Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:23][CH3:24])=[C:7]([CH:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[CH3:11])[CH2:2]1.CO.[CH3:27][C:28]([CH3:30])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.O.C1COCC1>[Cl:12][C:9]1[C:10]([CH3:11])=[C:5]([CH:3]2[CH2:4][N:1]([CH:28]([CH3:30])[CH3:27])[CH2:2]2)[C:6]([O:23][CH3:24])=[C:7]([CH:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH3:14])[CH:8]=1
Reactant: CC(C)=O
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CN(C(C)C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl [1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate (20 mg, 0.06 mmol) in acetonitrile (0.2 mL)/methanol (0.2 mL)/THF (0.2 mL) was added acetone (48 μL, 0.65 mmol). The mixture was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (36 mg, 0.17 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was then diluted with water and extracted with dichloromethane. The organic layers were dried over MgSO4 and concentrated to give the crude product. LCMS calculated for C21H34ClN2O3 (M+H)+: m/z=397.2. found: 397.2.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[CH2:8][CH2:7][CH:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1>O1CCOCC1>[ClH:1].[NH2:9][CH:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCC(=O)CC1
Reaction time: 1 h

Procedure:
A solution of hydrogen chloride in dioxan (0.5 ml, 2.0 mmol, 4M) was added to a stirred solution of tert-butyl 4-oxocyclohexylcarbamate (0.043 g, 0.20 mmol, commercially available from Astatech Inc., Philadelphia, USA) in dioxan (0.5 ml) and the mixture was stirred at room temperature. After 1 h, the reaction mixture was evaporated to give Intermediate 56 as a cream solid (34 mg). 1H NMR (400 MHz in d6-DMSO, 27° C., δ ppm) 8.09 (br. s, 3H), 3.51 (tt, 11, 3.5 Hz, 1H), 2.45 (m, 2H, partially obscured), 2.29 (m, 2H), 2.16 (m, 2H), 1.76 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH2:14])[CH:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:5]2.Cl[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:14][CH2:13][CH2:12][N:7]1[CH:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH2:8]1
Reactant: NCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Reactant: Clc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(CC2Cc3cc(F)ccc3CN2CCNc2ccccn2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
40 mg of 2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 180-b), 17 mg of 2-chloropyridine, and 36 mg of potassium carbonate were dissolved in 0.4 mL of DMF, followed by stirring at 120° C. overnight. After completion of the reaction, the reaction liquid was left to be cooled, and water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:ammonia saturated methanol=10:1) to obtain 6 mg (yield 13%) of a title compound as a light yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([CH2:14][CH3:15])([F:13])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[H-].[Na+].[CH3:24]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:24])[C:10](=[O:12])[C:9]([CH2:14][CH3:15])([F:13])[CH2:8][N:7]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:6]=2[N:21]=1
Reactant: CI
Reactant: CCC1(F)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC1(F)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 2-chloro-9-cyclopentyl-7-ethyl-7-fluoro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (890 mg, 2.85 mmol) in 10 mL of DMA was added sodium hydride (60% dispersion in mineral oil, 116 mg, 2.9 mmol) at 0° C., followed by the dropwise addition of methyl iodide (0.18 mL, 2.9 mmol). The reaction mixture was warmed up to rt and stirred for 1 h. The whole was poured into ice-water, extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The solution was concentrated in vacuo followed by precipitation from ether/EtOA to afford the product (750 mg, 80% yield) as light tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.3 Hz, 3 H) 1.55-1.98 (m, 10 H) 3.28 (s, 3 H) 3.70-3.93 (m, 2 H) 4.74 (t, J=7.9 Hz, 1 H) 8.25 (s, 1 H). [M+H] calc'd for C15H20ClFN4O, 327; found 327.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][CH2:29][NH:30][C:31]([C:33]2[C:37](C)=[C:36]([CH:39]=O)[NH:35][C:34]=2[CH3:41])=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][CH2:29][NH:30][C:31]([C:33]2[CH:37]=[C:36]([CH3:39])[NH:35][C:34]=2[CH:41]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl) 1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (96.8 mg, 72%).
Reaction SMILES: O1CCOCC1.[CH2:7]([O:9][CH:10]1[CH2:15][CH2:14][C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][CH2:11]1)[CH3:8].[CH3:24][N:25]1[CH2:33][C:32]2[C:27](=[C:28]([N+:43]([O-:45])=[O:44])[CH:29]=[CH:30][C:31]=2B2OC(C)(C)C(C)(C)O2)[C:26]1=[O:46].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH2:7]([O:9][CH:10]1[CH2:15][CH2:14][C:13]([C:31]2[CH:30]=[CH:29][C:28]([N+:43]([O-:45])=[O:44])=[C:27]3[C:32]=2[CH2:33][N:25]([CH3:24])[C:26]3=[O:46])=[CH:12][CH2:11]1)[CH3:8]
Reactant: CN1Cc2c(B3OC(C)(C)C(C)(C)O3)ccc([N+](=O)[O-])c2C1=O
Reactant: CCOC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC1CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 60 °C

