Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([NH:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[C:20]([OH:37])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:49][C:50](Cl)=[O:51].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]4[N:30]([CH:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[C:50](=[O:51])[CH2:49][O:37][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(NC4CCOCC4)cc3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(C3CCOCC3)C(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of tert-butyl(1-(4-(6-hydroxy-3-phenyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)phenyl)cyclobutyl)carbamate (240 mg, 0.46 mmol) in dry THF (11 mL) was added N,N-diisopropylethylamine (0.41 mL, 2.32 mmol). 2-chloroacetyl chloride (0.19 mL, 2.32 mmol) was added dropwise at 0 C. The resulting mixture was stirred overnight at room temperature. A saturated solution of NaHCO3 (8 mL) was added and the mixture was stirred under reflux for 2 hours. After allowing to cool to room temperature, the organic phase was separated and the aqueous phase extracted with AcOEt (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 50% EtOAc in cyclohexane) to give the title compound (154 mg, 59%). 1H NMR (500 MHz, CDCl3): 7.45 (1H, s), 7.24-7.22 (5H, m), 7.19-7.17 (2H, m), 7.14-7.12 (2H, m), 4.94 (1H, s), 4.71 (2H, s), 4.60-4.55 (1H, m), 4.07-4.03 (2H, m), 3.45 (2H, t), 2.63-2.54 (2H, m), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (3H, m), 1.40-1.10 (9H, br).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=O)(=[O:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:17]([C:16]3[CH:15]=[C:14]([C:11](=[O:13])[CH3:12])[CH:22]=[CH:21][CH:20]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: CC(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-acetylbenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 2.72 (s, 3 H), 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 7.80 (t, J=8.1 Hz, 1 H), 8.31 (ddd, J=8.1, 1.4, 1.2 Hz, 1 H), 8.47 (ddd, J=8.1, 1.4, 1.2 Hz, 1 H), 8.59 (ddd, J=8.1, 2.0, 1.8 Hz, 1 H), 8.75 (dd, J=5.2, 1.6 Hz, 1 H), 8.81 (t, J=1.4 Hz, 1 H), 9.32 (dd, J=2.4, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([N:6]3[C:2]([OH:1])=[C:3]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=4)[CH:4]=[N:5]3)=[N:8][CH:9]=2)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NC4CC4)cn3)c2O)ccn1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and cyclopropanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.49-0.57 (m, 2 H) 0.63-0.71 (m, 2 H) 2.80 (td, J=7.3, 3.8 Hz, 1 H) 3.82 (s, 3 H) 7.41 (br. s., 1 H) 7.48 (d, J=5.6 Hz, 1 H) 8.01 (d, J=5.8 Hz, 1 H) 8.27-8.35 (m, 1 H) 8.38 (br. s., 1 H) 8.51-8.68 (m, 2 H) 8.76-8.85 (m, 1 H). MS m/z 352 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[Na].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(N)nc(Cl)n1
Agent: [Na]
Product: Nc1nc(N)nc(OCc2ccccc2)n1
Temperature: 130 °C

Procedure:
2,4-Diamino-6-chloro-s-triazine (2.25 g, 15.0 mmol) was added to a solution of sodium (0.43 g, 18.8 mmol) in benzyl alcohol (30 mL) under argon. The suspension was heated in a 130° C. oil bath for 3.5 h. The excess benzyl alcohol was removed under vacuum and the resulting solid was collected with the aid of benzene, and washed with water (100 mL): yield, 1.83 g (56%); mp 184-185° C. (lit. 186-188° C.; Wakabayashi et al., Nippon Dojo-Hiryogaku Zasshi, 41, 193-200 (1970)); UV (pH 1) λmax 233 nm (sh) (ε=0.589×104); (pH 6.9) 238 (sh) (0.111×104); (pH 13) 240 (sh) (0.073×104); 1H NMR δ 5.25 (s, 2H, ArCH2), 6.63 (s, 4H, NH2, exchange with D2O), 7.30-7.42 (m, 5H, ArH); MS (EI) calcd. m/z for C10H11N5O 217.0963, found 217.0955.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.O.[N+:9]([CH:12]([CH:15]=O)[CH:13]=O)([O-:11])=[O:10].[Na].CC(O)=O>O>[CH3:1][C:2]1[C:6]2[C:5](=[N:7][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:15]=2)[NH:4][N:3]=1
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Cc1cc(N)[nH]n1
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 90 °C
Yield: 52.1 %

