Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.C([SiH](CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(O)(C(F)(F)F)=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:7][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(Cc2ccccc2)cc1Cl
Reaction time: 18 h
Yield: 31.7 %

Procedure:
Sodium borohydride (1.45 g) was added to a solution of 3-chloro-4-nitrobenzophenone (2.0 g) (prepared as described by R. B. Davis and J. D. Benigni, J. Org. Chem., 1962, 27, 1605) in ethanol and the mixture was stirred for 18 hours. Volatile material was removed by evaporation and the residue was suspended in water (100 ml) and cautiously acidified with dilute aqueous hydrochloric acid (50 ml) and stirred a further 2 hours. The reaction mixture was basified with 2M aqueous sodium hydroxide solution and extracted with DCM. The extracts were combined, dried and concentrated by evaporation to give an oil. This was dissolved in TFA (12.1 ml) with cooling with an ice bath then treated dropwise with triethylsilane (5.05 ml) and stirred overnight. The reaction mixture was poured onto aqueous sodium carbonate solution and extracted with DCM. The extracts were combined, dried and evaporated to give an oil which was purified by chromatography eluting with 20-50% ethyl acetate/hexane to give the title compound (0.60 g) as an oil. NMR (CDCl3): 4.0 (s, 3H), 7.1-7.4 (m, 8H); MS (CI): 247 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]=O)=[C:5]([CH3:11])[N:4]([CH:12]([CH3:14])[CH3:13])[C:3]1=[O:15].BrBr.C(O[CH2:22][CH3:23])(=O)C>C(Cl)(Cl)Cl.ClCCl>[CH2:13]1[C:22]2[C:23](=[CH:11][CH:5]=[CH:6][CH:7]=2)[CH2:14][CH:12]1[N:4]1[CH:9]=[C:6]2[C:5]([N:4]([CH:12]([CH3:14])[CH3:13])[C:3](=[O:15])[N:2]([CH3:1])[C:7]2=[O:8])=[CH:11]1
Reactant: Cc1c(C=O)c(=O)n(C)c(=O)n1C(C)C
Reactant: CCOC(C)=O
Agent: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)n1c(=O)n(C)c(=O)c2cn(C3Cc4ccccc4C3)cc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3,6-Dimethyl-5-formyl-1-(1-methylethyl)pyrimidine-2,4-dione (J. Med. Chem., 1995, 38, 2557, 1.70 g) was dissolved in chloroform (25 ml) and the solution was heated to 50° C. A solution of bromine (0.413 ml) in chloroform (20 ml) was added dropwise to the aldehyde solution over 24 minutes. The reaction was maintained at 50° C. for a further 15 minutes, then allowed to cool to ambient temperature. The reaction mixture was diluted with dichloromethane and was washed successively with water, dilute sodium thiosulphate solution (twice) and brine. The resultant solution was dried, filtered and evaporated to a crude oil which was dissolved in ethanol (50 ml). Triethylamine (3.38 ml) was added to the solution followed by 2-aminoindane (1.49 g) and the mixture was stirred under nitrogen overnight. The reaction mixture was filtered, the white solid collected was washed with a little ethanol and the filtrate was evaporated to give a brown oil. Ethyl acetate was added to the oil and the resultant precipitate was collected by filtration and was washed with a little ethyl acetate. The filtrate was washed with hydrochloric acid (HCl) (2.5 M) and then brine. The resultant ethyl acetate phase was dried, filtered and evaporated to an oil. The oil was purified by chromatography, eluting with isohexane:acetone (4:1) to give a solid which was triturated with hot ethyl acetate:isohexane (3:1) to give the subtitle compound (0.50 g).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=[O:6])[CH:4]=[CH2:5].Br[C:9]1[CH:10]=[CH:11][C:12]([O:29][CH2:30][CH3:31])=[C:13]([C:15]2[NH:16][C:17](=O)[C:18]3[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=3[N:20]=2)[CH:14]=1>>[CH3:1][N:2]([CH3:7])[C:3](=[O:6])/[CH:4]=[CH:5]/[C:9]1[CH:10]=[CH:11][C:12]([O:29][CH2:30][CH3:31])=[C:13]([C:15]2[NH:16][CH2:17][C:18]3[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=3[N:20]=2)[CH:14]=1
Reactant: C=CC(=O)N(C)C
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Product: CCCc1nn(C)c2c1N=C(c1cc(/C=C/C(=O)N(C)C)ccc1OCC)NC2

