Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Yield: 91.1 %

Procedure:
A solution of 4-(3-fluoro-4-methoxy-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester (4.7 g, 14.6 mmol) in methanol (400 mL) was allowed to stir under atmospheric pressure of hydrogen at room temperature in the presence of 10% palladium on carbon (0.8 g) for 16 hours. Removal of the catalyst by filtration and evaporation of the filtrate gave a crude oil. Silica gel chromatography eluting with ethyl acetate in hexane (10%) gave the title compound (4.3 g, 99%) as a colourless oil.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1NC(=O)CCC(=O)O
Temperature: 25 °C

Procedure:
A mixture of 4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylamine (100 mg, 0.304 mmol), succinic anhydride 31 mg, 0.304 mmol) and triethylamine in methylene chloride was stirred at rt. overnight. The mixture was quenched with water, and extracted with methylene chloride. The organic layer was separated, dried and concentrated to give a solid. The title compound was isolated as a white crystal after silica gel column chromatography.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=2[CH3:35])=[O:22])[CH:17]=[CH:18][CH:19]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43]([N:47]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[N:42][CH:41]=[CH:40]2.O.[C:63]([OH:67])(=[O:66])[CH:64]=O>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:64]([NH:36][C:37]3[CH:38]=[C:39]4[C:44](=[CH:45][CH:46]=3)[C:43]([N:47]([C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[N:42][CH:41]=[CH:40]4)[C:63]([OH:67])=[O:66])=[CH:28][C:27]=2[CH3:35])=[O:22])[CH:17]=[CH:18][CH:19]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc([C@H](C)NC(=O)OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: O=CC(=O)O
Solvent: O
Product: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)ccc1CCOC(=O)Nc1cccc([C@H](C)NC(=O)OCc2ccccc2)c1
Yield: 63 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 59D (280 mg, 0.588 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 59E (313 mg, 63%) as an oil. MS (ESI) m/z 848.7 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:11]3=[N:13][N:14]=[N:15][N:10]3[C:9](=[O:16])[N:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]=2[N:6]=[CH:5]1)C=C.N1CCOCC1.N#N.Cl>C1COCC1.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.C(Cl)Cl>[CH2:17]([N:8]1[C:7]2[N:6]=[CH:5][NH:4][C:12]=2[C:11]2=[N:13][N:14]=[N:15][N:10]2[C:9]1=[O:16])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C=CCn1cnc2c1c1nnnn1c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n2nnnc2c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
A mixture of 9-allyl-6-pentyl-6,9-dihydro-5H-tetrazolo[5,1-i]purin-5-one (0.10 g, 0.35 mmol) and morpholine (0.2 mL, 2.0 mmol) in THF (3 mL) was degassed for 5 min using N2 and tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.086 mmol) was added to the mixture. After being stirred at room temperature overnight, the reaction mixture was mixed with 2 M HCl aqueous solution and DCM. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified using preparative LCMS to provide the product as a white powder (0.030 g, 35%). LCMS calculated for C10H14N7O (M+H): 248.0; found: 248.0.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[CH2:47]([O:49][C:50]([CH2:52][N:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=[C:54]1[C:62](Cl)=[O:63])=[O:51])[CH3:48].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:62]([C:54]1[N:53]([CH2:52][C:50]([O:49][CH2:47][CH3:48])=[O:51])[C:61]2[C:56]([CH:55]=1)=[CH:57][CH:58]=[CH:59][CH:60]=2)=[O:63])=[O:43]
Reactant: CCOC(=O)Cn1c(C(=O)Cl)cc2ccccc21
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C(=O)NCc2nnc(C)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (7.4 g) was dissolved in dimethylformamide (70 ml). 1-Ethoxycarbonylmethylindole-2-carbonyl chloride (3.03 g) and triethylamine (7.0 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 8 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was crystallized from ethanol to give 4.33 g of ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1([NH:15]C2C=CC=CC=2)C=CC=CC=1.[S-]C#N.BrBr>>[NH2:15][C:9]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1S
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: BrBr
Agent: N#C[S-]
Product: Nc1nc2ccccc2s1

