Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH3:31])=[CH:25][C:23]=1[NH2:24].Cl.N1C=CC=CC=1>C(OCCO)C.C(=O)(O)[O-].[Na+]>[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH3:31])=[CH:25][C:23]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2cc3c(Nc4cc(OC)c(Cl)cc4Cl)c(C#N)cnc3cc2cc1O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
A mixture of 0.7 g (2.46 mmol) of 4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.57 g (2.95 mmol) of 2,4-dichloro-5-methoxyaniline and 0.28 g (2.46 mmol) of pyridine hydrochloride in 7 mL of 2-ethoxyethanol is heated at 120° C. for 2 hours, then cooled to room temperature. The product mixture is diluted with saturated solution of sodium bicarbonate and stirred for 15 minutes. The resulting solid is collected by filtration, washed with water and dried. The crude product is purified by silica gel chromatography, utilizing a 98:2 to 90:10 gradient of methylene chloride/methanol to give 0.71 g of 4-(2,4-dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid, mp, 238-240° C.
Reaction SMILES: C(OC1C=CC=CC=1[C:15]1[N:20]=[C:19](OCC(N)=O)[C:18](C#N)=[C:17](S(C)=O)[CH:16]=1)C1C=CC=CC=1.C[N:32]([CH:34]=[O:35])C>>[NH:20]1[CH2:15][CH2:16][CH:17]([C:34]([NH2:32])=[O:35])[CH2:18][CH2:19]1
Reactant: CS(=O)c1cc(-c2ccccc2OCc2ccccc2)nc(OCC(N)=O)c1C#N
Reactant: CN(C)C=O
Product: NC(=O)C1CCNCC1

Procedure:
A mixture of 2-{[6-[2-(benzyloxy)phenyl]-3-cyano-4-(methylsulfinyl)-2-pyridinyl]-oxy}acetamide (500 mg, 1.19 mmol), which was obtained in the step (4) of Example 34-1, and isonipecotamide (228 mg, 1.78 mmol) in DMF (2 mL) was stirred at 130° C. for 5 hrs. After cooled to room temperature, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give 1-{2-(2-amino-2-oxoethoxy)-6-[2-(benzyloxy)phenyl]-3-cyano-4-pyridinyl}-4-piperidinecarboxamide as a solid (485 mg, yield; 84%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N+:15]([O-])=[C:14]([CH3:19])[C:13]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:24][CH2:19][C:14]1[C:13]([CH3:20])=[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][N:15]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCCOCc2ccccc2)cc[n+]([O-])c1C
Product: CC(=O)OCc1nccc(OCCOCc2ccccc2)c1C
Reaction time: 1 h

Procedure:
A mixture comprising 6.5 g of 4-(2-benzyloxyethoxy-2,3-dimethylpyridine N-oxide and 56 ml of acetic anhydride was stirred at 80° to 90° C. for one hour and distilled to remove the acetic anhydride. The obtained residue was made weakly basic with an aqueous solution of sodium carbonate and extracted with methyl ethyl ketone. The extract was dried over magnesium sulfate and distilled to remove the methyl ethyl ketone. Thus, 7.0 g of 2-acetoxymethyl-4-(2-benzyloxyethoxy)-3-methylpyridine was obtained. This intermediate was dissolved in 90 ml of ethanol, followed by the addition of 1.43 g of sodium hydroxide. The obtained mixture was stirred at 40° C. for one hour, followed by the addition of water. The mixture was extracted with methyl ethyl ketone. The obtained extract was dried over magnesium sulfate to obtain 5.4 g of 4-(2-benzyloxyethoxy)-2-hydroxymethyl-3-methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[N:11](C(OC(C)(C)C)=O)[CH:12]=[CH:13][CH:14]=3)[N:4]2[N:3]=1.[CH:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:9]1[N:4]2[N:3]=[C:2]([NH:1][C:28]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc2nc(N)nn12
Product: O=C(Nc1nc2cccc(-c3ccc[nH]3)n2n1)C1CCCC1

Procedure:
The title compound was prepared following procedure and work up described for example 9, but starting from tert-butyl 2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate ((A6), 50 mg; 0.17 mmol; 1.0 eq.) and cyclopentanecarbonyl chloride (44 mg; 0.33 mmol; 2.0 eq.) as a white solid (25.4 mg, 51%). HPLC, Rt: 3.17 min. (purity 99.7%). LC/MS, M+(ESI): 296.4, M−(ESI): 294.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[S:13][C:12]([C:14]#[C:15][C@H:16]([N:18]([OH:22])[C:19]([NH2:21])=[O:20])[CH3:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>CC(C)=O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[S:13][C:12](/[CH:14]=[CH:15]\[C@H:16]([N:18]([OH:22])[C:19]([NH2:21])=[O:20])[CH3:17])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](C#Cc1ccc(Cc2ccc(F)cc2)s1)N(O)C(N)=O
Agent: [Pd]
Solvent: CC(C)=O
Solvent: c1ccc2ncccc2c1
Product: C[C@H](/C=C\c1ccc(Cc2ccc(F)cc2)s1)N(O)C(N)=O
Reaction time: 24 h
Yield: 28.8 %