Procedure:
The title compound was prepared from N,N-dimethylacrylamide and 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one following the procedure of Example 19 and was obtained, following crystallisation from ethyl acetate-hexane, as colourless crystals (38%), m.p. 219°-221° C. Found: C,64.15; H,6.46; N,16.96. C22H27N5O3 requires C,64.53; H,6.65; N,17.10%
Reaction SMILES: F[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([F:16])[C:3]=1[CH2:4][O:5][C:6](=[O:8])[CH3:7].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O.O>[F:16][C:9]1[C:3]([CH2:4][O:5][C:6](=[O:8])[CH3:7])=[C:2]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)OCc1c(F)ccc([N+](=O)[O-])c1F
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)OCc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Yield: 81.5 %

Procedure:
A solution of acetic acid 2,6-difluoro-3-nitrobenzyl ester (3 g, 12.9 mmol) and aniline (1.5 mL, 16.9 mmol) in DMSO (10 mL) was heated at 100° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3×15 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a brown oil (3.2 g, 81%). 1H NMR 400 MHz 6 (CDCl3): 8.21 (1H, dd, J=9.4, 5.9 Hz), 7.30-7.24 (2H, m), 7.10-7.04 (1H, m), 6.97-6.92 (2H, m), 6.83 (1H, dd, J=9.3, 8.4), 4.93 (2H, d, J=2.0 Hz), 1.94 (3H, s)
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[C:14]([C:18]1[CH:22]=[C:21]([NH2:23])[O:20][N:19]=1)([CH3:17])([CH3:16])[CH3:15].C(NC(C)C)(C)C>O1CCCC1.ClCCl>[C:14]([C:18]1[CH:22]=[C:21]([NH:23][C:7]([C@@H:5]2[CH2:4][CH2:3][C:2](=[O:1])[NH:6]2)=[O:9])[O:20][N:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CC(C)(C)c1cc(N)on1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCC(=O)N2)on1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 25.9 %

Procedure:
To solution of the (S)-5-oxo-pyrrolidine-2-carboxylic acid (6 g, 46.47 mmol) in tetrahydrofuran (50 mL) is added thionyl chloride (6.75 ml, 92.94 mmol) and stirred at room temperature for 2-3 hours. The solvent is removed under reduced pressure and the residue is dissolved in tetrahydrofuran (20 mL) and added dropwise to a solution of 3-tert-butyl-isoxazol-5-ylamine (6.514 g, 46.47 mmol) and diisopropylamine (24.28 ml, 139.41 mmol) in tetrahydrofuran (50 mL) at room temperature. The reaction is stirred overnight at room temperature then diluted with dichloromethane and washed sequentially with water and saturated brine solution. The organics are dried over sodium sulfate, filtered and solvents removed under vacuum. The crude residue is purified by flash column chromatography eluting with 5-10% methanol/dichloromethane. The product rich fractions are pooled and evaporated to afford 3.02 g title compound, 32.7% yield. ESI m/z 252=MH+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N+:30]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[CH3:41])[CH2:36]Cl)([O-:32])=[O:31]>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[C@H:7]([N:11]([CH2:36][C:35]1[CH:38]=[CH:39][C:40]([CH3:41])=[C:33]([N+:30]([O-:32])=[O:31])[CH:34]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: Cc1ccc(CCl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(C)c([N+](=O)[O-])c2)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid tert-butyl ester (0.15 g, 0.44 mmol) and potassium carbonate (0.32 g, 2.32 mmol) in dry dimethylformamide (15 mL) was added 3-nitro-4-methylbenzyl chloride (81.1 mg. 0.44 mmol). The reaction mixture was stirred overnight and then concentrated on the rotoevaporator. The residue was dissolved in a 1:1 ethyl acetate and brine (50 mL). The organic phase was isolated, dried over magnesium sulfate, and concentrated to give 2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid tert-butyl ester (0.196 g) as a yellow viscous oil which was converted to 2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxy-benzenesulfonyl)amino]-3-methylbutyric acid by following the procedure described in Example 10, Step 8 below. 2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxybenzenesulfonyl)-amino]-3-methylbutyric acid is then converted to N-hydroxy-2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide by following Example 1, Steps 6 and 7 above.
Reaction SMILES: [CH3:1][C:2]([CH3:55])=[CH:3][CH2:4][CH2:5][C@@:6]([OH:54])([C@@H:8]1[C@H:12]2[C@H:13]([OH:52])[CH2:14][C@@H:15]3[C@@:20]4([CH3:50])[CH2:21][CH2:22][C@H:23]([O:27][C@@H:28]5[O:33][C@H:32]([CH2:34][OH:35])[C@@H:31]([OH:36])[C@H:30]([OH:37])[C@H:29]5[O:38][C@@H:39]5[O:44][C@H:43]([CH2:45][OH:46])[C@@H:42]([OH:47])[C@H:41]([OH:48])[C@H:40]5[OH:49])[C:24]([CH3:26])([CH3:25])[C@@H:19]4[CH2:18][CH2:17][C@@:16]3([CH3:51])[C@:11]2([CH3:53])[CH2:10][CH2:9]1)[CH3:7]>O>[CH3:1][C:2]([CH3:55])=[CH:3][CH2:4][CH2:5][C@:6]([OH:54])([C@@H:8]1[C@H:12]2[C@H:13]([OH:52])[CH2:14][C@@H:15]3[C@@:20]4([CH3:50])[CH2:21][CH2:22][C@H:23]([O:27][C@@H:28]5[O:33][C@H:32]([CH2:34][OH:35])[C@@H:31]([OH:36])[C@H:30]([OH:37])[C@H:29]5[O:38][C@@H:39]5[O:44][C@H:43]([CH2:45][OH:46])[C@@H:42]([OH:47])[C@H:41]([OH:48])[C@H:40]5[OH:49])[C:24]([CH3:25])([CH3:26])[C@@H:19]4[CH2:18][CH2:17][C@@:16]3([CH3:51])[C@:11]2([CH3:53])[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(C)=CCC[C@@](C)(O)[C@H]1CC[C@]2(C)[C@@H]1[C@H](O)C[C@@H]1[C@@]3(C)CC[C@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)C(C)(C)[C@@H]3CC[C@]12C
Solvent: O
Product: CC(C)=CCC[C@](C)(O)[C@H]1CC[C@]2(C)[C@@H]1[C@H](O)C[C@@H]1[C@@]3(C)CC[C@H](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)C(C)(C)[C@@H]3CC[C@]12C
Reaction time: 4 h

