Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][N:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][OH:28].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1COCC1>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:8]1[C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:10][C:5]2[N:6]([C:2]([O:28][CH2:27][C:26]([F:30])([F:29])[F:25])=[N:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Reactant: OCC(F)(F)F
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: FC(F)(F)COc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A mixture 3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (38 mg, 0.1 mmol), 2,2,2-trifluoroethanol (22 μL, 0.2 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (60 μL, 0.3 mmol) and anhydrous THF (0.5 mL) in a sealed tube was stirred at 70° C. for 3 days. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 60% to 100% B, 10 min gradient, 100% B hold for 5 min, (A=90% H2O, 10% MeOH and B=10% H2O, 90% MeOH); Flow rate at 20 mL/min, UV detection at 220 nm) to yield 30 mg of the desired product with 90% purity. The impure product was further purified using a silica gel cartridge (4 g) eluting with a gradient of EtOAc (30-100%) in hexanes to afford 24 mg (55%) of the title compound as a white solid. HPLC/MS (method A): retention time=3.81 min, (M+H)+=439.1. 1H NMR (CDCl3, 400 MHz): δ 7.92 (s, 1H), 7.40-7.49 (m, 1H), 7.29-7.33 (m, 2H), 7.14-7.30 (m, 3H), 7.09 (d, J=8.56 Hz, 2H), 5.05-5.07 (m, 2H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[CH:10][C:11]=1[CH3:12]>ClCCl>[F:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[C:8]([OH:13])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)cc1F
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(O)cc1F
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
70% Nitric acid (0.759 mL, 8.42 mmol) was added dropwise to a solution of 3-fluoro-4-methylphenol (966 mg, 7.66 mmol) in dichloromethane (25 mL) at rt. The reaction was stirred for 30 min before being washed with water. The aqueous layer was extracted with dichloromethane (1×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a yellow/orange solid. The residue was purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give 5-fluoro-4-methyl-2-nitrophenol (D21, 873 mg, 67% yield) as a yellow solid.
Reaction SMILES: C([N:8]([CH2:16][C:17]1[O:21][C:20]([C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][NH:32][CH:33]2[C:42]3[N:41]=[CH:40][CH:39]=[CH:38][C:37]=3[CH2:36][CH2:35][CH2:34]2)[C:26]([OH:28])=[O:27])=[O:23])=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(OC(C)(C)C)=O.[ClH:43].O1CCOCC1>CO>[ClH:43].[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH2:16][C:17]1[O:21][C:20]([C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH2:31][NH:32][CH:33]2[C:42]3[N:41]=[CH:40][CH:39]=[CH:38][C:37]=3[CH2:36][CH2:35][CH2:34]2)[C:26]([OH:28])=[O:27])=[O:23])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCNC2CCCc3cccnc32)C(=O)O)o1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(N[C@@H](CCCNC1CCCc2cccnc21)C(=O)O)c1ccc(CNCc2ccccn2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound obtained in Example 11-5 (30.6 mg) was dissolved in methanol (0.7 ml), and 4 mol/l hydrochloric acid/dioxane solution (0.7 ml) was added. The mixture was stirred for 3 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (1 g, chloroform/methanol/water=7/3/0.5). The obtained product was added with an aqueous solution of hydrochloric acid, concentrated and then azeotropically distilled with water. The resulting solid was washed with ether to obtain a hydrochloride of the title compound (22.7 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[CH2:31][S:32](Cl)(=[O:34])=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][S:32]([CH2:31][C:30]4[CH:36]=[CH:37][CH:38]=[CH:39][C:29]=4[Cl:28])(=[O:33])=[O:34])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NS(=O)(=O)Cc4ccccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-chlorobenzylsulfonyl chloride.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[C:7]([N:12]=[C:13]=[O:14])(=[O:11])[C:8]([CH3:10])=[CH2:9]>C(Cl)(Cl)Cl.ClCCCl>[C:7]([NH:12][C:13](=[O:14])[O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: CN(C)CCO
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)OCCN(C)C
Yield: 99.9 %

Procedure:
Dimethylaminoethanol (0.89 g; 10 mmol) was dissolved in dry chloroform (20 ml) under ice-cooling, and a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (5 ml) was dropwise added thereto under nitrogen stream. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure to give dimethylaminoethyl N-methacryloylcarbamate (2.00 g), which was recrystallized from a mixture of benzene and hexane to give colorless needle-like crystals. M.P., 71°-73° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(N(CC)C(C)C)(C)C>CCOC(C)=O>[Cl:11][C:12]1[C:13]([C:14]([NH:1][C:2]2[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[O:15])=[CH:17][CH:18]=[CH:19][N:20]=1