Procedure:
A 5 mL reaction vessel was charged with 3-methyl-1H-pyrazol-5-amine (68 mg, 0.70 mmol), sodium nitromalonaldehyde monohydrate (121 mg, 0.77 mmol) and AcOH (2 mL). The flask was heated to 90° C. under a nitrogen atmosphere overnight. The following day the mixture was poured into water (10 mL), and the precipitate was filtered and rinsed with water (3×5 mL). The precipitate was triturated with minimal Et2O to provide 3-methyl-5-nitro-1H-pyrazolo[3,4-b]pyridine as a solid (65 mg, 52% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2
Reaction time: 2 h

Procedure:
To 5-methoxyindole (5.0 g) in glacial acetic acid (90 mL, 15-17° C.) was added sodium cyanoborohydride (6.41 g, 3 eq.), and the mixture was stirred 2 h. Water (250 mL) was added to the mixture, which was then cooled in an ice bath and made strongly basic with sodium hydroxide pellets. The solution was extracted with ether, which was then washed with water and brine and dried over MgSO4. The ether solution was concentrated to give 5-methoxyindoline, which was reacted without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:46])[CH:28]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH2:29][CH3:30])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:46])[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:33][CH:32]=1)[CH2:29][CH3:30])[CH3:25]
Reactant: CCOC(=O)C(CC)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Product: CCOC(=O)C(CC)c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-butyric acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C(=O)CCC1C(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A suspension containing (2S)5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (10.00 g, 0.044 mol, 1.0 equivalent), benzyl bromide (7.88 g, 0.046 mol, 1.05 equivalents), and potassium carbonate (15.20 g, 0.11 mol, 2.5 equivalents) in DMF (200 ml) was allowed to stir at 65° C. overnight. The reaction was allowed to cool to room temperature and the mixture was filtered through Celite. The solid was rinsed with ethyl acetate (100 ml) and the resulting filtrate was partitioned between ethyl acetate and saturated brine solution. The organic layer was washed with saturated brine (3×100 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude, colorless oil was chromatographed on silica to afford 5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester as a colorless oil (8.20 g, 0.026 mol, 59% yield). Analysis H1 NMR (400 MHz, CDCl3): 7.36 (5H, broad s), 5.20 (2H, d), 4.64 (1H, dd), 2.44–1.96 (4H, m), 1.41 (9H, s). MS (LC-MS): Calculated for C17H21NO5 319.14, found 320.19 (M+H)+.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH:7]=[O:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[C:13]([Mg]Br)#[CH:14]>C1COCC1>[S:1]1[C:5]([CH2:6][CH:7]([OH:8])[C:13]#[CH:14])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: C#C[Mg]Br
Reactant: O=CCc1cc2ccccc2s1
Solvent: C1CCOC1
Product: C#CC(O)Cc1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of crude 9-3 (8.77 g) in THF (100 mL) was added to a solution of ethynylmagnesium bromide (450 mL, 225 mmol, 0.5 M/THF) at 0° C. by cannula. The mixture was stirred for 1 h at 0° C. and for 1 h at room temperature. The reaction was then quenched by addition of 200 mL saturated NH4Cl solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (10% 20% ethyl acetate/hexanes) gave 8-4 (7.67 g, 37.9 mmol, 84% from 9-2).
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O1CCCC1>[CH2:10]([O:17][C:18]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(N)CC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-aminobutyric acid (0.52 g), 2 mol/L aqueous sodium hydroxide solution (10 mL) and tetrahydrofuran (10 mL) was added benzyloxycarbonyl chloride (1.07 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue (solid) was treated with n-hexane. The crystals were collected by filtration, washed with n-hexane and dried under reduced pressure to give 3-benzyloxycarbonylaminobutyric acid (0.59 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added 1,1′-carbonylbis-1H-imidazole (0.59 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia solution (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with diethylether. The insoluble material was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 3-benzyloxycarbonylaminobutyramide (0.54 g). The obtained 3-benzyloxycarbonylaminobutyramide (76 mg) was dissolved in methanol (3 mL). To the solution was added 10% palladium-carbon powder (20 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (32 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[C:20]5[CH2:21][CH2:22][CH:23]([C:25]([OH:27])=O)[CH2:24][C:19]=5[S:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.C(O)(=O)C(O)=O.[O:34]1[C:37]2([CH2:40][NH:39][CH2:38]2)[CH2:36][CH2:35]1>>[O:34]1[C:37]2([CH2:40][N:39]([C:25]([CH:23]3[CH2:22][CH2:21][C:20]4[C:13]5[C:12]([NH:11][C:9]6[CH:8]=[CH:7][C:5]7[NH:6][C:2](=[O:1])[S:3][C:4]=7[CH:10]=6)=[N:17][CH:16]=[N:15][C:14]=5[S:18][C:19]=4[CH2:24]3)=[O:27])[CH2:38]2)[CH2:36][CH2:35]1
Reactant: C1CC2(CNC2)O1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Agent: O=C(O)C(=O)O
Product: O=C(C1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1)N1CC2(CCO2)C1