Procedure:
Take 100 ml of 20(R)-ginsenoside Rg3 composition solution obtained from Operation Example 1, add water for injection to 1000 ml, and add 0.1 grams of injection grade active carbon and mix to uniformity. Leave it at 80° C. for 30 minutes, remove the pyrogen with 0.45 μm micropore membrane filtering, sterilize with a 0.22 μm micropore filter membrane under sterile conditions, dispense into a 10 ml sterile antibiotics tube vial under sterile conditions, and the quantity of each tube vial is 4.5˜4.9 ml:5 mg. After the dispensed, the antibiotics tube vials are half-corked, they are transferred onto the plate of lyophilizer (LYO-5, manufactured in Shanghai). Close the door of the lyophilizer, turn on the lyophilizer and first freeze to below −40° C. and keep for 4 hours, and then start vacuum drying as following program for sublimation: −45˜−30° C. for 4 hours, −30˜−20° C. for 4 hours, −20˜−15° C. for 2 hours. Finally, dry for 4 hours at 15˜30° C., and the lyophilization process is complete. After lyophilization, the corks are fully plugged and aluminum covers are pressed on with a sealing machine. Sample some sample for testing. Pack the qualified tube vials. 1000 tube vials of lyophilized powder for injection (3.1 mg Rg3/vial) are obtained. The above-mentioned procedures can be carried out for Example 2-40 to produce water-soluble powder of ginsenoside Rg3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[C:6]([C:9](=[CH2:15])[C:10](OCC)=[O:11])=[N:7][CH:8]=[C:2]12.[NH3:16]>CO>[S:1]1[CH:5]=[CH:4][N:3]2[C:6]([C:9](=[CH2:15])[C:10]([NH2:16])=[O:11])=[N:7][CH:8]=[C:2]12
Reactant: N
Reactant: C=C(C(=O)OCC)c1ncc2sccn12
Solvent: CO
Product: C=C(C(N)=O)c1ncc2sccn12
Temperature: 25 °C
Reaction time: 168 h
Yield: 83 %

Procedure:
A solution of 0.445 g of the ethyl 2-(imidazo[5,1-b]-thiazol-5-yl)acrylate obtained in Preparation 26 in 20 ml of methanol was saturated with ammonia gas with ice-cooling. This was sealed tightly, and stirred at room temperature for 7 days. The reaction solution was concentrated, and then purified by using a Sephadex LH 20 column (500 ml), eluting with a 1:1 mixture of methanol and chloroform to give 0.320 g (yield 83%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH2:7][CH:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:1][C:2]1[S:6][C:5]2[CH2:7][CH:8]([CH3:11])[CH:9]([OH:10])[C:4]=2[C:3]=1[CH3:12]
Reactant: Cc1sc2c(c1C)C(=O)C(C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1sc2c(c1C)C(O)C(C)C2
Reaction time: 8 h

