Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH2:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.ClCCl>[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Reactant: N[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](N)C2)cc1
Temperature: 135 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A mixture of tert-butyl 4-fluorobenzoate (1, 1.00 g, 5.1 mmol), (S)-3-aminopyrrolidine (1.5 eq) and K2CO3 (0.84 g, 6.1 mmol, 1.2 eq.) is suspended in 4 mL of anhydrous DMSO. The suspension is stirred at 135° C. under N2 for 16 h in a sealed flask, cooled to room temperature, diluted with dichloromethane (300 mL) and successively washed with saturated aqueous NaHCO3 and water, dried over MgSO4, filtered and concentrated in vacuo to afford title compound 17 (1.22 g, 91% yield). 1H NMR: (DMSO-d6) δ(ppm): 7.65 (d, J=8.8 Hz, 2H), 6.47 (d, J=9.0 Hz, 2H), 3.65 (quint, J=5.3 Hz, 1H), 3.40 (t, J=9.8 Hz, 1H), 3.38 (t, J=9.8 Hz, 1H), 3.29-3.23 (m, 1H), 2.91 (dd, J=9.8, 4.7 Hz, 1H), 2.03 (sext, J=5.9 Hz, 1H), 1.74-1.63 (m, 3H), 1.48 (s, 9H). m/z: 263.1 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[C:7]([O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[N:6]2)[CH2:3][CH2:2]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CC1C=C(C)C=C(C)N=1>[CH:1]1([CH2:4][N:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[C:7]([O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][O:33][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[N:6]2)[CH2:3][CH2:2]1
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1CC1CC1
Reactant: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(CC3CC3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.050 g) in 2,4,6-trimethylpyridine (1 mL) was added ethyl chloroformate (0.035 g), and the mixture was stirred at room temperature overnight. Citric acid monohydrate (3.3 g) and water were added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 1-(cyclopropylmethyl)-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl ]-5-methyl-1H-pyrazole (0.043 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.Cl[CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[CH2:19]([O:18][CH2:17][N:5]1[C:6]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=[C:4]1[Br:3])[CH2:20][CH2:21][CH3:22]
Reactant: Cc1nc(Br)[nH]c1C(=O)OC(C)C
Reactant: CCCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOCn1c(Br)nc(C)c1C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a suspension of 293 milligrams (1.22 mM) of sodium hydride in 30 ml of anhydrous tetrahydrofuran was added, in portions, 3 g (1.22 mM) of isopropyl 2-bromo-4-methyl-5-imidazolecarboxylate. The resulting suspension was cooled to 0° C. and 1.5 g (1.22 mM) of chloromethyl-n-butyl ether was added dropwise. The reaction mixture was stirred overnight at room temperature. The precipitated sodium chloride was removed by filtration and concentration of the filtrate in vacuo gave 3.6 g of isopropyl N-n-butoxymethyl-2-bromo-4-methyl-5-imidazolecarboxylate as a golden oil (87%). Subsequent analysis indicated that the 3-isomer/1-isomer ratio was 91/9.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH2:32][NH:33][OH:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[Cl-].[NH4+].ClCCl.CO>O1CCOCC1>[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2([CH2:32][N:33]([OH:34])[C:6]([NH2:5])=[O:7])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: ONCC1(c2ccc(OCc3ccc4ccccc4n3)cc2)CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)N(O)CC1(c2ccc(OCc3ccc4ccccc4n3)cc2)CCCCC1
Temperature: 100 °C

Procedure:
0.94 g (8.13 mmol) of trimethylsilyl isocyanate is added dropwise under an argon atmosphere at room temperature to a solution of 2.7 g (7.45 mmol) of N-[4-(quinolin-2-yl-methoxy)phenyl-cyclohexyl]methyl-hydroxylamine in 25 ml of dioxane p.a. The reaction mixture is heated at 100° C. under an argon atmosphere for 2.5 h, cooled to room temperature and treated with saturated ammonium chloride solution. It is extracted several times with ether, and the organic phase is dried over sodium sulphate and concentrated in vacuo. The product is obtained after column chromatography on silica gel using dichloromethane/methanol (9:1).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH3:20])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (1 g) in DMF (20 mL) was added sodium hydride (230 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added iodomethane (815 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (5%-25% EtOAc/hexanes) to yield the title compound as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[N:13][OH:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[S:22]([O:14][N:13]=[C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:9][CH2:8][CH2:7]1)([C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)C(=NO)CCO2
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(=NOS(=O)(=O)c1ccc(C)cc1)CCO2
Temperature: 0 °C
Yield: 87.8 %

