Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]([CH3:17])=[CH:14][N:13]([CH2:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)([OH:21])[CH3:20])[CH:12]([CH3:30])[C:11]=3[N:10]=[N:9]2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]([CH3:17])[CH2:14][N:13]([CH2:18][C:19]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)([OH:21])[CH3:20])[CH:12]([CH3:30])[C:11]=3[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(C)(O)CN2C=C(C)c3c(nnn3-c3ccc(F)cc3)C2C)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(C(C)(O)CN2CC(C)c3c(nnn3-c3ccc(F)cc3)C2C)cc1
Temperature: 80 °C
Yield: 46.2 %

Procedure:
To a solution of the product of Example 238, Step 2 (200 mg, 0.49 mmol) in MeOH (2 mL) was added Pd/C (52 mg, 0.049 mmol) and ammonium formate (93 mg, 1.45 mmol). The reaction vessel was sealed and heated 80° C. for 16 h. The reaction mixture was then filtered through Celite, concentrated and purified on silica gel with 0-2% NH3 MeOH/CH2Cl2 to afford the title compound (93 mg, 46%). MS (ESI) mass calcd. C23H27FN4O2, 410.2. m/z found, 411.20 [M+H]+.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:16])[C:12]([CH3:15])([OH:14])[CH3:13])=[CH:9][N:10]=1.Cl.O.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:16][CH:11]([C:8]1[S:7][C:6]([CH:2]=[O:1])=[N:10][CH:9]=1)[C:12]([OH:14])([CH3:15])[CH3:13]
Reactant: CC(C)(O)C(O)c1cnc(C2OCCO2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)C(O)c1cnc(C=O)s1
Temperature: 60 °C
Reaction time: 6 h
Yield: 77.6 %

Procedure:
A mixture of 1-[2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]-2-methylpropane-1,2-diol (0.33 g), 1M hydrochloric acid (1 mL), water (2 mL) and tetrahydrofuran (6 mL) was stirred at 60° C. for 6 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (0.21 g, yield 77%) was obtained as a yellow oil from a fraction eluted with ethyl acetate. MS: 202 (MH+).
Reaction SMILES: [C:1]1([OH:9])[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[C:2]=1[OH:8].[C:10](=O)(O)[O-].[K+].CI>CC(C)=O>[CH3:10][O:8][C:2]1[C:3]([OH:7])=[CH:4][CH:5]=[CH:6][C:1]=1[OH:9]
Reactant: O=C([O-])O
Reactant: Oc1cccc(O)c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(O)cccc1O
Temperature: 25 °C
Yield: 27 %

Procedure:
To a stirring solution of benzene-1,2,3-triol (2 g, 15.87 mmol) in acetone was added potassium bicarbonate (1.90 g, 19.04 mmol) and methyl iodide (3.38 g, 23.80 mmol) and the resultant reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to RT and filtered through celite bed. The filtrate was concentrated under reduced pressure, triturated with diethyl ether and the obtained solid was separated and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (silica gel, 0-15% ethyl acetate in pet ether) afforded 2-Methoxybenzene-1,3-diol as a solid (600 mg, 27.2%). 4-Bromo-2-methoxybenzene-1,3-diol: To a stirring solution of 2-methoxybenzene-1,3-diol (3.0 g, 21.42 mmol) in tetrahydrofuran (30 mL) at −78° C. was added N-bromosuccinimide (4.57 g, 25.71 mmol) and the reaction mixture was stirred at −78° C. for 2 h. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained residue has mixture of products (mono and dibromo) which was used as such for further reactions (4.2 g).
