Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([N:19]1[CH2:24][CH2:23][C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1)C1C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH2:4]([O:3][C:1]([N:19]1[CH2:20][CH2:21][C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:23][CH2:24]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc(CN2CCC(c3ccccc3)(N3CCCC3)CC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(c2ccccc2)(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
60 g (3.5 eq) Cbz chloride were added dropwise to a solution of 33 g (1 eq) 1-benzyl-4-phenyl-4-(pyrrolidin-1-yl)piperidine in 330 ml chloroform over a period of 10 min and the reaction mixture obtained was stirred for 30 min at room temperature. The reaction course was monitored by thin-layer chromatography (ethyl acetate). Once the conversion was complete, the solvent was distilled off completely and the residue adjusted to a pH of ˜6 with 10% HCl solution and washed 3 times with 100 ml EtOAc. In an ice bath the aqueous solution was adjusted to a pH of ˜9 with NaOH solution and then extracted 3 times with 100 ml chloroform. The combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 20% EtOAc/heptane). 11 g (29%) of product were obtained in the form of a yellow solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9].I[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1>[Cu]Br.CN(C=O)C>[Cl:17][C:14]1[CH:15]=[C:16]([N:3]2[CH2:8][CH2:7][S:6][CH2:5][C:4]2=[O:9])[CH:11]=[CH:12][C:13]=1[Cl:18]
Reactant: Clc1ccc(I)cc1Cl
Reactant: O=C1CSCCN1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CSCCN1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 81 %

Procedure:
Under a nitrogen atmosphere in a flame-dried flask, sodium hydride (72 mg, 1.79 mmol, 60% oil dispersion) was washed with hexanes and then treated with 6 mL of anhydrous DMF, and cooled to 0° C. Thiomorpholin-3-one (200 mg, 1.71 mmol) was added in one portion with stirring. After gas evolution had stopped (ca. 30 min), 4-iodo-1,2-dichlorobenzene (700 mg, 2.56 mmol) was added, followed after 5 minutes by copper (I) bromide (490 mg, 3.42 mmol). After heating at 75° C. overnight, the mixture was partitioned between ethyl acetate and 1N lithium chloride, filtered through diatomaceous earth and combined with additional ethyl acetate washes of the diatomaceous earth filter cake. The organic layers were washed with additional 1N lithium chloride, brine (saturated sodium chloride) and dried over calcium sulfate (CaSO4). Concentration in vacuo gave 363 mg of light brown oil which was flash chromatographed (30-50% ethyl acetate in hexanes) to give a white solid, 108 mg.
Reaction SMILES: [C:1]1([CH:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:12]/[CH:13]=[CH:14]\[CH2:15]Cl>>[C:1]1([C@@H:7]([N:8]2[CH2:15][CH:14]=[CH:13][CH2:12]2)[CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(CO)c1ccccc1
Reactant: ClC/C=C\CCl
Product: OC[C@@H](c1ccccc1)N1CC=CC1
Yield: 58 %