Procedure:
A solution of (R)-N-{3-[5-(4-fluorophenylmethyl)thien-2-yl]-1-methyl-2-propynyl}-N-hydroxyurea (0.50 g, 1.57 mmol), prepared as in step 4, quinoline (0.25 mL, 2.11 mmol), and 5% palladium on calcium chloride poisoned with lead (0.025 g) in acetone (15 mL) was allowed to stir under hydrogen (atmospheric pressure) for 24 hours. The solution was filtered through celite and solvents removed in vacuo. The resulting oil was taken up in ethyl acetate (50mL) and washed with aqueous 1M H3PO4 (3×25 mL) and aqueous NaHCO3 (3×25 mL). The solution was dried (MgSO4) after which the solvent was evaporated to yield a yellow oil. The residue was purified by chromatography on silica gel (50% ethyl acetate/hexane/1% acetic acid). The resulting solid was crystallized from hot ethyl acetate/hexane to yield 0.145g (29%) of Z-N-[3-(5-(4-Fluorophenylmethyl)-thien-2-yl)-1-[R]-methyl-2-propenyl]-N-hydroxyurea. m.p. 123°-4° C., MS. (DCI/NH3) m/e 321 (M+H)+, 338 (M+NH4)+. 1H NMR (DMSO-d6, 300 MHz) δ1.16 (d,J=6.3 Hz, 3H), 4.1 (s, 2H), 5.25 (m, 1H), 5.67 (rid, J=9.0, 11.7 Hz, 1H), 6.35 (s, 2H), 6.43 (d, J=11.7 Hz, 1H), 6.83 (d, J=3.6 Hz, 1H), 6.94 (d, J=3.6 Hz, 1H), 7.13 (m, 2H), 7.32 (m, 2H), 9.18 (s, 1H). Anal calcd for C17H17FN2O2S: C, 59.98; H, 5.35; N, 8.74. Found C, 59.79; H, 5.25; N, 8.71.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH:21]([CH3:30])[C:22]([O:28][CH3:29])=[CH:23][C:24]([O:26]C)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:21]([CH3:30])[C:22]([O:28][CH3:29])=[CH:23][C:24]([OH:26])=[O:25])=[CH:9][CH:10]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reactant: COC(=O)C=C(OC)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=CC(=O)O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy) phenol (6.9 mmol.), methyl 4-bromo-3-methoxy-2-pentenoate (8.9 mmol.) and potassium carbonate (1.5 equis.) in acetone (15 ml.) is refluxed for 48 hours. After filtration, the filtrate was concentrated and the residue chromatographed on silica gel using 20% ethylacetate/hexane to give the methyl ester of 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoic acid.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])=[S:2].[CH3:18]OS(F)(=O)=O.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>C(N(CC)CC)C>[CH3:24][O:25][CH:26]1[CH:1]([S:2][CH3:18])[N:3]([CH2:4][C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:6])[C:27]1=[O:28]
Reactant: COCC(=O)Cl
Reactant: COS(=O)(=O)F
Reactant: O=C(CNC=S)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Product: COC1C(=O)N(CC(=O)OCc2ccc([N+](=O)[O-])cc2)C1SC

Procedure:
Following the procedure of Preparation 24, but using p-nitrobenzyl thioformylglycinate (254 mg.), magic methyl (81 μl.), triethylamine (350 μl) and methoxyacetyl chloride (91 μl.), there were obtained 26 mg of the desired product.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH2:13][CH:12](OS(C)(=O)=O)[CH2:11][CH2:10]2)(=[O:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH:12]1[CH2:13][C:14]2[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:10][CH2:11]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1cccc2c1CC(OS(C)(=O)=O)CC2
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc2c1CC(N=[N+]=[N-])CC2
Temperature: 50 °C
Yield: 96.9 %