Reaction SMILES: C([O:8][C:9](=[O:46])[C@H:10]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:11][C:12](=[O:38])[CH2:13][NH:14][C:15](=[O:37])[CH2:16][NH:17][C:18](=[O:36])[C@H:19]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])C1C=CC=CC=1.[H][H]>[Pd].CO>[C:24]([O:23][C:21]([NH:20][C@H:19]([C:18]([NH:17][CH2:16][C:15]([NH:14][CH2:13][C:12]([NH:11][C@H:10]([C:9]([OH:46])=[O:8])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:38])=[O:37])=[O:36])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
To a solution of 3.6 parts N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-phenylalanine benzyl ester in 160 parts methanol is added 0.4 part palladium black metal catalyst. The resulting mixture is shaken with hydrogen at room temperature at atmospheric pressure for about 5 hours. The catalyst is then removed by filtration, and the solvent removed by evaporation under reduced pressure. The resulting crude material is purified using low-pressure chromatography to afford N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-phenylalanine.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[N:6]=[C:7]([C:10]2[N:11](COCC[Si](C)(C)C)[CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]3[CH3:22])[S:8][CH:9]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>CN1C(=O)CCC1>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][O:3][CH2:4][C:5]2[N:6]=[C:7]([C:10]3[NH:11][CH:12]=[C:13]4[C:18]=3[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]4[CH3:22])[S:8][CH:9]=2)=[CH:35][CH:34]=1
Reactant: Cn1c(=O)c2c(-c3nc(CO)cs3)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(COCc2csc(-c3[nH]cc4c3c(=O)n(C)c(=O)n4C)n2)cc1
Reaction time: 1 h

Procedure:
Sodium hydride (60% wt, 0.637 g, 15.93 mmol) was added portionwise to a solution of 5-(4-(hydroxymethyl)thiazol-2-yl)-1,3-dimethyl-6-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 2) (4.43 g, 7.97 mmol) NMP (Volume: 44 ml) at 0° C. and stirred for 1 hour. para-Methoxybenzyl chloride (1.404 ml, 10.36 mmol) was added and the mixture stirred at room temperature for 5 hours. Further portions of para-methoxybenzyl chloride (220 μl) and sodium hydride (60% wt, 64 mg) were added and the mixture stirred for a further 16 hours. The reaction was quenched at 0° C. with saturated NaHCO3(aq) (50 ml), diluted with water (200 ml) and EtOAc (100 ml) and the phases separated. The aqueous phase was extracted with EtOAc (3×100 ml). The combined organic extracts were washed with water (2×100 ml) and brine (100 ml), dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 40-60% EtOAc/hexane afforded the title compound and 5-(4-(((4-methoxybenzyl)oxy)methyl)thiazol-2-yl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione as a mixture which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>Cl.CCOCC>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(O)cc1OC
Reactant: C1=COCCC1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(OC2CCCCO2)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4-Dimethoxyphenol (30.8 g) was added in small portions to a mixture of dihydropyran (29.2 ml) and conc. hydrochloric acid (3 drops) under nitrogen so that the temperature did not rise above 50° C. After the addition was complete the dark solution was stirred at room temperature for 3 hrs. and then diluted with ether. The resulting solution was washed with water, 2 N sodium hydroxide solution, water, dried (sodium sulphate) and evaporated to give 3,4-dimethoxyphenol tetrahydropyranyl ether.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][CH2:14]1.Br[CH2:21][CH2:22][CH2:23][Cl:24]>C1COCC1.C(OCC)C>[Cl:24][CH2:23][CH2:22][CH2:21][CH:16]([CH:13]1[CH2:15][CH2:14]1)[C:17]([OH:19])=[O:18]
Reactant: ClCCCBr