Procedure:
50 mg (125 μmol) (RS)-4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to example 2) were transformed in analogy to example 3 using 1-oxa-6-azaspiro[3.3]heptane ethanedioate (1:1) to give after working up and purification 31.7 mg (50%) of the title compound.
Reaction SMILES: CC(C)=O.[C:5]1([C@@H:11]([NH2:13])[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:5]1([C@H:11]([NH2:13])[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[C@H](N)c1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H](N)c1ccccc1
Yield: 234 %

Procedure:
The above two crystals were combined (0.89 g), 13 ml of a mixed solution of acetone:water=8:5 was added, and stirring was carried out at 55° C. 0.47 g of (S)-(−)-1-phenylethylamine was added to this solution, and it was stirred at room temperature for 15 hours. The resulting crystals were filtered, yielding 1.10 g of (R)-(−)-1-phenylethylamine salt.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:25])[N:15]([CH3:24])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2ccccc2n(C)c1=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(=O)c(C(=O)NC2CCCCC2)c(O)c2ccccc21
Yield: 69.5 %

Procedure:
Cyclohexylamine (2.0 mL, 18.20 mmol) was added to a solution of Compound 1 (2.25 g, 9.1 mmol) in toluene (20 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered to yield 1.9 g (70%) of white solids. M.P. 145° C. 1H NMR (DMSO-d6): δ 1.26 (m, 1H), 1.38 (m, 4H), 1.54 (m, 1H), 1.68 (m, 2H), 1.86 (m, 2H), 3.62 (s, 3H), 3.87 (m, 1H), 7.37 (t, J=7.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.80 (t, J=8.4 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 10.46 (s, 1H), 17.46 (s, 1H). EIMS m/z 301 (M+1), 323 (M+23). Anal. (C17H20N2O3) C, H, N.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH:4]1[CH2:13][C:12]2[CH:11]=[C:10]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5]1)[CH3:2].C(N(CC)CC)C.[CH:41]([N:44]=[C:45]=[O:46])([CH3:43])[CH3:42]>C(Cl)Cl>[CH:41]([NH:44][C:45]([N:31]1[CH2:30][CH2:29][CH:28]([CH2:27][N:3]([CH2:1][CH3:2])[CH:4]2[CH2:5][CH2:6][C:7]3[C:12](=[CH:11][C:10]([NH:14][C:15](=[O:26])[C:16]4[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=4)=[CH:9][CH:8]=3)[CH2:13]2)[CH2:33][CH2:32]1)=[O:46])([CH3:43])[CH3:42]
Reactant: CCN(CC1CCNCC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
To an ice-cold solution of N-[7-(ethyl-piperidin-4-ylmethyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-4-methanesulfonyl-benzamide (1.3 g, 2.3 mmol) in methylene chloride (40 mL) under a nitrogen atmosphere was added the triethylamine (1.3 mL, 9.2 mmol, 4 eq.) in a single portion followed by the isopropylisocyanate (0.33 mL, 3.3 mmol, 1.4 eq). The reaction was allowed to warm to room temperature and stirred for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (75 mL) and 10% aq. sodium hydroxide (40 mL). The aqueous layer was extracted with EtOAc (2×30 mL) and the combined EtOAc layers were dried over MgSO4, filtered, and concentrated. Trituration with ether afforded 4-({ethyl-[7-(4-methanesulfonyl-benzoylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid isopropylamide 1 as a light pink solid (1.1 g). [M+H]+=555.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([Br:31])[N:14]=1)[N:11]([C@@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@H](C)c2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2[C@H](C)c2ccccc2)c1O
Yield: 67.7 %