Procedure:
This was prepared from R-(−)-(2-phenylglycinol and cis-1,4-dichloro-2-butene in 58% yield according to the procedures similar to those described in Preparation 1.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[CH2:11][CH2:12][C:13](Cl)=[O:14].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:13]1(=[O:14])[C:7]2[C:6](=[CH:5][C:4]3[CH2:3][CH2:2][CH2:1][C:9]=3[CH:8]=2)[CH2:11][CH2:12]1
Reactant: c1ccc2c(c1)CCC2
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2cc3c(cc21)CCC3
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The mixture of 11.8 g indane (0.1 mol) and 10 ml 3-chloropropionyl chloride (0.12 mol) was added to suspension of 16 g AlCl3 (0.55 mol) in 100 ml CH2Cl2 at 0° C. After then reaction mixture was poured into ice and HCl, the organic layer was isolated; the aqueous one was extracted with CH2Cl2 (2*50 ml). The combined organic phase was washed by NaHCO3, dried over MgSO4 and evaporated. The residue was added carefully to conc. H2SO4 (100 ml), warmed to 70° C. and stirred after then 30 min at the same temperature. The mixture was cooled and poured into ice. Precipitate was filtered, washed by water and dried, to give 12.4 g of product (72%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([NH:13][CH:14]3[CH2:16][CH2:15]3)[N:10]3[N:17]=[CH:18][C:19]([CH:20]=O)=[C:9]3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:22]1[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24].N1CCCCC1>C(O)C>[CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([NH:13][CH:14]3[CH2:16][CH2:15]3)[N:10]3[N:17]=[CH:18][C:19](/[CH:20]=[C:28]4/[C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22]/4)=[C:9]3[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(NC3CCCC3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(NC4CCCC4)nc23)N1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
5-(Cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (1.0 eq, 20 mg, 0.070 mmol) was mixed in a vial with hydantoin (2.8 eq, 20 mg, 0.20 mmol) in Ethanol (0.3 ml). Piperidine (2.9 eq, 20 ul, 0.202 mmol) was added and the mixture was stirred at 90° C. for 3 hours. The mixture was cooled down, the precipitate was filtered, washed with ethanol and dried. (Z)-5-((5-(cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione was isolated as a solid (25 mg, 100%). LCMS (ES): >95% pure, m/z 368 [M+H]+.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:13](O)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[C:1]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:13]([Cl:23])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1OC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1OC(=O)c1ccccc1

Procedure:
A solution of 3-benzoyloxy-4-methoxybenzoic acid (29.3 g; that is prepared as described in Reference Example 9) in toluene (300 mL) is treated with thionyl chloride (30 mL) and heated on the steam bath for 6 hours. It is then cooled, filtered and concentrated, to give 3-benzoyloxy-4-methoxybenzoyl chloride (28.7 g), m.p. 120-122° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[OH:13].[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[C:5]([Cl:12])=[CH:4][C:3]=1[OH:13])=[O:18]
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1O
Reactant: O=C(O)c1ccncc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1Cl
Temperature: 80 °C
Yield: 57.3 %

Procedure:
A mixture of 0.50 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.36 g of 3-chloroisonicotinic acid, 0.56 g of WSC and 5 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.46 g of 3-chloro-N-[4-chloro-2-hydroxy-5-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[C:24]([N+:30]([O-:32])=[O:31])[CH:23]=2)[CH:17]=1.O>O1CCCC1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[CH:5][C:3]#[N:4])=[C:24]([N+:30]([O-:32])=[O:31])[CH:23]=2)[CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccnc(-c2ccc(C=O)c([N+](=O)[O-])c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccnc(-c2ccc(C=CC#N)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 192 mg) in tetrahydrofuran (10 ml) was added a solution of diethyl cyanomethylphosphonate (0.777 ml) dropwise at 0° C., and the mixture was stirred at ambient temperature for 30 minutes. Then to the resultant mixture was added a solution of 4-(4-methoxypyridin-2-yl)-2-nitrobenzaldehyde (1.03 g) in tetrahydrofuran (20 ml) dropwise at 0° C., and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered and dried to give 4-(4-methoxypyridin-2-yl)-2-nitrocinnamonitrile (1.11 g) as a mixture of regioisomers.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.CC(C)([O-])C.[K+]>O>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([NH:3][CH2:2][CH2:1][NH2:4])[CH:7]=1
Reactant: Clc1cccnc1
Reactant: NCCN
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: NCCNc1cccnc1
Temperature: 118 °C