Procedure:
Dioxane (20 mL) and water (5 mL) were taken in a three necked RB flask equipped with a nitrogen inlet and a thermometer. The solvents were deoxygenated for 15 min using nitrogen gas. Trifluoro-methanesulfonic acid 4-ethoxy-cyclohex-1-enyl ester (Compound 166D, 300 mg, 1.1 mmol), 2-methyl-7-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one (Compound 205E, 630 mg, 1.64 mmol), tetrakis triphenyl phosphine palladium catalyst (114 mg, 0.01 mmol) and cesium carbonate (889 mg, 2.7 mmol) were added. The reaction mixture was heated to 60° C. for 3 hrs. The solvents were evaporated and the residue was purified over silica gel column using (methanol:methylene chloride: 1:99). Yield: 300 mg (86%). 1H NMR (CDCl3, 400 MHz): δ1.2 (t, 3H, J=7 Hz), 1.8-2.4 (m, 6H), 3.15 (s, 3H), 3.50-3.64 (m, 3H), 4.36 (s, 2H), 5.79 (m, 1H), 7.4 (d, 1H, J=8.1 Hz), 7.63 (d, 1H, J=8.1 Hz).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:22]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=O)=O)=CC=1.[Na+].[I-:35]>CC#N>[I:35][CH2:12][C:13]12[CH2:20][CH2:19][C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:22]=3)([CH2:17][CH2:18]1)[O:15][CH2:14]2
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4cccc(Oc5ccccc5)c4)(CC2)OC3)cc1
Agent: [Na+]
Solvent: CC#N
Product: ICC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 70 °C
Yield: 86.3 %

Procedure:
A mixture of (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate (1G; 950 mg, 2.05 mmol) and NaI (3.07 g, 20.45 mmol) in MeCN (10 mL) was heated to 70° C. for 72 h. The reaction mixture was cooled to rt, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography to give the title compound (745 mg, 1.77 mmol; 87% yield) as a white solid. LCMS, [M+H]+=421; 1H NMR (400M Hz, CDCl3) δ 7.38-7.23 (m, 3H), 7.19-7.08 (m, 3H), 7.04-6.98 (m, 2H), 6.87 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 3.88 (s, 2H), 3.07 (s, 2H), 2.18-1.95 (m, 4H), 1.87-1.68 (m, 4H).
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])=[N+]=[N-].[C:25]([O:28][C:29]([CH3:31])=[CH2:30])(=[O:27])[CH3:26]>ClCCl>[C:25]([O:28][C:29]1([CH3:31])[CH2:30][N:1]1[C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])(=[O:27])[CH3:26]
Reactant: C=C(C)OC(C)=O
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Solvent: ClCCl
Product: CC(=O)OC1(C)CN1C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Yield: 17 %

