Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[CH2:40]([S:43](Cl)(=[O:45])=[O:44])[CH2:41][CH3:42]>C(Cl)Cl>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][CH2:21][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][S:43]([CH2:40][CH2:41][CH3:42])(=[O:45])=[O:44])=[CH:3][C:4]=2[O:31][CH3:32])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])([CH3:18])[NH:14]2
Reactant: CCCS(=O)(=O)Cl
Reactant: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Oc1ccc(-c2ccc3c(c2CNc2ccccc2OC)C(C)=CC(C)(C)N3)c(OC)c1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 25.0 mg, mmol) was dissolved in methylene dichloride (0.5 mL), triethylamine (16.2 μL, 0.116 mmol) and 1-propanesulfonyl chloride (6.5 μL, 0.058 mmol) were added thereto, and then the mixture was stirred under ice cooling for 30 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (26.8 mg) as a colorless amorphous product. (Yield 86%)
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:36])([F:19])[F:37])[CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(OC(F)(F)F)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(OC(F)(F)F)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: CC1C=CC=C(C#CC=C2CCNCC2)N=1.[OH:17][C:18]([CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)([CH3:21])[C:19]#[CH:20]>>[NH:25]1[CH2:26][CH2:27][CH:22]([C:18]([OH:17])([C:19]#[CH:20])[CH3:21])[CH2:23][CH2:24]1
Reactant: C#CC(C)(O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cc1cccc(C#CC=C2CCNCC2)n1
Product: C#CC(C)(O)C1CCNCC1

Procedure:
The title compounds were obtained following the procedure described for the compound of Example 3 and replacing the Compound of Example 2 with Compound 312a refluxing for 6 h. The crude was used without further purification in the next step.
Reaction SMILES: CNC.[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[C:9]=1[S:16]([OH:19])(=[O:18])=[O:17])([O:6]C)=[O:5].B(Br)(Br)Br>C(Cl)Cl>[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=1[S:16]([OH:19])(=[O:18])=[O:17])([OH:6])=[O:5]
Reactant: COC(=O)c1cccc(OC)c1S(=O)(=O)O
Agent: BrB(Br)Br
Agent: CNC
Solvent: ClCCl
Product: O=C(O)c1cccc(O)c1S(=O)(=O)O
Temperature: -20 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
2-Carbomethoxy-6-methoxybenzenesulfonic acid dimethylamine salt (9.0 mmoles, 2.6 g) was added dropwise at -20° C. to a solution of boron tribromide (27 mmoles, 3.8 ml) in 50 ml methylene chloride and stirred at -20° C. for 10 minutes and at room temperature overnight. The reaction was quenched with water. The pH was adjusted to 8.0 using 2N NaOH. The aqueous solution was washed with methylene chloride. The pH of the water layer was adjusted to 1.0 with 2N HCL. The intermediate was extracted with ethyl acetate and condensed. The solid triturated with ethyl acetate and filtered to yield 1.6 g of 2-carboxy-6-hydroxybenzenesulfonic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:1]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]#[N:7])[CH3:11]
Reactant: BrCCCCCBr
Reactant: CCc1cc(C#N)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1cc(C#N)ccc1N1CCCCC1
Temperature: 160 °C
Yield: 18.8 %

Procedure:
4-Amino-3-ethylbenzonitrile (3.0 g, 20.5 mmol), 1,5-dibromopentane (11.1 mL, 82.1 mmol), potassium carbonate (5.67 g, 41.0 mmol) and water (39.6 mL) were all split equally between ten microwave vials and each heated at 160° C. for 1 h. All the reaction mixtures were combined and extracted twice with ethyl acetate (40 mL) and the combined organic fractions dried (phase separator) and concentrated in vacuo. Dichloromethane was added, the mixture filtered and then the filtrate was purified by silica chromatography, eluting with 2-5% ethyl acetate in hexane to give the title compound as a colourless oil (823 mg, 3.85 mmol). Analysis indicated that the compound contained small amounts of a dibromopentane impurity. MS (ES): C14H18N2 requires 214; found 215 (MH+).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[O:23]=[C:21]1[CH2:22][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Reaction time: 14 h
Yield: 20 %