Procedure:
A mixture of 1.32 g of ethylenediamine, 250 mg of 3-chloropyridine, and 740 mg of potassium tert-butoxide was heated at 118° C. in a sealed tube for 18 h. The reaction was cooled to room temperature, diluted with water and extracted with chloroform. The organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title product as a red oil. MS (M+H)+=137.9.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[C:11]([O:18][CH3:19])[C:10]=1OC)C1C=CC=CC=1.[CH2:22]([OH:24])C>[Pd]>[NH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[O:18][CH2:19][O:24][CH3:22]
Reactant: CCO
Reactant: COc1c(CCN)ccc(OCc2ccccc2)c1OC
Agent: [Pd]
Product: COCOc1cc(O)ccc1CCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 18.00 g of 2-(4-benzyloxy-2-methoxy-methoxyphenyl)ethylamine, 3.6 g of 10% palladium on carbon (Degussa Inc. :E101 NE/W) and 230 mL of ethanol was stirred under a hydrogen atmosphere at room temperature for 1 hour. After the catalyst was filtered off through a diatomaceous earth, the filtrate was concentrated under reduced pressure to give 12.65 g of 4-(2-aminoethyl)-3-methoxymethoxyphenol as a colorless solid.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[NH:8][C:9]=1[C:10]([O:12][CH2:21][CH3:22])=[O:11])([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Agent: O=S(=O)(O)O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Temperature: 25 °C
Yield: 74 %

Procedure:
3.0 grams of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid (formula III) from Example 4, 30 ml of ethanol, and 0.3 ml of concentrated sulfuric acid were added into 100 ml three-necked flask, and refluxed until the reaction completed. The reaction mixture was then allowed to cool to ambient temperature, the solvent was evaporated, 30 ml of ethyl acetate and 30 ml of water were added, and the mixture was adjusted to basic using sodium bicarbonate. The organic layer was separated and the aqueous layer was further extracted with 10 ml×3 of ethyl acetate. The organic portion was washed once with saturated saline solution, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated to give 2.5 grams of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate, resulting in a yield of 74%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([O:12][C:11](=[O:13])[CH:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:46]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COc1cccc(NC(C(=O)O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
(3-Methoxy-phenylamino)-phenyl-acetic acid (0.58 g, 2.25 mmol), HOBT (0.45 g, 2.93 mmol) and DCC (0.60 g, 2.93 mmol) are dissolved in THF (100 mL) and stirred at RT for 20 minutes. Then, (R)-quinuclidin-3-ol (0.57 g, 4.51 mmol) is added and the resulting reaction is stirred at the same temperature for one day. The solvent is evaporated, the residue is taken up with EtOAc and the insoluble is filtered off. The organic solution is washed with 1M K2CO3 and then with brine. The crude is purified by flash chromatography (DCM/MeOH=99/1 to 80:20) to obtain the title compound as a yellow solid (0.43 g, 52% yield, mixture of diastereoisomers).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:25]=[C:24]([O:26]CC)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH2:25][C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cc(NCCCOc2cccc(CN3CCCCC3)c2)nc2ccccc12
Agent: Cl
Product: O=C1CC(NCCCOc2cccc(CN3CCCCC3)c2)=Nc2ccccc21

Procedure:
2-[3-[3-(Piperidinomethyl)phenoxy]propylamino]-4-ethoxyquinoline (liberated from the dimaleate (3.0 g)) was stirred under reflux in concentrated hydrochloric acid (30 ml) for 41/2 hours. The reaction mixture was cooled, reduced in volume by evaporation under reduced pressure, taken to pH 9 (aqueous NaHCO3), washed with ether, and extracted into chloroform (3 x). The chloroform extracts were combined, dried (MgSO4), evaporated under reduced pressure and the resultant white oil was treated with hot ethylacetate to give the title compound (0.89 g), m.p. 171°-171.5° C. (recrystallised from methanol).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=3[CH3:15])[CH2:24][CH2:25]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 80.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-methanesulfonylbenzoic acid (1 g) and 1-(2,4-dimethylphenyl)piperazine (684 mg), the title compound (1.3 g) was obtained.
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[N:21]([C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)=[N+:22]=[N-:23]
Reactant: CS(=O)(=O)O[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Yield: 91.4 %

