:48][N:24]1[C:20](=[O:30])[C:21]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:22]2[C:23]1=[O:25]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)n1C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(=O)c(OCc2ccccc2)c(CN2C(=O)c3ccccc3C2=O)n1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.6 %

Procedure:
8.6 g triphenylphosphine (32 mmol, 1.2 equiv) and 4.8 g phthalimide (32 mmol, 1.2 equiv) were added to a stirred suspension of 58 (7 g, 27 mmol, 1 equiv) in 150 ml THF at 0° C. 6.47 g Diisopropyl azodicarboxylate [DIAD] (32 mmol, 1.2 equiv) was added dropwise over 30 minutes. The solution was allowed to warm to room temperature and was stirred for a further 17 hours, after which time the solution was filtered. The solid was washed with cold THF to give 9.92 g of a white amorphous solid in 95% yield.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>C(Cl)(Cl)Cl.CO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:10]=1
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Reactant: NCc1ccccn1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Fc1nc(NCc2ccccn2)c2nc[nH]c2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a stirred solution of 6-chloro-2-fluoro-9H-purine (prepared according to Gray, N. S.; Kwon, S.; Schultz, P. G. Tetrahedron Lett 1997, 38, 1161-1164; 0.4 g, 2.31 mmol) in BunOH (25 mL) under Ar, cooled to 0° C., was added Pri2NEt (1.13 mL, 6.49 mmol) followed by 2-(aminomethyl)pyridine (0.48 mL, 4.66 mmol). The reaction mixture was stirred at 0° C. for 3 h, and then allowed to return to RT over 30 min. and stirred at this temperature for 1 h, when TLC (9:1 CHCl3/MeOH) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between citric acid solution (200 mL, 10% aq) and EtOAc (200 mL), the aqueous phase was separated and extracted with more EtOAc (2×100 mL). The pH of the aqueous phase was adjusted to 7.0 with NaOH solution (50% w/v, aq), extracted with EtOAc (4×100 mL), and the bulked organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel, eluted with CHCl3/MeOH (95:5→85:15), to afford the title compound as a light yellow solid (0.40 g, 71%). Mp 217-220° C. 1H-NMR (d6-DMSO, 250 MHz): δ 4.58 (d, 2H, J=5.68 Hz, —HNCH2-Pyr), 7.29, 7.71, 8.49 (3×m, 4H, Pyr), 8.10 (s, 1H, —N═CH—NH—), 8.69 (bs, 1H, —HNCH2-Pyr), 13.07 (bs, 1H, —N═CH—NH—). FAB-MS m/z (relative intensity): 245 ([M+H]+, 55), 176 (30), 154 (100), 136 (85). Accurate Mass (M+H): Actual: 245.0951, Measured: 245.0942. Microanalysis (Expected:Measured) C11H9N6F.0.4H2O: C, 52.55:52.91; H, 3.93:3.49; N, 33.42:33.26.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]([OH:27])([CH3:26])[CH3:25])[N:18]=[C:17]2[CH2:28][CH2:29][CH3:30])=[CH:11][CH:10]=1)#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C.[OH-].[Na+]>O.C1(C)C=CC=CC=1>[OH:27][C:24]([C:19]1[N:18]=[C:17]([CH2:28][CH2:29][CH3:30])[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:33][N:32]=[N:31][N:2]=3)=[CH:14][CH:13]=2)[C:20]=1[C:21]([OH:23])=[O:22])([CH3:25])[CH3:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
Into a 500-ml flask equipped with a reflux condenser, thermometer and stirrer were placed 43.5 g (0.10 mole) of ethyl ester of 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid, 19.5 g (0.30 mole) of sodium azide, 41.3 g (0.30 mole) of triethylamine hydrochloride and 206 ml of toluene. The mixture was heated with stirring to a temperature of 95° to 100° C. to undergo a reaction for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Then, 35.0 g (0.42 mole) of a 48 wt % aqueous solution of NaOH and 335 ml of water were added. The mixture was fractionated after 2 hours' stirring at room temperature. The aqueous layer was washed and fractionated with the addition of 103 ml of toluene. The aqueous layer was adjusted to a pH of 2 to 3.5 with 36 wt % hydrochloric acid to separate out crystals, which were collected by filtration and dried. The crystals were heated, washed with methanol with stirring, cooled, filtered for collection and dried, giving 32.6 g (0.07 mole) of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid (yield 72.4% based on ethyl ester of 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid). The reaction is illustrated below with chemical formulas. ##STR29##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(N3CCC(c4ccc(OC)cc4)CC3)c(-c3ccc(F)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C2CCN(c3nc4ccc(C(=O)O)cc4nc3-c3ccc(F)cc3)CC2)cc1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-fluorophenyl)-2-(4-(4-methoxyphenyl)piperidin-1-yl)quinoxaline-6-carboxylate (123.9 mg, 0.24 mmol, 1.00 equiv, 93%) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (52.6 mg, 1.31 mmol, 5.00 equiv) in water (3 mL), which was added dropwise with stirring. The resulting solution was stirred for overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 60 mg (52%) of 3-(4-fluorophenyl)-2-(4-(4-methoxyphenyl)piperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[C:21]=1[O:22][CH3:23])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])=[O:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:31].CC(=CC)C.Cl([O-])=O.[Na+]>CO>[O:18]=[S:10]1(=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([C:6]([C:5]2[CH:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[C:21]([O:22][CH3:23])=[C:3]([CH:4]=2)[C:1]([OH:31])=[O:2])=[O:7])[CH2:9]1
Reactant: COc1c(C=O)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C(F)(F)F
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CO
Product: COc1c(C(=O)O)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(3-formyl-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (248 mg) was dissolved in methanol (2.5 mL) and an aqueous 10% citric acid solution (2.5 mL), and 2-methyl-2-butene (0.33 mL) and sodium chlorite (84 mg) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% sodium thiosulfate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (277 mg) as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[NH2:4])[CH3:2].C1C=CC=CC=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:5][CH3:6])[NH:4][C:13](=[O:15])[CH3:14])[CH3:2]
Reactant: CCN(N)CC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCN(CC)NC(C)=O