Procedure:
A mixture of methanesulfonic acid 8-acetylamino-1,2,3,4-tetrahydronaphthalen-2-yl ester (3.8 g, 13 mmol) and sodium azide (1.7 g, 27 mmol) in dimethylformamide (70 mL) was heated at 50° C. for 6 h. The solvent was removed by rotoevaporation in vacuo and the residue partitioned between methylene chloride and water. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to give a dark solid. The product was purified by column chromatography on silica gel (1:1 ethyl acetate:hexane as eluant) to give a white solid (2.9 g) in 97% yield.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:22]=[CH:21][C:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH:7]=1.CO>ClCCl.C(O)(C)C>[F:5][C:6]1[CH:22]=[CH:21][C:9]2[C:10]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[N:11][O:12][C:8]=2[CH:7]=1
Reactant: COc1ccc(-c2noc3cc(F)ccc23)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: CC(C)O
Solvent: ClCCl
Product: Oc1ccc(-c2noc3cc(F)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
Add a 1.0 M solution of boron tribromide (2.31 L, 2.31 mol) in dichloromethane (1.87 L) to a cold (0° C.) solution of 6-fluoro-3-(4-methoxy-phenyl)-benzo[d]isoxazole (187.2 g, 0.77 mol) in dichloromethane, over ˜2 hours. Warm to room temperature overnight. Cool reaction mixture to ˜3° C. and add methanol (4 L) over a period of time of 1 hour, keeping the temperature of the reaction mixture at 3-10° C. Gas evolution occurs. Concentrate (40-50° C., 50 torr) reaction mixture to give a gray solid. Heat to dissolve the gray solid in isopropyl alcohol (550 mL) at reflux. Cool (room temperature), followed by 0-5° C. for 1 hour. Filter off the solid and wash filter cake with cold (0° C.) isopropyl alcohol (265 mL) and dry to air. Subsequently dry the solid in the oven (60° C., 50 torr) overnight to give the title compound (147.2 g, 83% Yield): 1H NMR (DMSO-d6, 200 MHz) δ 7.0 (d, 2H), 7.4 (t, 1H), 7.8 (d, 1H), 7.84 (d, 2H), 8.18 (m, 1H). Purity by LC/MS (APCl)=100% area, [M+H]+=230 m/e.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)#[N:3].[CH2:12]([O:19][C:20](=[O:29])[NH:21][CH:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C>[CH2:12]([O:19][C:20](=[O:29])[NH:21][CH:22]1[CH2:23][C:24]2[C:8]3[C:7](=[CH:6][CH:5]=[C:4]([C:2]#[N:3])[CH:9]=3)[NH:10][C:25]=2[CH2:26][CH2:27]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)OCc1ccccc1)CC3
Temperature: 25 °C
Yield: 69.3 %

Procedure:
Combine 4-cyanophenylhydrazine hydrochloride (27.4 g, 162 mmol) and (4-oxo-cyclohexyl)-carbamic acid benzyl ester (Preparation 42) (40.0 g, 162 mmol) in acetic acid (800 mL). Heat the reaction to 90° C. overnight, then cool to room temperature and concentrate under reduced pressure. Triturate the residue in dichloromethane and discard the filter cake. Concentrate the filtrate under reduced pressure. Purify the resulting residue by flash chromatography (silica gel, 9:1 chloroform:acetone). Recrystillize the resulting material from benzene to provide 38.8 g (69%) of the title compound. m.p.=141-143° C.; mass spectrum (m/e): 344 [C21H19N3O2−1]−; 1H NMR (300 MHz, CDCl3): δ 8.15 (s, 1H), 7.73 (s, 1H), 7.29-7.38 (m, 7H), 5.12 (s, 2H), 4.89-4.92 (m, 1H), 4.18 (m, 1H), 3.09 (dd, J=5.0, 15.5 Hz, 1H), 2.78-2.91 (m, 2H), 2.59 (dd, J=7.0, 15.5 Hz, 1H), 2.07-2.17 (m, 1H), 1.93-2.05 (m, 1H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([OH:10])[CH:5]=[CH:6][CH:7]=2)[O:2]1.CN1CCOCC1.[C:18](OCC1C=CC=CC=1)(=[O:21])[C:19]#[CH:20]>C1COCC1>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][CH:6]=[C:5]3[C:4]=2[O:10][CH2:20][CH2:19][C:18]3=[O:21])[O:9]1
Reactant: Oc1cccc2c1OCO2
Reactant: C#CC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C1CCOc2c1ccc1c2OCO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-methylenedioxyphenol (27 g) and N-methyl morpholine (19.6 g) in THF (100 ml) was added benzyl propiolate (38 g) over a period of 30 minutes with cooling. After the addition was complete the reaction was stirred at room temperature for 1.5 hours followed by concentration. The residue was taken up into Et2O (500 ml), washed with 10% HCl (2×100 ml), dried over MgSO4. filtered and concentrated. This material was subjected to hydrogenation with 10%Pd/C in methanol at 4 atm. The reaction was filtered and concentrated. The resulting saturated acid was dissolved into methanesulfonic acid (350 ml) and stirred for 24 hours. The reaction was poured onto ice and extracted with CH2Cl2. The organic layer was washed with saturated Na2CO3, dried over MgSO4, filtered and concentrated to provide the desired material.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C.Cl.C(N(CC)CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1>ClCCl>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](=[O:42])[NH:27][CH2:26][CH2:25][CH2:24][NH:23][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:2][CH2:3]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Yield: 92.1 %