Reactant: COc1nccc(C)c1N
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nccc(C)c1NC(=O)c1cccnc1Cl
Reaction time: 10 h
Yield: 86.9 %

Procedure:
To a solution of 0.4 g (2.9 mmol) of 3-amino-2-methoxy-4-methylpyridine and 0.5 g (2.9 mmol) of 2-chloronicotinoyl chloride in EtOAc at 0° C. was added 0.4 g (3.0 mmol) of N,N-diisopropylethylamine. Stirring was continued for 10 h at which point the mixture was washed with 0.1N HCl , dried (MgSO4), concentrated and purified by flash chromatography on silica gel (1:1 EtOAc:hexanes) to yield 0.7 g (88%) of the desired material. m.p.: 145°-146° C. (Recrystallized from ethyl acetate).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1.C1COCC1.C([Li])CCC.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[C:3]1[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cn1ccc2cccnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1c(B2OC(C)(C)C(C)(C)O2)cc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
To a −78° C. solution of 1-methyl-1H-pyrrolo[2,3-b]pyridine (example Rupp-28) (1.17 g, 8.85 mmol) and THF (12 mL) is added 1.6M n-Bu—Li (6.6 mL, 10.62 mmol). The solution is heated to a reflux for 1 hour, cooled to ambient temperature, and 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.60 mL, 17.70 mmol) is added. After 1 hour, the solution is diluted with CH2Cl2 (100 mL), washed with water (2×100 mL), brine (75 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (5%-15% EtOAc gradient) to furnish the title compound (0.25 g, 0.97 mmol, 11%). 1H NMR (CDCl3), δ 1.38 (s, 12H), 4.07 (s, 3H), 7.02 (dd, J=7.9, 4.7 Hz, 1H), 7.07 (s, 1H), 7.92 (d, J=7.9, 1.8 Hz, 1H), 8.39 (d, J=4.7, 1.8 Hz, 1H) ppm. LC/MS (m/z): calcd. for C14H19BN2O2 (M+H)+: 259.2. found: 258.7.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[CH3:16][O:15][CH2:14][C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a stirred solution of 463 mg (2.43 mmol) of BOC-leucinol in 2 ml of tetrahydrofuran at -78° C. under argon is added 2.4 mL (2.4 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran. After 10 minutes, 0.3 ml (4.8 mmol) of methyliodide was added and the resulting mixture is allowed to warm to room temperature. It is then heated to reflux for 1 hour and then cooled. The mixture is partitioned between 40 ml of dichloromethane and 30 ml portions of dichloromethane. The combined residue is chromatographed on silica gel with 15% ethyl acetate in hexane to give 405 mg (1.75 mmol, 83%) of BOC-leucinol methyl ether. 1H-NMR (CDCl3): δ0.9 d (d, d×3H, J=6 Hz), 1.44, 3.33.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[NH:44][CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].[CH:50](=O)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(O)(=O)C>CN(C)C=O>[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[N:44]([CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (1.083 g) was added to a mixture of 1-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester (981 mg, Example 121), benzaldehyde (434.1 mg) and acetic acid (245.6 mg) in dimethylformamide (15 mL). The reaction was stirred under nitrogen at room temperature for 2 hours. The reaction was quenched by the addition of saturated NH4Cl solution (2 mL), followed by the addition of H2O (10 mL). The resulting solution was diluted with 120 mL of H2O which caused precipitation of product. The solution was neutralized with saturated NaHCO3 solution to pH=7 to precipitate additional product. The mixture was filtered thru a celite pad. The collected solid was rinsed with water (35 mL×2). The solid was dissolved with EtOAc (50 mL) and then eluted through the celite pad. The filtrate (EtOAc solution) was washed with H2O (15 mL×2) and brine (15 mL×1), dried over Na2SO4 and concentrated to give crude product, which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 1-{3-[(R)-((2S,5R)-4-benzyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester as pink solid (570 mg; 49%). 1H NMR (300 MHz, CDCl3) δ 7.47 (m, 3H), 7.26 (m, 6H), 7.07 (dd, J=8.0, 8.0 Hz, 1H), 6.60 (m, 2H), 6.54 (s, 1H), 5.04 (s, 1H), 4.50 (m, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.98 (d, J=13.0 Hz, 1H), 3.69 (m, 1H), 3.18 (d, J=13.0 Hz, 1H), 3.02 (m, 2H), 2.70-2.52 (m, 5H), 2.00 (m, 3H), 1.73 (m, 31H), 1.26 (t, J=7.0 Hz, 3H), 1.10 (d, J=6.0 Hz, 3H), 1.02 (d, J=6.3 Hz, 3H).