Procedure:
Two solutions of p-nitrobenzyl 2-azidocarbapen-2-em-3-carboxylate (52 mg and 24 mg, 231 micromol) and 2-acetoxy-1-propene (0.25 ml each) in dichloromethane were kept 2.5 days at ambient temperature. The mixtures were combined, filtered through florisil, and evaporated under vacuum. The residue was chromatographed on four 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plates developed with 5:1 (v/v) diethyl ether-ethyl acetate. The band centered at Rf 0.25 was eluted with ethyl acetate and the eluate evaporated under vacuum to provide 15.9 mg (17%) p-nitrobenzyl 2-(2-acetoxy-2-methylaziridin-1-yl)-carbapen-2-em-3-carboxylate; IR (CH2Cl2): 1770, 1735 cm-1, NMR (CDCl3): δ 1.69 s (3H), 2.11 s (3H), 2.16 d (J=7 Hz, 1H), 2.22 d (J=7 Hz, 1H), 2.74 dd (J=8 Hz, J2 =17 Hz, 1H), 2.79 dd (J1 =3 Hz, J2 =16 Hz, 1H), 2.84 dd (J1 =5 Hz, J2 =17 Hz, 1H), 3.21 dd (J1 =6 Hz, J2 =16 Hz, 1H), 4.30 m (1H), 5.29 d (J=12 Hz, 1H), 5.35 d (J=12 Hz, 1H), 7.57 d (J=9 Hz, 2H), 8.29 d (J=9 Hz, 2H); MS (m/e): 402 (M+), 359, 342, 316, 300, 274, 258, 222.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Pd](Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ncc(Br)cc1C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
To a degassed solution of 8.35 g (36.3 mmol) of 5-bromo-3-methyl-pyridine-2-carboxylic acid methyl ester [Wu, G. G.; Wong, Y.-S.; Poirier, M. Organic Letters (1999), 1(5), 745-747] in 180 ml of dioxane were added 13.79 g (72.6 mmol) of 3-(trifluoromethyl)phenyl boronic acid and 11.54 g (108.9 mmol) of sodium carbonate (dissolved in 55 ml of H2O). While stirring, 1.33 g (1.89 mmol) of (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) was added and the reaction mixture was stirred at RT for 4 hours, then heated up to 50° C. After 90 min, it was cooled down to RT, poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 9:1 to 1:1) to give 9.35 g (87%) of the title compound as light yellow solid. MS: 296.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:6]([OH:8])[CH:7]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>CCO>[Cl:27][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:9][N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)=[C:6]([OH:8])[CH:7]=3)=[CH:18][CH:19]=[N:20]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(CN2CCOCC2)c(O)c1
Solvent: CCO
Product: Oc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1CN1CCOCC1
Yield: 39.6 %

Procedure:
5-amino-2-(morpholin-4-ylmethyl)phenol (58 mg, 0.28 mmol) and 4,7-dichloroquinoline (61 mg, 1.1 eq) were refluxed overnight in 1 mL of EtOH. The reaction mixture was then evaporated and purified by flash chromatography (DCM/MeOH/NH4OH 9:1:0.1) to yield expected compound as a brown solid (41 mg, 40% yield). LC-MS: m/z (ESI) 470.1-472.1 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10]
Reactant: Fc1ccccc1CBr
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccccc1F)OC

Procedure:
Following the procedure of Compound 11, 2-fluorobenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:29]([CH3:33])[C:30]([OH:32])=O)[CH:21]=3)=[O:19])[CH:15]=[N:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:34][NH:35][CH3:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:29]([CH3:33])[C:30]([N:35]([CH3:36])[CH3:34])=[O:32])[CH:21]=3)=[O:19])[CH:15]=[N:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Reactant: CNC
Product: CC(C(=O)N(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 at 50° C. using racemic 2-{5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}propanoic acid (Example 354) and dimethylamine.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([Cl:17])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc2ccccc2c1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)Cc1ccc2ccccc2c1

Procedure:
A solution of β-naphthylacetic acid (25 g.) in chloroform (25 ml.) was added to a solution of thionyl chloride (50 ml.) in chloroform (80 ml.) and the mixture was heated under reflux for 1 hour, cooled and evaporated to dryness. The solid residue was crystallised from petroleum ether (b.p. 80°-100° C.) to give β-naphthylacetyl chloride, m.p. 67°-70° C.
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[CH2:8]([NH:14][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCN
Reactant: COCC(Cl)C=O
Solvent: Cc1ccccc1
Product: CCCCCCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Hexylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued fo a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-hexylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].N[C:37]1[CH:38]=[N:39][CH:40]=CC=1>>[OH:35][CH:7]1[CH:8]([OH:34])[CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:14]=3[N:13]=[N:12]2)[CH2:10][CH:6]1[C:4]([NH:3][C:1]1[CH:40]=[N:39][CH:38]=[CH:37][CH:2]=1)=[O:5]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Reactant: Nc1cccnc1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)Nc4cccnc4)C(O)C3O)c2n1

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 1, step c) and 3-aminopyridine.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:20]=[C:21]([C:24](Cl)=[O:25])[S:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29]>N1C=CC=CC=1>[CH2:2]([NH:18][C:19]1[CH:20]=[C:21]([C:24]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:25])[S:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)Cl)c1
Reactant: CS(N)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)NS(C)(=O)=O)c1