Procedure:
A mixture of (R)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (90 mg, 0.225 mmol) and N-bromosuccinimide (44 mg, 0.248 mmol) in CH2Cl2 (1 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes+1% AcOH) to give 73 mg of the title compound as a yellow solid. MS: (−) m/z 477.19, 479.15 (M−1, 79/81Br).
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:5][CH:4]([NH:6][C:7](=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:9]=2)[CH2:3]1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=1[F:33].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:18]2[CH2:17][CH2:16][N:15]([CH2:14][C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[C:7]([NH:6][CH:4]3[CH2:5][C:2]([F:1])([F:22])[CH2:3]3)=[O:21])[CH2:20][CH2:19]2)=[O:29])=[CH:26][C:25]=1[F:33]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: O=C(NC1CC(F)(F)C1)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC4CC(F)(F)C4)c3)CC2)cc1F
Reaction time: 1 h
Yield: 54.7 %

Procedure:
N-(3,3-Difluorocyclobutyl)-3-(piperazin-1-ylmethyl)benzamide (5.14 mmol, 1.59 g), 4-amino-3-fluorobenzoic acid (5.14 mmol, 0.797 g) and triethylamine (15.42 mmol, 2.143 mL, 1.560 g) were stirred in dichloromethane (30 mL) at room temperature. 1-Propanephosphonic acid cyclic anhydride (7.71 mmol, 4.59 mL, 4.91 g, 50% solution in ethyl acetate) was added dropwise and the reaction stirred for 1 hour. The reaction mixture was concentrated under vacuum and the residue taken up in ethyl acetate. The organic phase was washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated under vacuum to afford the title compound (1.255 g). MS (ESI) m/z 447.5 [M+H]+
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[N:3][CH:2]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:20]([NH:27][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([NH:10][C:4]2[C:5]3[NH:9][CH:8]=[CH:7][C:6]=3[N:1]=[CH:2][N:3]=2)[CH:12]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1cccc(Nc2ncnc3cc[nH]c23)c1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cccc(Nc2ncnc3cc[nH]c23)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.9 %

Procedure:
A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153 mg), benzylamine (96 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg), 1-hydroxybenzotriazole (138 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate containing tetrahydrofuran. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→50:50). Ethyl acetate and diethyl ether were added and the precipitate was collected by filtration to give the title compound (128 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][S:10]/[C:9]/1=[N:14]\[CH:15]([CH3:17])[CH3:16].[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH:28]=O)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:18]1[C:23]2[CH:24]=[CH:25][C:26](/[CH:28]=[C:11]3/[C:12](=[O:13])[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])/[C:9](=[N:14]/[CH:15]([CH3:17])[CH3:16])/[S:10]/3)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: Cc1ccccc1N1C(=O)CS/C1=N\C(C)C
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccccc1N1C(=O)/C(=C/c2ccc3c(c2)OCCO3)S/C1=N\C(C)C
Temperature: 25 °C

Procedure:
A solution of 3-(2-methylphenyl)-2-[(Z)-isopropylimino]-thiazolidin-4-one (50 mg, 0.200 mmol), 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (49 mg, 0.300 mmol) and sodium acetate (33 mg, 0.400 mmol) in acetic acid (1 mL) is stirred at 110° C. for 5 h. The reaction mixture is cooled to rt and subjected to prep. HPLC purification. The product containing fractions are evaporated and dried to give 5-(2,3-dihydro-benzo[1,4]dioxin-6-ylmeth-(Z)-ylidene)-2-[(Z)-isopropylimino]-3-o-tolyl-thiazolidin-4-one.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C>N>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Agent: N
Product: O=C(O)[C@@H]1CCCN1C(=O)CCS

Procedure:
1-(3-Acetylthiopropanoyl)-L-proline (0.8 g.) is dissolved in 5.5 N methanolic ammonia (5 ml.) and the solution kept under argon at room temperature. After 2 hours the solvent is removed in vacuo, the residue is dissolved in water and applied to an ion exchange column on the H+ cycle [Dowex 50 (Analytical grade)] and eluted with water. The fractions that give thiol positive reaction are pooled and concentrated to dryness, yield 0.6 g. This product is crystallized from ethyl acetate-hexane as in Procedure A to obtain 1-(3-mercaptopropanoyl)-L-proline.