Procedure:
PCC (4.94 g, 22.8 mmol) was added portion wise to a stirred solution of tert-butyl-3-hydroxyazetidine-1-carboxylate (3.3 g, 19 mmol) in DCM (50 mL) at 20-35° C. and the reaction mixture was stirred continuously at the same temperature for 12-16 h. The reaction mixture was filtered and the filtrate was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography (using 60-120 silica gel and 10% EtOAc in Hexane as eluent) to afford 650 mg of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 4.66 (4H, s), 1.4 (9H, s) ppm.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17]([NH2:19])=O)[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CN(C)P(=O)(N(C)C)N(C)C>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17]#[N:19])[C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C1CCCc2ccc(-c3ccccc3)nc21
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CC1CCCc2ccc(-c3ccccc3)nc21
Temperature: 220 °C
Yield: 44.9 %

Procedure:
2-Phenyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (6 g.) was dissolved in hexamethylphosphorictriamide (24 ml.) and the solution heated at 220° C for 2 hours. The cooled reaction mixture was poured onto water (50 ml.), extracted with chloroform (3 × 100 ml.) and the combined extracts washed with water (3 × 100 ml.), dried and evaporated to dryness. The residual oil was chromatographed on silica gel by elution with chloroform giving 2-phenyl-8-cyano-5,6,7,8-tetrahydroquinoline (2.5 g.) recrystallised from ether as colourless needles mpt. 100° C. Further elution with chloroform gave N,N-dimethyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (1.1 g.) which recrystallised from ether as colourless needles mpt. 140° C. Found: C, 77.17; H, 7.22; N, 10.24%. C18H20N2O requires: C, 77.11; H, 7.19; N, 9.99%.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)=O>>[O:31]1[C:30]2[CH:35]=[CH:36][C:27]([C:25]3[N:12]=[C:11]([C:9]4[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=4)[S:13][CH:24]=3)=[CH:28][C:29]=2[O:34][CH2:33][CH2:32]1
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3ccc4c(c3)OCCO4)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 71 %

Procedure:
4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (205 mg, 71%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethan-1-one (available from Alfa Aesar) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J=1.8 Hz, 2H), 8.24 (dd, J=8.0, 1.9 Hz, 1H), 8.11-8.16 (m, 2H), 7.78 (t, J=7.8 Hz, 1H), 7.52-7.68 (m, 3H), 7.43 (t, J=8.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 1H), 4.29 (s, 4H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCN
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
2-Acetylthiomethyl-3-phenylpropanoic acid is reacted with oxalyl choride and the resulting acid chloride is then reacted with β-alanine, ethyl ester, hydrochloride in the presence of diisopropylethylamine as more fully described in Example 1 of European Patent Application 136,883 to give (±)-3-[[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]propanoic acid, ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH:13]2[CH2:15][CH2:14]2)=[CH:11][C:10]([N+:16]([O-])=O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:12]([CH:13]2[CH2:14][CH2:15]2)=[CH:11][C:10]([NH2:16])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc([N+](=O)[O-])cc1C1CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1nc(N)cc1C1CC1
Yield: 90.7 %

Procedure:
1.2 g (4.74 mmol) of tert-butyl-3-nitro-5-cyclopropyl-1H-pyrazole-1-carboxylate were dissolved in 20 ml of ethanol and hydrogenated in presence of 200 mg of palladium on charcoal 10% at 50 psi and room temperature to give, after filtration on celite and evaporation of the solvent, 0.96 g (95% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:24]([O-])(O)=O.[Na+]>C1COCC1>[CH3:24][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[N:9]=[C:8]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C([O-])O
Reactant: Cc1cccc2nc(-c3ccccc3[N+](=O)[O-])[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cccc2c1nc(-c1ccccc1[N+](=O)[O-])n2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A solution 4-methyl-2-(2-nitrophenyl)-benzimidazole (5.06 g, 20 mmol) in THF (50 mL) was added to a stirring suspension of NaH (1.2 g, 60% dispersion in mineral oil, 30 mmol) in THF (50 mL) at 0° C. under N2. The mixture was stirred at 0° C. for 30 min. and was then allowed to warm to r.t for 1 h to form a orange solution. MeI (8.52 g, 60 mmol) was transfered into the above mixture dropwisely by a cannular at r.t under N2. This mixture was stirred for 24 h under N2 to result in a pale yellow solution. Saturated NaHCO3 (100 mL) was added. The water layer was extracted with CHCl3, the combined extracts was washed with brine, dried over Na2SO4. After removing of solvent, the residue was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate (1:1) as the eluent to give N-methyl-4-methyl-2-(2-nitrophenyl)-benzimidazole (3.0 g, 58%) as a yellow needle crystal. Rf=0.21 (hexane/ethyl acetate 1:1); 1H NMR (300 MHz, CDCl3) δ 2.68 (s, 3H), 3.60 (s, 3H), 7.12 (m, 1H), 7.26 (m, 2H), 7.65-7.80 (m, 3H), 8.23 (d, J=7.9 Hz, 1H). HRMS: Calcd for C15H13N3O2 267.1007, found 267.1007.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:65][C@H:66]([C:71](O)=[O:72])[CH2:67][CH:68]([CH3:70])[CH3:69])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:65][C@@H:66]([CH2:67][CH:68]([CH3:70])[CH3:69])[C:71]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:72]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.6 %