Reaction SMILES: C[O-].[Na+].I.[NH:5]=[C:6]1[N:10]([CH3:11])[CH2:9][CH2:8][S:7]1.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH3:11][N:10]1[CH2:9][CH2:8][S:7][C:6]1=[N:5][C:19]([NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:20]
Reactant: S=C=Nc1ccccc1
Reactant: CN1CCSC1=N
Agent: C[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Product: CN1CCSC1=NC(=S)Nc1ccccc1

Procedure:
Sodium methoxide (2.16 g) was added to a mixture of 2-imino-3-methylthiazolidine hydroiodide (10.0 g) in ethanol (50 ml) and brought to reflux, with stirring. Phenylisothiocyanate (5.4 g) in ethanol (20 ml) was added to the mixture over 5 minutes and the resultant mixture heated under reflux, with stirring, for one hour then cooled in ice. Filteration gave analytically pure product, mpt 169°-170°, which may be recrystallised from isopropanol.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.CO.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C@@H:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[CH3:53])[C@@H:43]([C:54]([OH:56])=[O:55])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[CH3:1][O:55][C:54]([C@@H:43]1[C@H:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[CH3:53])[CH2:45][CH2:46][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:40])[CH2:42]1)=[O:56]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (2.66 g) in THF (30 ml) was added diethyl azodicarboxylate (1.58 mL) at 0° C. After 30 minutes, methanol (1.58 mL) and a solution of (3R,4R)-4-o-tolyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester in THF (30 mL) were added subsequently at 0-5° C. The reaction mixture was stirred for 3 h at room temperature. The reaction was quenched with a saturated aqueous solution of NH4Cl, tert-butyl methyl ether was added, and the phases were separated. The inorganic one was extracted with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, CH2Cl2 to CH2Cl2/MeOH 95:5) yielded (3R,4R)-4-o-tolyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a colorless gum, MS: 334.1 ([M+H])+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:24][CH:25]([NH2:30])[C:26]([F:29])([F:28])[F:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][C@@H:25]([CH3:24])[C:26]([F:29])([F:28])[F:27])=[O:21])=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(N)C(F)(F)F
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Product: C[C@H](NC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1)C(F)(F)F
Yield: 98 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (150 mg, 0.45 mmol) was converted, using L-2,2,2-trifluoro-1-(methyl)ethylamine instead of ethanolamine, to the title compound (190 mg, 98%) which was obtained as a white solid. MS: m/e=424.0 [M−H]−.
Reaction SMILES: [C:1](Cl)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.ON1C(=O)CCC1=O.[NH2:31][CH2:32][CH2:33][SH:34]>O>[C:1]([NH:31][CH2:32][CH2:33][SH:34])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: NCCS
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC(=O)NCCS
Temperature: 23 °C
Reaction time: 4 h

Procedure:
Myristoyl chloride (1.0 mmol) was added with vigorous string to ice-cooled dry pyridine (1.0 ml), and followed immediately by N-hydroxysuccinimide (1.5 mmol). The mixture was stirred for 4 h at ambient temperature (˜23° C.). 2-aminoethanethiol free base (1.1 mmol) was added as solid to the mixture and allowed to react for 6 h at ambient temperature, followed by 3 days at 4° C. The product was treated with water (5 ml), stirred for 1 h at ambient and filtered, washing with cold water. The white solid was dissolved in dimethylsulphoxide and reprecipitated with water and then vacuum dried over phosphorous pentoxide. The final yield was 0.21 g (˜70%). Thiol titration using Ellman's reagent indicated that the product contained ˜45% free thiol.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: Fc1ccccc1CBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2F)cc1
Temperature: 80 °C
Yield: 79.2 %

Procedure:
A suspension of 1-(bromomethyl)-2-fluorobenzene (D91, 11.5 g, 60.8 mmol), 4-hydroxybenzaldehyde (5.3 g, 43.3 mmol) and K2CO3 (12.0 g, 86.8 mmol) in acetone was divided in three equal parts and heated in a microwave apparatus at 80° C. for 40 min. The mixtures were diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. The residue was purified via flash chromatography (cyclohexanes:ethyl acetate 95:5) to give the title compound (7.9 g, 79%). Rf (cyclohexanes:ethyl acetate 8:2): 0.38.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[O:22][CH2:23][O:24][CH3:25])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[CH3:21][O:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:8]=3[N:9]=2)=[C:13]([O:22][CH2:23][O:24][CH3:25])[CH:14]=1
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(CBr)cccc2o1