Procedure:
If the desired 2-amino benzenethiol 8-scheme 3 is not commercially available it can be synthesized by reaction of the phenyl aniline with the thiocyanate anion in the presence of an oxidant(like bromine) to produce the 2-amino benzthiazole 7-scheme 3. This thiazole can then be hydrolyzed to the desired 2-amino benzenethiol 8-scheme 3 with a strong base like NaOH in a protic solvent (i.e., EtOH). ##STR11##
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][C:13]([N:15]1[CH2:23][C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16]1)=[O:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:25]>C(O)C>[OH2:10].[CH2:1]([C@@H:8]([CH2:12][C:13]([N:15]1[CH2:16][C@H:17]2[C@H:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:23]1)=[O:14])[C:9]([O-:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:25]
Reactant: O=C(O)[C@H](CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O
Product: O=C([O-])[C@H](CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1

Procedure:
To a solution of (S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid (1.38 g) in ethanol (5 ml) was added 2N sodium hydroxide solution (2.19 ml). After the solvent was evaporated under reduced pressure, the residue was crystallized from ethyl acetate to give 1.44 g of sodium (S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate monohydrate.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.CO.[C].[Pd]>[ClH:1].[NH:9]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: O=C1CCN(Cc2ccccc2)CCN1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: O=C1CCNCCN1
Yield: 96 %

Procedure:
1M HCl in ethanol (7.2 mL) and 10% palladium-carbon (0.34 g) were added to 1-benzylhexahydro-1H-1,4-diazepin-5-one (1.490 g) in methanol (10 mL) at room temperature, and the resultant mixture was stirred in a hydrogen atmosphere for 4 hours. After the reaction atmosphere was purged with nitrogen, insoluble matter was removed by filtration. The solvent of the filtrate was evaporated under reduced pressure, and diethyl ether was added to the residue, and then the precipitated solid was recovered by filtration, to thereby give the title compound (1.045 g, 96%).
Reaction SMILES: [C@@H:1]1([C:10]2[C:11](=[O:17])[NH:12][CH:13]=[C:14](I)[CH:15]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(N(CC)CC)C.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C=O)C.[Cu]I.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>[C@@H:1]1([C:10]2[C:11](=[O:17])[NH:12][CH:13]=[C:14]([C:32]#[C:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:15]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: C#Cc1ccccc1
Reactant: O=c1[nH]cc(I)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=c1[nH]cc(C#Cc2ccccc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.7 %

Procedure:
3-(β-D-Ribofuranosyl)-5-iodopyridin-2(1H)-one prepared in Example 1(1) (71 mg, 0.20 mmol) was dissolved in DMF (1.0 ml), followed by addition of CuI (6 mg, 0.032 mmol), triethylamine (42 μl, 0.30 mmol), phenylacetylene (33 μl, 0.30 mmol) and Pd(Ph3P)4 (11 mg, 0.010 mol). The reaction mixture was stirred under an argon atmosphere at room temperature for 6 hours. After addition of ethyl acetate (10 ml), the reaction mixture was extracted three times with water (10 ml each). The combined aqueous layers were concentrated under reduced pressure and then purified by reversed-phase HPLC to give 3-(β-D-ribofuranosyl)-5-(2-phenylethynyl)-pyridin-2(1H)-one (60 mg, 92%) as a white product.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]2[CH2:22][CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)=[O:17])=[CH:11][CH:10]=1>O1CCOCC1>[ClH:1].[O:2]=[C:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([CH:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)=[O:17])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)C1CCCN1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.1 0.8 g (5.2 mmol) of 1-hydroxybenzotriazole hydrate, 1.12 g (5.2 mmol) of D-Boc-proline, 2 g (10.4 mmol) of N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) and 1.26 ml of N-methylmorpholine are added successively to a solution of 1.0 g (5.2 mmol) of 4-(4-aminophenyl)morpholin-3-one in 25 ml of dimethylformamide, and the resultant solution is stirred at room temperature for 12 hours. The reaction solution is subsequently evaporated to dryness under reduced pressure, the residue is taken up in 10 ml of 5% sodium hydrogencarbonate solution, and the sodium hydrogencarbonate solution is extracted twice with 10 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the solid residue is triturated with 20 ml of diethyl ether, giving 1.4 g of tert-butyl 2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as a white powder; ESI 390. 1.2 40 ml of 4N hydrochloric acid in dioxane are added to a solution of 1.4 g (3.60 mmol) of tert-butyl 2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate in 20 ml of dioxane, and the mixture is stirred at room temperature for 12 hours. The precipitate is subsequently filtered off with suction and washed successively with 10 ml of dioxane and 10 ml of diethyl ether and dried under reduced pressure, giving 1.1 g of N-[4-(3-oxomorpholin-4-yl)phenyl]pyrrolidine-2-carboxamide hydrochloride as a white powder; ESI 290. 1.3 95 mg (0.61 mmol) of 4-chlorophenyl isocyanate are added to a solution of 200 mg (0.61 mmol) of N-(4-(3-oxomorpholin-4-yl)phenyl]pyrrolidine-2-carboxamide hydrochloride and 1 ml of triethylamine in 5 ml of methylene chloride, and the reaction solution is stirred at room temperature for two hours. The reaction solution is subsequently washed with 5 ml of 1N hydrochloric acid and 5 ml of water, and the methylene chloride solution is dried over sodium sulfate. After the solvent has been stripped off under reduced pressure, the crude product is recrystallised from ethanol/diethyl ether, giving 120 mg of the title compound (“A1”) as a white powder; ESI 443; m.p. 227.6°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:13]#N)[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C1C=CC(C2(C=[O:29])CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:13]=[O:29])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: N#CC1(c2cccc(Cl)c2)CCCC1
Product: O=CC1(c2cccc(Cl)c2)CCCC1