Procedure:
A solution of 2,3,5-trimethyl-5,6-dihydro-4H-cyclopenta[b]thiophene-4-one (11 g, 61 mmol) in 100 mL of ether was slowly added to a solution of LiAlH4 (1.16 g, 30 mmol) in 100 mL of ether and stirred overnight. The resulting suspension was poured into a mixture of ice and water, the organic layer was isolated, while the water layer was extracted with ether (3×50 mL). The combined organic layers were washed with water, dried over MgSO4 and evaporated off to dryness. The 2,3,5-trimethyl-5,6-dihydro-4H-cyclopenta[b]thiophen-4-ol so obtained was dissolved in 100 mL of benzene, added of 1 g of p-toluenesulfonic acid and was refluxed for 10 min. Then the reaction mixture was cooled to room temperature and treated with a saturated aqueous solution of Na2CO3. The organic phase was isolated, dried over MgSO4 and evaporated off to dryness. Yield 8 g (80% based on starting ketone).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](#[N:16])[CH:14]=[CH2:15].C([O-])(=O)C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C[Si](C=[N+]=[N-])(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:2](/[CH:15]=[CH:14]/[C:13]#[N:16])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)ccc1Br
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1/C=C/C#N
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To an N,N-dimethylformamide solution (100 mL) of methyl 2-bromo-5-chlorobenzoate (25, 100 mmol) was added palladium(II) acetate (480 mg, 2.1 mmol) tri(o-tolyl)phosphine (1.2 g, 3.9 mmol), acrylonitrile (6 g, 113 mmol), and anhydrous sodium acetate (10 g, 122 mmol). The mixture was heated at 120° C. Additional palladium(II) acetate (224 mg, 1 mmol) and tri(o-tolyl)phosphine (600 mg, 2 mmol) were added, after 36 hours. The mixture was heated at 120° C. for 24 hours. N,N-Dimethylformamide was removed in vacuo and the remaining mixture was quenched with 1 N HCl(aq) and extracted with ethyl acetate. The ethyl acetate extracts were concentrated and the residue was dissolved in 1:1 dichloromethane:methanol (50 mL). (Trimethylsilyl)diazomethane (30 mL, 2 N in diethyl ether, 60 mmol) was added dropwise. After stirring overnight, the mixture was quenched with acetic acid, concentrated under reduced pressure and purified by silica gel column chromatography eluting with 2:1 hexanes:ethyl acetate to afford the title compound (2:1 E/Z isomers). 1H NMR (E isomer, Example 45A, 300 MHz, DMSO-d6) δ ppm 8.08 (d, J=16.2 Hz, 1H), 7.91 (d, J=2.1 HZ, 1H), 7.84 (d, J=8.7 HZ, 1H), 7.78 (dd, J=2.1, 8.4 Hz, 1H), 6.45 (d, J=16.5 Hz, 1H), and 3.88 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17](N)=[C:12]3[C:11]([CH3:20])=[CH:10]2)=[C:4]([CH3:21])[CH:3]=1.[OH:22]S(O)(=O)=O.N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[CH:16]=[C:17]([OH:22])[C:12]=3[C:11]([CH3:20])=[CH:10]2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(N)c2c(C)cn(-c3c(C)cc(Cl)cc3C)c2n1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(O)c2c(C)cn(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
With ice-cooling, to a suspension of 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-ylamine (17.9 g) in a mixture of 1,4-dioxane (45 mL) and water (45 mL) was added dropwise a mixture of concentrated H2SO4 (17.8 mL) and water (90 mL) and then a solution of NaNO2 (6.2 g) in water (62 mL). The mixture was stirred at room temperature for 20 minutes, and heated at 100° C. for 1.5 hours. After cooling in an ice-cooling bath, the reaction mixture was poured into a cold saturated NaHCO3 aqueous solution and extracted with CHCl3. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was washed with a mixture of ethyl acetate and diisopropylether (1:5) to give 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-ol (14.4 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[C:19]([C:13](=[CH:12][NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:23])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)C=CNc1ccccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=CNc1ccccc1OC)C(=O)C(C)C
Temperature: 25 °C
Yield: 77.6 %