Reactant: O=C(O)CC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: O=C(O)C(CCCCl)C1CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (2.64 M solution in hexane, 3.8 ml) was added dropwise to a solution of diisopropylamine (1.5 ml) in THF (15 ml) at −30° C., and the reaction solution was stirred at the same temperature for 15 minutes. The reaction solution was cooled to −78° C. Then, a solution of cyclopropylacetic acid (CAS No. 5239-82-7, 500 mg) in THF (3 ml) was added dropwise and the reaction solution was further stirred at room temperature for three hours. The reaction solution was cooled to 0° C., and then 1-bromo-3-chloropropane (CAS No. 109-70-6, 0.55 ml) was added dropwise. The reaction solution was stirred at the same temperature for 10 minutes and at room temperature for further one hour. Ice water and diethyl ether were added to the reaction solution, and the aqueous layer was separated. Then, 5 N hydrochloric acid (3 ml) and ethyl acetate were added to the aqueous layer, and the organic layer was separated. The resulting ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain crude 5-chloro-2-cyclopropyl-valeric acid (550 mg).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C:24]1([CH:49]=[CH:48][C:47]([CH2:50][CH2:51][CH2:52][CH3:53])=[CH:46][CH2:45]1)[NH:25][C:26]1[C:39]2[C:38](=[O:40])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31](=[O:41])[C:30]=2[CH:29]=[CH:28][C:27]=1[C:42](O)=[O:43]>ClC1C=CC=CC=1Cl>[CH2:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:42]([C:27]2[CH:28]=[CH:29][C:30]3[C:31](=[O:41])[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:38](=[O:40])[C:39]=3[C:26]=2[NH:25][C:24]2([NH2:23])[CH:45]=[CH:46][C:47]([CH2:50][CH2:51][CH2:52][CH3:53])=[CH:48][CH2:49]2)=[O:43])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=CCC(N)(Nc2c(C(=O)O)ccc3c2C(=O)c2ccccc2C3=O)C=C1
Reactant: CCCC[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Product: CCCCC1=CCC(N)(Nc2c(C(=O)O[C@H]3CC[C@H](CCCC)CC3)ccc3c2C(=O)c2ccccc2C3=O)C=C1

Procedure:
To 200 ml of orthodichlorobenzene were added 31.6 g of trans-4-n-butylcyclohexanol, 5.6 g of p-toluenesulfonic acid, and 28 g of 1-amino-4-n-butylanilinoanthraquinone-2-carboxylic acid. The mixture was heated slowly to 110° to 115° C. and maintained at this temperature for 17 hours with stirring. The orthochlorobenzene solution was concentrated to 70 ml under reduced pressure, and 1500 ml of methanol was added. The resulting precipitates was filtered out and then purified by column chromatography wherein silica gel was used as a carrier and chloroform was used as a solvent to obtain 17.3 g of 1-amino-4-n-butylanilinoanthraquinone-2-carboxylic acid-trans-4-n-butylcyclohexyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([O:14]CC)=O)=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[S:5][C:6]=1[CH3:7].[OH-].[Na+].CC(O)=O>CCO>[CH3:1][C:2]1[C:3]2[C:12](=[O:14])[NH:11][C:9](=[S:10])[NH:8][C:4]=2[S:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)c1c(NC(N)=S)sc(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1sc2[nH]c(=S)[nH]c(=O)c2c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.2 %

Procedure:
To a suspension of ethyl 4,5-dimethyl-2-thioureidothiophene-3-carboxylate (Example 50a) (37 mg, 0.17 mmol) in dry EtOH (10 mL) was added sodium hydroxide (21 mg, 0.52 mmol). The reaction mixture was then stirred at room temperature for 5 minutes and refluxed for 10 minutes. The reaction mixture was cooled to room temperature, neutralized with 10% AcOH and then concentrated to dryness. The residue was purified by chromatography on silica gel (Gradient 0-50% EtOAc in Hexanes) to give the title compound (8 mg) in 24% yield. 1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 6H), 12.24 (s, 1H), 13.27 (s, 1H). MS 202 (MH+).