Procedure:
5.68 g (29.4 mmol) of 6-methoxychroman-4-one oxime were dissolved under argon atmosphere in 30 ml of dry pyridine. At 0° C. 6.05 g (31.8 mmol) of 4-methylbenzene-1-sulfonyl chloride were added in small portions over 40 min. The mixture was stirred at 0° C. for an additional hour and then warmed to room temperature and stirred over night. The mixture was poured onto 260 ml ice water, stirred, and the suspension was filtered. The solid residue was washed with a small amount of cold water (2×) and cold ethanol (1×), and dried to yield 8.96 g (25.8 mmol, 88%) of desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([F:13])[C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:19]([F:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([F:13])[C@H:9]1[C:14](=[O:16])[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[C:19]=1[F:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 20 h

Procedure:
To a solution of (2R,3R)-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (45.0 mg, 0.193 mmol) in CH2Cl2 (5 mL) were added successively 3-chloro-2-fluorobenzylamine (0.024 mL, 0.193 mmol), HBTU (110 mg, 0.289 mmol) and DIPEA (0.067 mL, 0.386 mmol), and stirring was continued at RT for 20 h. The reaction mixture was then diluted with CH2Cl2, and the organics were washed with 0.1N aqueous HCl (2×), aqueous NaHCO3 (2×) and brine (1×), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/c-hexane gradient 1:4 to 1:3) to afford the title compound. TLC Rf (EtOAc/c-hexane 1:1)=0.31; MS (LC/MS): 397 [M+Na]+, 319 [MH−tBu]+, 275 [MH−Boc]+; tR (HPLC conditions b): 4.37 min.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:28])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:26]=[CH:25][C:20]3[N:21]=[N:22][N:23]([CH3:24])[C:19]=3[CH:18]=2)[C:8]=1[CH3:27]>C1COCC1.O.C(Cl)Cl>[CH3:27][C:8]1[N:9]([CH2:16][C:17]2[CH:26]=[CH:25][C:20]3[N:21]=[N:22][N:23]([CH3:24])[C:19]=3[CH:18]=2)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]=1[CH2:6][C:5]([OH:28])=[O:4]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc3nnn(C)c3c2)c2ncccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc2nnn(C)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1M Lithium hydroxide (116 μl) is added to a cooled (0° C.) solution of [2-methyl-1-(3-methyl-3H-benzotriazol-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.041 g, 0.116 mmol) in THF/water (4 ml of a 1:1 mixture). After stirring at room temperature for 4 hours, the reaction mixture is diluted with DCM (3 ml) and stirred vigorously for 10 minutes. The resulting mixture is passed through a phase separation cartridge and the aqueous portion is acidified to pH 1-3 with 1M HCl. This portion is extracted with DCM (2×3 ml) and the organic extracts are combined and concentrated in vacuo to yield the titled compound as a white solid. (MH+ 336)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[NH:5][CH3:6].C(N(C(C)C)CC)(C)C.ClCCl.[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([N:5]([CH3:6])[C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH:7]=[CH:8][CH:9]=1
Reactant: CNc1cccc(Br)c1C
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1N(C)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Bromo-N,2-dimethylaniline (150 mg) and diisopropylethylamine (291 mg) were added to dichloromethane (5 mL). Cyclohexanecarbonyl chloride (115 mg) was added and the solution was stirred at room temperature for 16 hours. The solution was diluted with ethyl acetate and washed two times with 1M aqueous HCl and once with brine. The solution was dried on anhydrous sodium sulfate, filtered, and the solvent was removed to provide the title compound which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:5][C:4]=2[N:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:8]1[CH2:7][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[C:9]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccn1)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(n1)CC(c1ccccn1)CC2=NNC(=N)N
Yield: 91.5 %

Procedure:
A mixture of 2,4-dimethyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.08 g), aminoguanidine hydrochloride (0.037 g), concentrated hydrochloric acid (0.079 ml), water (0.079 ml) and ethanol (10 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from water-ethanol to give 5-guanidinoimino-2,4-dimethyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 87) (0.1 g) as colorless crystals.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)[CH3:2].[CH:15]1(Br)[CH2:18][CH2:17][CH2:16]1>CN(C=O)C>[CH:15]1([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([S:3][CH2:1][CH3:2])[CH:12]=3)[C:8]([C:13]#[N:14])=[CH:9]2)[CH2:18][CH2:17][CH2:16]1
Reactant: BrC1CCC1
Reactant: CCSc1ccc2c(C#N)c[nH]c2c1
Solvent: CN(C)C=O
Product: CCSc1ccc2c(C#N)cn(C3CCC3)c2c1
Temperature: 85 °C
Yield: 95.8 %