Procedure:
To a solution of propyl 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoate (12, 190 mg, 0.44 mmol), DCC (111 mg, 0.54 mmol) and DMAP (6 mg, 0.045 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (158 mg, 0.45 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (6 mL) and cooled to 0° C. Dimethylamine (6 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 30% ethyl acetate in petroleum ether as an eluent to yield 122 mg (51%) of the title compound as a colorless semi solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Br[CH2:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>CN(C=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:1]4[CH2:34][CH2:35][CH2:36][C:37]4=[O:38])[CH:3]=3)[C:13]2=[O:14])=[CH:17][CH:18]=1
Reactant: COc1nn(-c2cccc(N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Reactant: O=C(Cl)CCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nn(-c2cccc(N3CCCC3=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 80 °C
Yield: 5.2 %

Procedure:
According to Scheme 9 Step 2: To a solution of 2-(3-aminophenyl)-4-(4-chlorobenzyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione (100 mg, 0.27 mmol) (1 mL) and NEt3 (78 μL, 0.55 mmol) in DMF was added bromobutyryl chloride (36 μL, 0.30 mmol). The reaction mixture was heated at 80° C. for 4 hours then quenched with water and extracted with ethyl acetate. The organic layers were combined and successively washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified on a prepacked silica column (10 g) 8:2 cyclohexane/Ethyl acetate 80/20 to afford 4-(4-chlorobenzyl)-6-methoxy-2-(3-(2-oxopyrrolidin-1-yl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 4.145 as a white solid (6 mg, 5%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[N:9]([CH2:12][C:13](OCC)=[O:14])=[C:10]=[S:11].C(N(CC)CC)C>C(#N)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][N:7]1[C:13](=[O:14])[CH2:12][NH:9][C:10]1=[S:11])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)CN=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1C(=O)CNC1=S
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
Glycine ethyl ester hydrochloride (140 mg, 1 mmol) and ethyl isothiocyanatoacetate (145 mg, 1 mmol) were dissolved in acetonitrile (6 mL), triethylamine (0.6 mL) was added thereto, and the mixture was stirred at room temperature (25° C.) for 10 minutes. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (1/1 (volume ratio)) as an eluent, to give ethyl-2-(5-oxo-2-thioxoimidazolidin-1-yl)acetate in a yield of 170 mg (yield 84.2%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([OH:17])=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[C:10]([CH:13]=1)[CH:11]=[O:12])[CH2:2][CH2:3][CH3:4].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([O:17][C:7]1[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCOc1cc(C=O)c([N+](=O)[O-])cc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1cc(C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
A mixture of 5-butoxy-4-hydroxy-2-nitrobenzaldehyde (31 g; 0.13 mole), benzyl chloride (20.2 g; 0.16 mole) and potassium carbonate (22.11 g; 0.16 mole) in 80 ml of dimethylformamide is heated for 2 hours under reflux with stirring. The reaction mixture is poured into 200 ml of ice-cold water and the precipitate filtered off. After recrystallization in a hexane/toluene mixture, 4-benzyloxy-5-butoxy-2-nitrobenzaldehyde (30.2 g; yield: 71%; yellow powder) is obtained; melting point 94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1.[Na]>C(O)C>[C:7]([C:6]([C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH:17][C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)#[N:8]
Reactant: O=Cc1cccnc1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: N#CC(=Cc1cccnc1)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of 4-chlorobenzyl cyanide (7.58 g) and pyridine-3-aldehyde (5.35 g) in absolute ethanol (50 ml) was warmed to 50° C.; 3.5 ml of a solution of sodium (2.74 g) in absolute ethanol (32 ml) was added and the mixture was left without further heating. After 1 hour, the solid product was filtered off, washed with ethanol, and then diethylether, and dried. Recrystallization of this material from ethanol (150 ml) with charcoal treatment gave 4 in 48% yield as pale yellow needles; m.p. 141°-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.I[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.CCO>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=3[CH:8]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc3cc(OC)ccc3o2)cc1
Reaction time: 2 h
Yield: 31.9 %