Procedure:
A solution of 20.5 g (72 mmol) of (R)-3-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylic acid, phenylmethyl ester in 100 ml of dry N,N-dimethylformamide was treated with 6.5 g (0.1 mol) of sodium azide and heated at 90° for four hours. The solvent was removed in high vacuo at 50° and the residue was partitioned between ethyl acetate/water (250 ml each). The aqueous layer was reextracted with ethyl acetate and the combined organic fractions were washed with water, dried (MgSO4) and evaporated in vacuo to give 16.2 g of the title compound.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[H][H]>CO.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC[C@H](NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 90.6 %

Procedure:
1.9 g of Z-Asp(OtBu)-Ser(tBu)-OtBu are hydrogenated in 100 ml of methanol in the presence of 0.1 g of Pd/C 10%. After the theoretical amount of hydrogen has been taken up the mixture is filtered and the filtrate is evaporated to dryness. Chromatography on silica gel with methylene chloride/MeOH (98:2) gives 1.28 g (91%) of H-Asp(OtBu)-Ser(tBu)-OtBu, MS: 389 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:3]=1[CH2:4][N:5](CC1C=CC=CC=1)[CH2:6][CH3:7].[H][H].C.[ClH:27]>CO>[ClH:27].[NH2:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7]
Reactant: CCOC(=O)c1ccc(N)c(CN(CC)Cc2ccccc2)c1
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: CCNCc1cc(C(=O)OCC)ccc1N

Procedure:
3.8 gm of 2-amino-N-benzyl-5-carbethoxy-N-ethyl-benzylamine were hydrogenated in a mixture of 50 ml of methanol and 1 ml of concentrated hydrochloric acid at room temperature and at a hydrogen pressure of 5 atmospheres in the presence of palladized charcoal. Then, the catalyst was filtered off, and the filtrate was evaporated to dryness in vacuo. The residue was recrystallized from ethanol by addition of ether, yielding 2-amino-5-carbethoxy-N-ethyl-benzylamine hydrochloride, m.p. 173-176° C (decomp.).
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29]([OH:31])=O)[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[C:33]([S:39][CH2:40][CH2:41][NH2:42])(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[C:1]([NH:6][C@H:7]([C:29]([NH:42][CH2:41][CH2:40][S:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:31])[CH2:8][S:9][C:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CC(C)(C)C(=O)SCCN
Agent: Cl
Product: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)C(C)(C)C

Procedure:
The coupling reaction of 13 (3.93 mmol) of S-pivaloylcysteamine hydrochloride is carried out according to method B described in the first synthetic route (example 1). After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: AcOEt/petroleum ether 70%). 16 is collected in the form of a foam which, after trituration in hexane, provides a colorless powder (Yd=88%). Rf (CH2Cl2/ether, 6/4): 0.82. M.p.=85-88° C. [α]D20=+5.9° (c 1.02, CHCl3).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([NH:32][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:30][CH2:31]1
Reactant: O=C(Nc1ccccc1OCC1CO1)c1ccccc1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Product: O=C(Nc1ccccc1OCC(O)CNC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)c1ccccc1
Temperature: 77.5 °C

Procedure:
To a solution of N-(2-Oxiranylmethoxy-phenyl)-benzamide (0.2 ml, 0.1M in DMSO) was added (0.2 ml, 0.1M in EtOH) of 1-(3,4-Dichloro-benzyl)-piperidin-4-ylamine. The resulting mixture was heated at 75-80° C. for 24 hours. The ethanol was removed and the product was purified with preparative LC/MS.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[C:28](B(O)O)=[CH:29][S:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[C:27]([CH3:26])=[CH:31][S:30][CH:29]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1cscc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cscc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 105 °C
Reaction time: 18 h
Yield: 64.1 %

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 200 mg, 64%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 200 mg, 64%).