Procedure:
50% Sodium hydride (4,8 g, 0.1 mol) was washed with petroleum ether and suspended in dry tetrahydrofuran (50 ml) under nitrogen at -10° C. Ethyl 3-(2-methoxyphenylamino)acrylate (22.4 g, 0.1 mol) in dry tetrahydrofuran (70 ml) was added dropwise to the suspension keeping the temperature to below 0° C. Cooling ws removed and the mixture was stirred at ambient temperature until a deep orange colour was obtained. The mixture was recooled to -20° C. and treated dropwise with a solution of isobutyryl chloride (11.0 ml, 0.11 mol) in dry tetrahydrofuran (30 ml). The cooling bath was again removed, and the mixture stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with dilute hydrochloric acid and brine, dried, filtered and evaporated. The crude product was chromatographed (silica gel, petroleum ether/dichloromethane) to afford ethyl 2-isobutyryl-3-(2-methoxyphenylamino)acrylate as an oil (22.6 g, 77.5%).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:51])[N:29]([C@H:31]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][N:41]([CH3:43])[CH3:42])[CH2:36][CH2:35]1)=[O:33])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C>ClCCl>[CH2:44]([C@@H:31]([N:29]([CH3:30])[C:28](=[O:51])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][N:41]([CH3:42])[CH3:43])[CH2:36][CH2:35]1)=[O:33])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CN(C)CC1CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC(CN(C)C)CC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 96.1 %

Procedure:
At 0° C., trifluoroacetic acid (18 ml) was added to a solution of N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)-ethyl)-N-methylcarbamic acid tert-butyl ester (1.05 g, 1.71 mmol) in dichloromethane (18 ml). The reaction mixture was stirred for 50 min at 0° C. The solvents were removed in vacuo. The residue was dissolved in dichloromethane (50 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (80 g), using dichloromethane/methanol/25% aqueous ammonia as eluent, to give 846 mg of (2R)—N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [C:1](=[N:4][C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][C:8]([CH2:13][C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[C:17]([N:22]=[C:23]([CH3:25])[CH3:24])=[C:16]([CH2:26][CH3:27])[CH:15]=2)=[CH:7][C:6]=1[CH2:28][CH3:29])([CH3:3])[CH3:2].C(O)C>[Pt].C(OCC)(=O)C>[CH:23]([NH:22][C:17]1[C:16]([CH2:26][CH3:27])=[CH:15][C:14]([CH2:13][C:8]2[CH:7]=[C:6]([CH2:28][CH3:29])[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[C:10]([CH2:11][CH3:12])[CH:9]=2)=[CH:19][C:18]=1[CH2:20][CH3:21])([CH3:24])[CH3:25]
Reactant: CCc1cc(Cc2cc(CC)c(N=C(C)C)c(CC)c2)cc(CC)c1N=C(C)C
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cc(Cc2cc(CC)c(NC(C)C)c(CC)c2)cc(CC)c1NC(C)C
Reaction time: 1.2 h
Yield: 70 %

Procedure:
N,N′-diisopropylidene-4,4′-methylenebis(2,6-diethylbenzeneamine) (2.6 g) and Pt(S)/C (0.35 g) were added to a mixture of ethanol (20 g) and ethyl acetate (20 g) in an autoclave. The closed autoclave was purged 3 times with 125 psig (9.63×105 Pa) of H2 at 22° C. to remove traces of air. The mixture was kept at 22° C. and 0-125 psi (0 to 8.62×105 Pa) of H2 for 1.2 hours, forming the corresponding N,N′-diisopropyl-4,4′-methylenebis(2,6-diethylbenzeneamine) in 70% yield, with 25% of the diimine underhydrogenated. Conversion of the diimine was 95%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2].[H-].[Na+].I[CH3:42]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][O:29][CH3:42])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(COC)c2)c1CCC(=O)OCC
Reaction time: 15 h
Yield: 80.7 %

Procedure:
To a solution of 4-[3-[6-(3-bromo-5-hydroxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.25 g, 2.1 mmol) in DMF (25 mL) were added sodium hydride (211 mg, 5.26 mmol) and iodomethane (747 mg, 5.26 mmol) at room temperature. The resulting suspension was stirred for 15 h and then the excess sodium hydride was quenched by slow addition of water (5 mL). The mixture was diluted with 1.0N hydrochloric acid (50 mL) and the organic compound was extracted into ethyl acetate (2×50 mL). The combined extracts were washed with brine solution (100 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under vacuum afforded the crude residue which was purified by using an ISCO 40 g column, eluting with 0-30% ethyl acetate in hexanes to obtain 4-[3-[6-(3-bromo-5-methoxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.03 g, 81%) as a colorless viscous oil: EI(+)-HRMS m/e calcd for C31H43BrO7 (M+Na)+ 629.2084. found 629.2085.