Procedure:
A solution of 25 g. of 4-hexadecylamino-2-thiophenecarbonyl chloride hydrochloride and 5.6 g. of methanesulfonamide in 250 ml. of pyridine is stirred under reflux for 2 hours and then concentrated in vacuo. The residue is partitioned between water and diethyl ether; the aqueous layer acidified with 1 N hydrochloric acid and the organic layer seperated, dried over magnesium sulfate, and evaporated. Crystallization of the residual white solid from 60% aqueous acetic acid and then from methylene chloride-hexane affords the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:12]C(N(C)C)=O)=[C:4]([C:8]([O:10]C)=[O:9])[S:5][C:6]=1[CH3:7].Cl>CO.[OH-].[Na+]>[Br:1][C:2]1[C:3]([SH:12])=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[CH3:7]
Reactant: COC(=O)c1sc(C)c(Br)c1SC(=O)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1sc(C(=O)O)c(S)c1Br
Temperature: 0 °C
Yield: 98.8 %

Procedure:
Methyl 4-bromo-3-{[(dimethylamino)carbonyl]thio}-5-methyl-2-thiophenecarboxylate (1.5 g, 4 mmoles) is stirred in a mixture of methanol (3 mL) and 5N sodium hydroxide (10 mL) and heated under reflux. After 21/2 hours the mixture is cooled, stirred into ice water, and acidified with concentrated HCl. The precipitate is filtered off, rinsed with water and dried to afford the product (1.0 g); mp 177° C. (dec).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[S:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:13]=2[CH:28]=1)=[O:8]>CC(C)=O.O.CC(C)=O>[CH:22]1([C:20]([NH:19][CH2:18][CH2:17][C:14]2[C:13]3[CH:28]=[C:9]([C:7]([OH:2])=[O:8])[CH:10]=[CH:11][C:12]=3[S:16][CH:15]=2)=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.7 g of potassium permanganate in 50 ml of an acetone/water mixture (50/50) are added at room temperature to a solution of 6.88 mmol of the product obtained in Step E in 30 ml of acetone. The solution is stirred for 2 hours at room temperature and then filtered. The filtrate is concentrated under reduced pressure and chromatographed over silica gel to yield the title product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[C:12](O)=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]>CO>[NH2:1][C:2]1[C:7]([CH:8]2[NH:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:13]([C:14]#[N:15])[C:12]=3[O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1C=O
Reactant: N#Cc1cccc(N)c1O
Solvent: CO
Product: N#Cc1cccc2c1OC(c1cccnc1N)N2
Temperature: 50 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 2-aminopyridine-3-carbaldehyde (300 mg) and 3-amino-2-hydroxy-benzonitrile (330 mg) in methanol (10 ml) was stirred at 50° C. for overnight. The resulting suspension was concentrated to dryness to afford 2-(2-amino-3-pyridyl)-2,3-dihydro-1,3-benzoxazole-7-carbonitrile (585 mg) as a pale brown solid, which was used without further purification. 2-(2-amino-3-pyridyl)-2,3-dihydro-1,3-benzoxazole-7-carbonitrile (585 mg) and manganese dioxide (4269 mg) in dichloromethane (50 ml) was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by preparative HPLC using a Waters X-Terra reverse-phase column (5 micron silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 2-(2-amino-3-pyridyl)-1,3-benzoxazole-7-carbonitrile (59.0 mg) as a pale brown solid. NMR Spectrum: (DMSOd6) 6.82 (dd, 1H), 7.59 (dd, 1H), 7.67 (bs, 2H), 7.93 (dd, 1H), 8.18 (dd, 1H), 8.28 (dd, 1H), 8.32 (dd, 1H); Mass spectrum: M+H+ 237;
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:27]([O:29]C)=[O:28])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([N:8]1[C:7](=[O:10])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([C:27]([OH:29])=[O:28])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[CH:14][CH:13]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2Cl)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nn(Cc2ccccc2)c(=O)n1Cc1ccc(OC(C(=O)O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the above ester (Step G), sodium hydride (3 equivalents), and dry DMF is stirred under N2 at room temperature for 2 hours. Next, benzyl bromide (5 equivalents) is added, and stirring at room temperature is continued for an additional 1.5 hours or until TLC indicates complete reaction. The mixture is quenched by cautious addition of sufficient acetic acid to destroy the excess sodium hydride and then partitioned between ethyl acetate and H2O. The ethyl acetate phase is washed repeatedly with H2O, then dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography of the residue on silica gel affords the title compound.