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCOc1cc(OC)c(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
A mixture of 6 (612 mg, 1.5 mmol), 2-(aminomethyl)pyridine (1.08 g, 10 mmol), and Na2CO3 (excess) in CH3CN (30 mL) was stirred overnight at room temperature. Insoluble material was removed by filtration and the filtrate was concentrated in vacuo. Water (20 mL) was added to the residue, which was extracted with ethyl acetate (20 mL) three times. The combined organic layer was washed with brine and water, dried over MgSO4, and evaporated. The resulting oily material was purified by silica gel column chromatography (CHCl3-ethyl acetate) to afford 7 as pale yellow oil (112 mg, 17%): 1H-NMR (500 MHz, CDCl3) δ53.56 (s, 3H), 3.95 (s, 3H), 3.97 (s, 3H), 4.02 (s, 2H), 4.30 (s, 2H), 5.27 (s, 2H), 6.85 (s, 1H), 7.15 (dd, 1H, J=7.5, 5.0 Hz), 7.28 (t, 1H, J=7.5 Hz), 7.33 (d, 1H, J=7.5 Hz), 7.42 (d, 1H, J=7.5 Hz), 7.47 (d, 1H, J=7.5 Hz), 7.64 (m, 2H), 8.55 (d, 1H, J=5.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[NH:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11](O)=[O:12]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]([NH:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:12]
Reactant: Cc1cc(N)no1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)CCN)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of DMAP (9.77 g, 0.08 mol), TEA (55.23 ml, 0.396 mol) and DCI (49.01 ml, 0.317 mol) in DCM (250 ml) is treated with 5-methyl-isoxazole-3-ylamine (28.8 g, 0.290 mol) and Boc-Beta-Ala-OH (50 g, 0.264 mol). The reaction mixture is stirred at room temperature for 18 hours and then diluted with DCM (1750 ml). The mixture is washed with 10% citric acid (2×500 ml), saturated sodium hydrogen carbonate solution (2×500 ml) and brine (600 ml). The organic portion is dried (MgSO4), concentrated in vacuo and the crude residue is stirred with iso-hexanes (750 ml) for 1 hour. The resulting solid is dissolved in dioxane (400 ml) and treated with 4M HCl in dioxane (350 ml). After 1 hour the precipitate is filtered and washed with dioxane (100 ml) to afford the title compound as the hydrochloride salt [MH+169.84].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([NH:14][CH3:15])=[O:13])=[C:7]([OH:16])[CH:6]=[CH:5]2.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([NH:14][CH3:15])=[O:13])=[C:7]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:6]=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNC(=O)c1c(O)ccc2cc(Br)ccc12
Agent: c1c[nH]cn1
Product: CNC(=O)c1c(O[Si](C)(C)C(C)(C)C)ccc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A mixture of 6-bromo-2-hydroxy-N-methyl-1-naphthamide (2.50 g), tert-butyldimethylsilyl chloride (1.61 g), and imidazole (912 mg) in DMP (30 mL) was stirred for 2 h at room temperature. After dilution with water, the resulting mixture was extracted with AcOEt. The organic layer was washed with water and brine followed by concentrating in vacuo. The residue was passed through silica gel plug (hexane:AcOEt=1:1). The elute was concentrated, and the residue was washed with hexane to give the titled compound (3.33 g) as colorless needles.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[H-].[Na+].[C:12]1([CH:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][CH2:20][O:21][C:22](=[O:28])[CH2:23][C:24]([CH2:26]Cl)=[O:25])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>C1COCC1>[C:12]1([CH:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][CH2:20][O:21][C:22](=[O:28])[CH2:23][C:24](=[O:25])[CH2:26][O:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCCc1ccccn1
Reactant: O=C(CCl)CC(=O)OCCC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(COCCc1ccccn1)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
503 mg (4.08 mmol) of 2-(pyridine-2-yl)ethanol was added dropwise to a suspension of 326 mg (8.16 mmol) of sodium hydride (60% oily) in 10 ml of THF at 0° C., and they were stirred for 30 minutes. A solution of 0.90 mg (2.72 mmol) of (3,3-diphenylpropane-1-yl)4-chloroacetoacetate in 3 ml of THF was added dropwise to the reaction mixture, and they were stirred at room temperature overnight. After the addition of methanol, the reaction mixture was concentrated and fractionated with ethyl acetate and water. After the drying over sodium sulfate followed by the purification by the silica gel chromatography (methylene chloride/methanol=100/1), the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](I)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:36][CH3:37])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: CCI
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2
Product: CCOc1cc2c(cc1OC)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl iodide