Procedure:
N',N'-diethylacethydrazide was prepared following essentially the teaching of Hinman and Fulton, J. Amer. Chem. Soc. 80, 1895-1900 (1958). A mixture of 8.2 g (0.094 mole) of freshly distilled N,N-diethylhydrazine and 75 ml of benzene was added to a three-necked 250-ml round bottom flask equipped with a stirrer, a thermometer and a pressure equilibrating addition funnel capped with a drying tube. The flask was cooled in an ice bath. To this stirred solution was added 12.3 g (0.12 mole) of acetic anhydride. The ice bath was removed and the reaction mixture was heated for 1 hr. at 48°-58°. A fractional distillation of the reaction mixture gave a cut, b.p. 83°-84° at 3 mm, which melted at 47.5°-49.5°. NMR (CCl4, TMS) τ 1.0 (3 H, t), 1.9 (3 H, s), 2.6 (2 H, quad), 8.5 (1 H, broad).
Reaction SMILES: Br[C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:13])=[C:8]([OH:23])[C:7]2[CH2:24][N:25]([C:27]([C:29]3[N:30]=[CH:31][S:32][CH:33]=3)=[O:28])[CH2:26][C:6]1=2.[CH3:38][N:39](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:38]([C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:13])=[C:8]([OH:23])[C:7]2[CH2:24][N:25]([C:27]([C:29]3[N:30]=[CH:31][S:32][CH:33]=3)=[O:28])[CH2:26][C:6]1=2)#[N:39]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccccc3Br)c1=O)CN(C(=O)c1cscn1)C2
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccccc3C#N)c1=O)CN(C(=O)c1cscn1)C2
Temperature: 110 °C

Procedure:
tert-Butyl N-{[1-(2-bromobenzyl)-4-hydroxy-2-oxo-6-(1,3-thiazol-4-ylcarbonyl)-2,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridin-3-yl]carbonyl}glycinate (0.2 g, 0.34 mmol, prepared in similar fashion to Intermediate 5) was dissolved in DMF (4 mL) and water (0.04 mL). Zn(CN)2 (40 mg, 0.34 mmol), dppf (24.8 mg, 0.045 mmol) and Pd2(dba)3 (17 mg, 0.019 mmol) were added and the flask was evacuated and backfilled with nitrogen 3 times. The mixture was heated at 110° C. overnight. The reaction was cooled and partitioned between EtOAc and 2 M HCl, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane affording the product.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:18][C:19]1[C:5]2[C:3](=[C:2]([I:1])[CH:8]=[C:7]([CH2:9][CH:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[CH:6]=2)[N:4]=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Nc1ccc(CC2CCOCC2)cc1I
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Temperature: 130 °C
Yield: 58 %

Procedure:
A mixture of 2-iodo-4-(tetrahydro-2H-pyran-4-ylmethyl)aniline (1.0 g) and diethyl ethoxymethylenemalonate (0.70 mL) is heated to 130° C. for 1 h. The mixture is cooled to room temperature. Diphenyl ether (20 mL) is added and the reaction is heated to 250° C. for 1 h. The mixture is cooled and the resulting solid is collected and washed with hexanes. The crude product is chromatographed (Biotage flash 40M, eluant 2% MeOH/CH2Cl2) to yield 0.80 g (58%) of ethyl 4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxylate as a solid, m.p. 218-222° C. (dec).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][C:10]([CH2:17][CH2:18][S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(C(O)=O)[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C>[C:20]1([S:19][CH2:18][CH2:17][CH:10]([CH2:9][CH2:8][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]([OH:13])=[O:12])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)C(CCSc1ccccc1)(CCSc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)C(CCSc1ccccc1)CCSc1ccccc1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
2,2-Bis-(2-phenylsulfanyl-ethyl)-malonic acid (5.628 g) was heated at 150° C. for 30 minutes. The reaction mixture was cooled to room temperature, dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. The ethyl acetate solution was washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane to give 4-phenylsulfanyl-2-(2-phenylsulfanyl-ethyl)-butyric acid (1.831 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].C(=O)([O-])[O-:9].[K+].[K+].[CH3:14][C@@:15]12[C@H:25]3[C@@H:26]([OH:39])[CH2:27][C@:28]4([CH3:38])[C@@:32]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:31][CH2:30][C@H:29]4[C@@H:24]3[CH2:23][CH2:22][C:21]1=[CH:20][C:18](=[O:19])[CH2:17][CH2:16]2>C(Cl)(Cl)Cl>[CH3:14][C@@:15]12[C@H:25]3[C@@H:26]([OH:39])[CH2:27][C@:28]4([CH3:38])[C@@:32]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:31][CH2:30][C@H:29]4[C@@H:24]3[CH2:23][CH2:22][C:21]1=[CH:20][C:18](=[O:19])[CH2:17][CH2:16]2.[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O-:6])=[O:9]
Reactant: O=C(Cl)CCCBr
Reactant: O=C([O-])[O-]
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C([O-])CCCBr
Reaction time: 120 h

Procedure:
Five portions of 4-bromobutanoylchloride (0.35 ml×5) and potassium carbonate (0.4 g×5) were added in 24 hours to a solution of hydrocortisone (1 g) in CHCl3 dried over P2O5 and stirred for 5 days. The solution was treated with water, the organic phase was separated, dried (Na2SO4) and deprived of the solvent at reduced pressure.