Procedure:
A mixture of 6-ethylsulfanyl-1H-indole-3-carbonitrile (2.13 g, 10.5 mmol) Cs2CO3 (6.9 g, 21 mmol), cyclobutyl bromide (1.78 g, 13.2 mmol) and DMF (20 mL) was heated to 85° C. overnight and, after cooling, partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over Mg2SO4, concentrated and purified on silica gel (EtOAc/hexane 5% to 30%) to provide 1-cyclobutyl-6-ethylsulfanyl-1H-indole-3-carbonitrile (2.58 g, 96%) as a light-yellow oil.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[O:13]>O>[NH4+:7].[CH3:6][N:7]1[C:8](=[O:13])[CH:9]=[CH:10][C:11]([S:2]([O-:5])(=[O:4])=[O:3])=[CH:12]1
Reactant: O=S(=O)(O)Cl
Reactant: Cn1ccccc1=O
Solvent: O
Product: Cn1cc(S(=O)(=O)[O-])ccc1=O
Product: [NH4+]
Temperature: 50 °C
Reaction time: 40 h
Yield: 48.3 %

Procedure:
Chlorosulphonic acid (2 ml, 30.1 mmol) was added cautiously dropwise by pipette over 5 minutes to stirred neat 1-methylpyridin-2(1H)-one (8.09 ml, 82 mmol) and the resulting viscous solution was stirred at 50° C. for 40 hours. The cooled solidified reaction mixture was then added cautiously to water (100 ml), giving a clear brown solution. This solution was concentrated in vacuo to 40 ml, then made basic with concentrated ammonia solution, and washed with dichloromethane (6×100 ml). The aqueous phase was then evaporated to give a brown slurry which was triturated in methanol and filtered. The filtrate was evaporated to give 1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonic acid, ammonium salt (3 g) as a brown solid. LCMS (Method F, ES-API): RT 0.46 min, m-H=188.0.
Reaction SMILES: CSC(SC)=[C:4]([C:7]#N)[C:5]#[N:6].CS[C:13](SC)=[C:14]([C:18]#[N:19])[C:15]([NH2:17])=[O:16]>CO>[O:16]1[C:15]2[CH:14]=[CH:13][CH:7]=[CH:4][C:5]=2[NH:6][C:13]1=[C:14]([C:18]#[N:19])[C:15]([NH2:17])=[O:16]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: CSC(SC)=C(C#N)C(N)=O
Solvent: CO
Product: N#CC(C(N)=O)=C1Nc2ccccc2O1

Procedure:
The procedure described in Example 1 is repeated using, instead of 3,3-bis(methylthio)-2-cyanoacrylonitrile, an equivalent amount of 3,3-bis(methylthio)-2-cyanoacrylamide and holding the mixture under reflux for 12 hours to obtain 2-benzoxazolinylidene-cyanoacetic acid amide of melting point 220°-222° C. (dec.) (from methanol).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([C:17](O)=[O:18])[N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[NH2:44][C@H:45]([C:49]([OH:51])=O)[CH2:46][CH2:47][SH:48]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([C:17](=[O:18])[NH:44][CH:45]3[CH2:46][CH2:47][S:48][C:49]3=[O:51])[N:13]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@@H](CCS)C(=O)O
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1C[C@@H](C(=O)NC1CCSC1=O)N(C(=O)OC(C)(C)C)C2
Reaction time: 16 h
Yield: 56.8 %

Procedure:
A solution of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,5-(S),6-tri-carboxylic acid 3,6-di-tert-butyl ester (0.30 g, 0.75 mmol) and triethylamine (0.21 mL, 1.51 mmol) in tetrahydrofuran (10 mL) was cooled to −20° C. before isobutyl chloroformate (103 μL, 0.75 mmol) was added. The reaction mixture was stirred 15 min at −20° C. before homocystein hydrochloride (116 mg, 0.75 mmol) was added. The cooling bath was removed and the reaction mixture was left for 16 hours at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography (SiO2, Flash 40, heptane/ethyl acetate 2:1) to give 212 mg (56%) of 2-amino-5-(S)-(2-oxo-tetrahydro-thiophen-3-ylcarbamoyl)-4,7-dihydro-5H-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>ClCCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[C:3]1([C@@H:2]2[CH2:1][C@H:11]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:3]1([C@H:2]2[CH2:1][C@H:11]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a suspension of styrene (3.00 g) and rhodium(II) acetate dimer (40.0 mg) in 1,2-dichloroethane (29.0 mL), a solution of ethyl diazoacetate (3.03 mL) in 1,2-dichloroethane (29.0 mL) was added over a period of 4 hours and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (n-hexane:diethyl ether=20:1) to give ethyl trans-2-phenylcyclopropanecarboxylate as a colorless oil (2.42 g) and ethyl cis-2-phenylcyclopropanecarboxylate as a colorless oil (1.51 g).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH2:20][OH:21])([CH3:15])([CH3:14])[CH3:13].CCN(CC)CC>C(Cl)Cl>[C:12]([O:16][C:17]([NH:18][CH2:19][CH2:20][O:21][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])=[O:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.7 %