Reaction SMILES: [C:1]([O:10][CH:11]([CH3:13])[CH3:12])(=[O:9])[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>CN(C=O)C>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:2]([C:3]([O:5][CH:6]([CH3:7])[CH3:8])=[O:4])[C:1]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
A 250-mL round bottom flask was charged with diisopropyl malonate (2.09 g, 11.1 mmol) in DMF (24 mL). Sodium hydride (60% suspension, 0.44 g, 11.1 mmol) was slowly added to this solution at 0° C. After 15 minutes, a solution of 4-nitrobenzyl bromide (2.00 g, 9.26 mmol, 1.0 eq.) in DMF (24 mL) was added in one portion and then the reaction was stirred for 19 h. After this time, the reaction was warmed to rt. The reaction was quenched with 2N HCl then diluted in water (300 mL) and extracted with methyl tert-butylether (3×50 mL). The combined extract was washed with saturated sodium chloride (2×25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with 9:1 hexanes/ethyl acetate to afford the title compound (2.02 g, 67%) as a colorless oil. MW=323.34. 1H NMR (DMSO-d6, 500 MHz) δ 8.15 (d, J=10.0 Hz, 2H), 7.53 (d, J=9.0 Hz, 2H), 4.88 (septet, J=6.5 Hz, 2H), 3.89 (t, J=8.5 Hz, 1H), 3.19 (d, J=8.5 Hz, 2H), 1.14 (d, J=6.5 Hz, 6H), 1.11 (d, J=6.5 Hz, 6H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].[OH:27][CH:28]([CH3:34])[CH2:29][CH2:30][CH2:31][C:32]#[CH:33].[B]1OC2C(=CC=CC=2)O1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH:33]=[CH:32][CH2:31][CH2:30][CH2:29][CH:28]([OH:27])[CH3:34])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C#CCCCC(C)O
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [B]1Oc2ccccc2O1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCOc1cnc(-c2ccc(C=CCCCC(C)O)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a reactor equipped with a stirrer and a thermometer, 5-decyloxy-2-(4-bromophenyl)pyrimidine (13.98 g), dry tetrahydrofuran (THF) (30 ml), tetrakis(triphenylphosphine)palladium (0.11 g) and sodium hydroxide (1.2 g) are charged. To the mixture, a solution of a reaction product of 6-hydroxy-1-heptyne and catechol borane (5 g) dissolved in THF (12 ml) is dropwise added, followed by heating up to a refluxing temperatur. After reacting for 4 hours, the reaction mixture is cooled to room temperature. To the mixture, toluene and water are added for extraction, and the organic layer is washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. A resulting residue is purified by silica gel column chromatography (eluent: toluene-ethyl acetate) to obtain (-)-5-decyloxy-2-[4-(6-hydroxyheptenyl)phenyl]pyrimidine (7.99 g).
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:3]=1[CH2:4][O:5][C@H:6]1[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[C@@H:17]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])[S:16][CH:7]1SCC1C=CC=CC=1.[C:45]([OH:48])(=[O:47])[CH3:46]>C(Cl)Cl>[Cl:1][C:2]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:3]=1[CH2:4][O:5][C@H:6]1[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[C@@H:17]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])[S:16][CH:7]1[O:47][C:45](=[O:48])[CH3:46]
Reactant: Clc1ccc(COC[C@H]2SC(SCc3ccccc3)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@H]2OCc2ccc(Cl)cc2Cl)c(Cl)c1
Reactant: CC(=O)O
Solvent: ClCCl
Product: CC(=O)OC1S[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@H]1OCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of mercuric acetate in acetic acid is added compound 1-4 from Step D and the resulting reaction mixture is stirred at room temperature for 2-3 h. The mixture is then diluted with CH2Cl2, washed with water, saturated aqueous sodium bicarbonate and 5% KCN solution. The organic layer is dried over anhydrous sodium sulfate, filtered, and evaporated. The residue is purified on a silica gel column using a mixture of cyclohexane and ethyl acetate as eluent. The appropriate fractions are combined and concentrated to give the title compound 1-5.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1.Br[C:50]1[CH:51]=[C:52]2[C:57](=[CH:58][CH:59]=1)[N:56]=[CH:55][CH:54]=[C:53]2[O:60][C:61]1[CH:66]=[CH:65][C:64]([NH:67][C:68]2[C:77]3[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=3)[C:71]([C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)=[N:70][N:69]=2)=[CH:63][CH:62]=1.[C:84]([NH2:87])(=[O:86])[CH3:85].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:78]1([C:71]2[C:72]3[C:77](=[CH:76][CH:75]=[CH:74][CH:73]=3)[C:68]([NH:67][C:64]3[CH:65]=[CH:66][C:61]([O:60][C:53]4[C:52]5[C:57](=[CH:58][CH:59]=[C:50]([NH:87][C:84](=[O:86])[CH3:85])[CH:51]=5)[N:56]=[CH:55][CH:54]=4)=[CH:62][CH:63]=3)=[N:69][N:70]=2)[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: Brc1ccc2nccc(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)c2c1