Procedure:
1-(3-Chlorophenyl)cyclopentanecarbaldehyde (495) was synthesized from 1-(3-chlorophenyl)cyclopentanecarbonitrile (494) following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbaldehyde (238).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: COc1ccc(N)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2ccccc2N)cc1
Yield: 72.9 %

Procedure:
A mixture of isatoic anhydride (4.894 g, 30 mmol), 4-methoxyaniline (3.695 g, 30 mmol) and toluene (60 mL) was heated to reflux for 5 h. After cooling, the reaction was filtered. The solid was triturated with CH2Cl2 (500 mL) This supernatant was combined with the above filtrate and concentrate. The residue was dissolved in CH2Cl2, decolorized with activated charcoal and crystallized from CH2Cl2/hexanes to give the title compound as a white solid (5.3 g, 73%); mp 116-7 C; MS(FD): 242.
Reaction SMILES: CO.Cl.[N+:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[CH2:16][C:17]([OH:19])=O)([O-])=O.[H][H]>CCO.[Pd]>[NH2:13][C:11]1[CH:12]=[C:7]2[C:8]([CH2:16][C:17](=[O:19])[NH:4]2)=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Nc1ccc2c(c1)NC(=O)C2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Methanol (15 mL) and 1.25 M HCl in EtOH (10 ml) was added to 2,4-dinitrophenylacetic acid (837 mg, 3.7 mmol) and Pd/C (10%; 205 mg) under Argon. The argon balloon was replaced with a hydrogen balloon and it was stirred at RT for 12 h and at 50° C. for 24 h. It was cooled to RT and filtered through celite. The solvent was removed and the residue was purified by silica gel chromatography (DCM/methanol gradient) to give the title compound as a red solid.
Reaction SMILES: C([O-])(=O)C.[OH:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8].C(O[C:53]([CH2:56][CH3:57])([CH3:55])[CH3:54])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl>[CH3:54][C:53]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH2:56][CH3:57])[CH3:55]
Reactant: CCC(C)(C)OC(C)=O
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Agent: CC(=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CCC(C)(C)O[C@H](C(=O)OC)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Reaction time: 3 h
Yield: 17.9 %