Procedure:
Tosyl chloride (1.50 g, 7.87 mmol) was added to a solution of (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (0.84 g, 5.2 mmol) and Et3N (1.23 mL, 8.82 mmol) in CH2Cl2 (26 mL), and the solution was stirred at room temperature for 17 h. The solution was washed with H2O (15 mL), and the aqueous phase was extracted with CH2Cl2 (10 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (20% EtOAc/hexanes) gave yellow crystals (1.29 g, 79%). 1H NMR (CDCl3) δ 1.41 (s, 9H), 2.45 (s, 3H), 3.38 (m, 2H), 4.07 (m, 2H), 4.82 (br s, 1H), 7.35 (d, 2H, J=8.1 Hz), 7.79 (d, 2H, J=8.1 Hz).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:11])[C:8]([NH2:10])=[O:9])=[CH:3][CH:2]=1.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1>O1CCCC1.O1CCOCC1>[NH2:10][C:8](=[O:9])[C@@H:7]([NH:11][CH2:13][CH2:12][CH2:18][S:15]([OH:17])(=[O:16])=[O:14])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC(=O)[C@@H](NCCCS(=O)(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
To a solution of L-Phenylglycine amide (670 mg, 5.9 mmol) in tetrahydrofuran (10 mL) and 1,4-dioxane (4 mL) was added 1,3-propanesultone (674 mg, 5.6 mmol). The solution stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in 50% water/EtOH mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (50 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (743 mg, 50%). 1H NMR (D2O, 500 MHz) δ ppm 7.38 (m, 5H), 4.92, (s, 1H), 3.01 (m, 1H), 2.91 (m, 1H), 2.78 (t, 2H, J=7.3 Hz), 2.0 (m, 2H). 13C (D2O, 125 MHz) δ ppm 170.15, 130.95, 130.24, 129.94, 128.74, 63.40, 47.99, 44.92, 21.27. [α]D=−124° (c=0.0041 in water), ES-MS 271 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[NH:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:10]3=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(#N)C>[ClH:20].[Cl:20][CH2:21][C:22]([N:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH:8]=2)[C:13]([CH3:17])([CH3:16])[CH2:14]1)=[O:23]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)CNc2cc(Cc3ccc(F)cc3)cnc21
Solvent: CC#N
Product: CC1(C)CN(C(=O)CCl)c2cc(Cc3ccc(F)cc3)cnc21
Product: Cl
Temperature: 20 °C
Reaction time: 1 h
Yield: 127.8 %

Procedure:
To a stirred suspension of 6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (6.68 g, 26 mol) in acetonitrile (20 mL) at 20° C. was added, steadily over 0.2 h, a solution of chloroacetyl chloride (3.83 g, 2.7 mL, 33.9 mmol) in acetonitrile (10 mL), maintaining the reaction mixture at or below 20° C. using an external ice-methanol bath. A clear solution resulted then, as the internal temperature reached 0° C., a solid began to crystallize from the reaction mixture. Stirring at 20° C. was continued for 1 h then toluene (20 mL) and 40-60 petroleum ether (20 mL) were added slowly and stirring continued for 0.2 h. The resulting colourless solid was collected by filtration to give the title compound (8.0 g, 83%). 1H NMR (Me-d3-OD): 8.81 (1H, s), 8.31 (1H, s), 7.39-7.29 (2H, m), 7.16-7.04 (2H, m), 4.45 (2H, s), 4.19 (4H, s), 1.58 (6H, s). MS: [M+H]+=333.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][N:5]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:8]=1>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([N:5]([CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:4][CH2:3][CH:2]([CH3:1])[CH3:32])=[O:26])=[CH:8][C:9]=1[NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCCN2CCCCC2)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
N,N-bis(3-methylbutyl)-4-nitro-3-[(3-piperidin-1-ylpropyl)amino]benzamide (1 g) in solution in a mixture of ethyl acetate/ethanol 2:1 (100 ml) and 10% palladium on charcoal (100 mg) are introduced into an autoclave. After stirring for 3 hours under a hydrogen atmosphere (3 bars) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (910 mg, 97% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH2:1][C:2]1[CH:7]([O:8][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6](=[CH2:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1O
Reactant: ClCc1ccccc1
Product: C=C1C=CN=C(N)C1OCc1ccccc1

Procedure:
2-amino-3-phenylmethoxy-4-methlylpyridine was prepared as an oil by reacting 2-amino-3-hydroxy-4-methylpyridine with benzyl chloride followingthe procedures of Example 1, Step A herein.