Procedure:
A solution of 5-Methoxy-benzofuran-2-boronic acid (1.9 g, 10 mmol), Methyl 4-iodobenzoate (2.61 g, 10 mmol), Pd(Ph3)4 (0.25 g), and 2M NaCO3 (10 ml) in toluene (40 ml) and EtOH (10 ml) was heated to reflux. After 2 hr, the reaction was cooled and the organic layer was separated dried, and concentrated to give a solid. The solid was triturated with MeOH, filtered to give 127 (0.90 g, 32%) which was used without further purification or characterization for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH3:17]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[C:20]([CH2:22]Cl)[N:21]=1.O>O1CCCC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[C:20]([CH2:22][N:3]2[C:2]([CH3:1])=[CH:6][N:5]=[CH:4]2)[N:21]=1
Reactant: Cc1c[nH]cn1
Reactant: COc1ccccc1-c1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1-c1nc(Cn2cncc2C)cs1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
To a solution of 82 mg of 4-methylimidazole in 10 ml of tetrahydrofuran at 5° C. was added 50 mg of sodium hydride in 50% oil and the resulting mixture stirred at 5° C. for 20 minutes. 2-(o-Methoxyphenyl)-4-chloromethylthiazole (240 mg) in 5 ml of the same solvent was added and the reation mixture heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and treated with 1 ml of water. The water and solvent were removed in vacuo and the residue dissolved in chloroform. The chloroform solution was washed with a brine solution, dried over sodium sulfate and concentrated to give 250 mg of crude product. The product was obtained by chromatography on 7 g of silica gel (chloroform-methanol), 40:1-v:v), 100 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]2[CH:32]=[CH:31][S:30][C:24]=2[NH:25][C:26](=O)[CH2:27][N:28]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]2[CH:32]=[CH:31][S:30][C:24]=2[NH:25][C:26](=[S:42])[CH2:27][N:28]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(CCc2ccc(C3=NCC(=O)Nc4sccc43)c(Cl)c2)cc(OC)c1OC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(CCc2ccc(C3=NCC(=S)Nc4sccc43)c(Cl)c2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution of 0.25 g (0.53 mmol) of the compound prepared in (e) above in 5 ml of toluene was added 0.13 g (0.32 mmol) of Lawesson's Reagent, and the resultant mixture was heated to 90° C. and maintained at this temperature for 3 hours. After cooling the reaction mixture to 25° C., the solvent it was diluted with 50 ml methylene chloride, washed successively with 1 ml of water and 10 ml of brine, dried over magnesium sulfate and evaporated. The crude residue was pruified by column chromatography on silica gel employing a mixture of ethyl acetate and hexane in 2:1 ratio as the eluent to yield an orange foam.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH2:3][CH2:4][CH3:5].[ClH:24]>C(OCC)(=O)C.CCOCC>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH2:3][CH2:4][CH3:5].[ClH:24]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(N)=O
Reaction time: 1 h
Yield: 83 %

Procedure:
4.12 g (12.5 mmoles) of BOC-Nva-Leu-NH2 are suspended in 15 ml of ethyl acetate, and 20 ml of a 6 n hydrochloric acid solution in ethyl acetate are added to the suspension. After one hour of standing the reaction mixture is diluted with ether, the separated precipitate is filtered off, and the resulting 3.64 g of crude product is recrystallized from 25 ml of methanol. 2.75 g (83%) of H-Nva-Leu-NH2.HCl are obtained; m.p.: 215°-216° C., Rf5 =0.45, [α]D25 =-3.47° (c=1%, in methanol).