Procedure:
Methyl (2S)-2-[(2-methylbutan-2-yl)oxy 1-24(228)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33), 11, 13, 15 (20),16,18-decaen-3-yl]acetate: To a stirred solution of methyl (2S)-2-hydroxy-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (50 mg, 0.084 mmol) in DCM (2 mL) and tert-pentyl acetate (0.692 mL, 5.85 mmol) at rt was added 70 wt % perchloric acid (0.022 mL, 0.251 mmol). After 3 h, the reaction mixture was diluted with DCM (25 mL), carefully quenched with sat. NaHCO3 (5 mL), organic layer separated and washed with brine (10 mL), dried (Na2SO4), filtered and concentrated to give yellow liquid. This was purified by flash column chromatograpgy on silica gel column using (10-50% EtOAc/Hex as eluant) to afford the desired methyl (25)-2-[(2-methylbutan-2-yl)oxy]-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (10 mg, 0.015 mmol, 17.90% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.82-7.76 (m, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.39-7.34 (m, 1H), 7.18 (d, J=1.9 Hz, 1H), 7.13 (dd, J=8.5, 2.0 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.90 (s, 1H), 5.90 (s, 1H), 4.66-4.59 (m, 1H), 4.58-4.52 (m, 1H), 3.84-3.79 (m, 1H), 3.77 (s, 3H), 3.50 (td, J=7.7, 3.1 Hz, 1H), 3.44-3.35 (m, 1H), 3.27 (d, J=12.3 Hz, 1H), 2.89 (d, J=11.3 Hz, 1H), 2.61 (s, 3H), 2.36 (s, 3H), 2.07-1.96 (m, 3H), 1.89-1.80 (m, 1H), 1.79-1.70 (m, 3H), 1.63-1.47 (m, 6H), 1.26 (s, 3H), 1.23 (s, 3H), 1.17 (d, J=6.0 Hz, 3H), 1.15 (s, 3H), 0.83 (t, J=7.5 Hz, 3H). LCMS (M+H)=669.4. 35 mg of starting material was also recovered.
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:12](=[O:15])[CH2:13][Cl:14].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>C(Cl)Cl>[ClH:14].[CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:12](=[O:15])[CH2:13][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC1(c2ccccc2)c2ccccc2CCN1C(=O)CCl
Reactant: C1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CC1(c2ccccc2)c2ccccc2CCN1C(=O)CN1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-methyl-1-phenyl-2-(2-chloroacetyl)-1,2,3,4-tetrahydroisoquinoline (1.0 g) in methylene chloride (10 ml) was added piperidine (0.82 ml) under ice-cooling, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium bicarbonate, sodium chloride aqueous solution and dried over magnesium sulfate, evaporated in vacuo. The residue was dissolved in ethanol (5 ml) and to the solution was added 6M ethanol solution of hydrogen chloride (1 ml). The mixture was evaporated in vacuo and the residue was recrystallized from isopropyl alcohol and diisopropyl ether. The crystal was washed with diethyl ether and dried in vacuo to give 1-methyl-1-phenyl-2-(2-piperidino-acetyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.4 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][C:9](OCC)=[O:10])([O-:3])=[O:2].Cl.CN.[CH:20]([N:23](C(C)C)CC)(C)C>CO.O>[CH3:20][NH:23][C:9](=[O:10])[CH2:8][O:7][C:6]1[CH:14]=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CCOC(=O)COc1cccc([N+](=O)[O-])c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
A mixture of ethyl 3-nitrophenoxyacetate (9.12 g, 40 mmol), methylamine hydrochloride (26.8 g, 400 mmol) and diisopropylethylamine (35.5 mL, 200 mL) in MeOH (100 mL) was stirred in a pressure vial at 90° C. for 6 h. The reaction was cooled to room temperature, diluted with water (1 liter), the solid formed was filtered, washed with water and dried to get the desired N-methyl 3-nitrophenoxyacetamide (8 g, 95%). 1H NMR CDCl3): δ 7.91 (dd, 1H, J=1.8 and 8.1 Hz), 7.78 (t, 1H, J=2.4 Hz), 7.50 (t, 1H, J=8.7 Hz), 7.29 (dd, 1H, J=1.8 and 8.4 Hz), 6.50 (bs, 2H), 4.57 (s, 2H), 2.95 and 2.93 (2s, 3H); LCMS: ret. time: 17.54 min.; purity: 100%; MS (m/e): 211 (MH+).
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CN(C=O)C.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[C:10]([O:11][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CCCCCCBr
Reactant: NC(=O)c1cccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1cccc(C(N)=O)c1F
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To the solution of 2-fluoro-3-Hydroxy-benzamide (0.12 g, 0.774 mmol) in 20 mL DMF 1-bromohexane (0.13 mL, 1.0 mmol), Potassium Carbonate (0.213, 1.4 mmol) was added. The reaction mixture was stirred at 90° C. for 4 h. DMF was distilled off and the reaction mixture was extracted with EtOAc. The obtained crude compound was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound. (0.05 g, 28%). 1H NMR (DMSO-d6, 400 MHz with D2O): δ 0.82-0.99 (m, 3H), 1.10-1.33 (m, 6H), 1.67-1.71 (m, 2H), 3.99-4.15 (t, 2H, J=8.0 Hz), 7.08-7.24 (m, 2H). MS ES+ (214.33), HPLC (method 6) Rt=11.15 min.