Reactant: CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2nccc(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)c2c1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared according to a method described in Garnier, E.; Andoux, J.; Pasquinet, E.; Suzenet, F.; Poullain, D.; Lebret, B.; Guillaumet, G. J. Org. Chem. 2004, 69, 7809. Xantphos (22 mg, 39 μmol) and 1,4-Dioxane (963 μl, 193 μmol) were added into a sealed tube. The tube was purged with argon, Palladium(II) acetate (4 mg, 19 μmol) was added, and the mixture was stirred under argon for 10 min. In a separate sealed tube, N-(4-(6-bromoquinolin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine (100 mg, 193 μmol), acetamide (57 mg, 963 μmol), potassium carbonate (798 mg, 5776 μmol), and 1,4-dioxane (963 μl, 193 μmol) were added. Then the Pd(OAc)2/Xantphos solution from the first tube was added with via syringe to the second tube. The resulting mixture was heated to 110° C. under an argon atmosphere with vigorous stirring until the halide disappeared. After 16 h, LCMS showed product at 1.324 as [M+H]+=498. The reaction was cooled to rt, quenched with water, extracted with CH2Cl2. The organic portions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The product was purified by RPLC on the acidic Gilson workstation. To provide N-(4-(4-(4-phenylphthalazin-1-ylamino)phenoxy)quinolin-6-yl)acetamide. MS Calcd for C31H23N5O2: [M]+=497. Found: [M+H]+=498.
Reaction SMILES: S(O)(O)(=O)=O.[C:6](=[NH:10])([O:8][CH3:9])[NH2:7].C[O-].[Na+].[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([C:34](=O)[CH2:35][CH2:36][CH2:37][CH3:38])[C:30](OC)=[O:31])=[CH:24][CH:23]=1)#[N:15]>CO>[CH2:35]([C:34]1[N:10]=[C:6]([O:8][CH3:9])[NH:7][C:30](=[O:31])[C:29]=1[CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:17]2[C:16]([C:14]#[N:15])=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:27][CH:26]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: COC(=N)N
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(OC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 37.2 %

Procedure:
A solution of methyl imidocarbamate sulfate (10 g), 28% sodium methoxide (29 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (9.8 g) in methanol (100 mL) was stirred at 70° C. overnight. The solvent was evaporated under reduced pressure, and water and acetic acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (3.9 g, 37%) as a pale-yellow solid.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11](=[O:45])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]2[O:33][CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)=[CH:16][CH:15]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>C[Si](C)(C)N[Si](C)(C)C.O1CCCC1>[CH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[CH:44][C:35]=1[CH2:34][O:33][CH:21]1[CH:20]([C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:11]3[O:45][C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:9][N:10]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCC(=O)NNC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCc3nnc(-c4ccccc4)o3)cc2)C(OCc2ccc3ccccc3c2)C1
Yield: 68.2 %

Procedure:
A solution of 106 mg (0.174 mmol) of tert-butyl (3RS,4RS)-4-[4-[3-(N'-benzoyl-hydrazino)-3-oxo-propyl]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 1.5 ml of hexamethyldisilazane was treated with 39 μl (0.039 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran and heated to reflux for 20 hours. For the working-up, the reaction mixture was treated with 50 ml of a 1:1 mixture of methylene chloride and water, the organic phase was subsequently separated and the aqueous phase was back-extracted twice with 25 ml of methylene chloride each time. The combined organic phases were dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel with a 7:3 mixture of hexane and ethyl acetate as the eluent. There were obtained 70 mg (68% of theory) of tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[2-(5-phenyl-[1,3,4]oxadiazol-2-yl)-ethyl]-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 590 (M+H)+.