Procedure:
A suspension of 2-[2-(3-aminopropylamino)-5-chloropyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (500 mg, 1.24 mmol) in dichloromethane (30 mL) is treated at room temperature with piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (340 mg, 1.48 mmol) in the presence of N,N-diisopropylethylamine (0.220 mL, 163 mg, 1.26 mmol), 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240 mg, 1.25 mmol), and 1-hydroxybenzotriazole (171 mg, 1.21 mmol) for 24 hours. The mixture is then diluted with dichloromethane (30 mL), filtered, washed with H2O (30 mL), and diethyl ether (30 mL), and dried to provide 4-{3-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propylcarbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (700 mg, 92%). A stirred mixture of this intermediate (695 mg, 1.13 mmol) in dichloromethane (25 mL) is treated at room temperature with TFA (2.5 mL) for 72 hours. The mixture is then concentrated under reduced pressure, and subjected to chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane: 16-40%, to provide the title compound (492 mg, 85% yield).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.Cl[C:18]1[N:23]2[N:24]=[CH:25][C:26]([N+:27]([O-:29])=[O:28])=[C:22]2[N:21]=[C:20]([CH3:30])[CH:19]=1.CN(C)C=O>O1CCOCC1>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:18]2[N:23]3[N:24]=[CH:25][C:26]([N+:27]([O-:29])=[O:28])=[C:22]3[N:21]=[C:20]([CH3:30])[CH:19]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc(Cl)n2ncc([N+](=O)[O-])c2n1
Reactant: NCCCn1ccnc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NCCCn2ccnc2)n2ncc([N+](=O)[O-])c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
2.88 g of 3-imidazol-1-ylpropylamine and 2.33 g of triethylamine in 20 cc of dioxane were introduced into a 100 cc three-necked round-bottomed flask equipped with a magnetic stirrer, a thermometer, a dropping funnel and a condenser. 4.5 g of 7-chloro-5-methyl-3-nitropyrazolo[1,5-a]pyrimidine in solution in 20 cc of dioxane and 5 cc of dimethylformamide were added dropwise. After 2 hours of stirring at room temperature, the precipitate was filtered off. It was washed with diisopropyl ether and dried under vacuum. This gave 7.2 g of crude product. This product was taken up under reflux in 28 cc of water, then filtered off at room temperature. This operation was repeated a second time. The product was washed with ethanol and with diisopropyl ether. This gave 4.1 g of (3-imidazol-1-ylpropyl)(5-methyl-3-nitropyrazolo[1,5-a]pyrimidin-7-yl)amine in the form of a beige powder, after drying under vacuum over phosphoric anhydride, with a yield of 65%.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[N:21][CH:22]=1)#[N:25]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(C#N)cn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (2 g, 8 mmol, 1 eq.) and 6-chloronicotinonitrile (2.78 g, 20 mmol, 2.5 eq.) in 50 ml DMF was added cesium carbonate (7.82 g, 24 mmol, 3 eq.). The reaction was stirred at room temperature overnight. The starting material was gone but no right mass was observed. The reaction was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/methanol=39:1 to 19:1) to give colorless oil (2.52 g, yield 89%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[N:18]=[C:19]=[S:20].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:18]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[C:19]1=[S:20])[CH3:2]
Reactant: S=C=Nc1ccc2ccccc2c1
Reactant: CCNCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccc3ccccc3c2)C1=S
Yield: 34.6 %

Procedure:
The tide compound was prepared by the procedure described in Example 4 using 9.2 g of N-ethyl glycine, 9.3 g of 2-naphthyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Title compound (4.7 g) was obtained as a light pink solid, m.p. 156°-159° C. Anal. Calcd. for. C15H14N2O S: C, 66.64; H, 5.22; N, 10.36 Found: C, 66.69; H,5.24; N, 10.42. Mass spectrum (El, M.+) m/z 270.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30].C(N(CC)C(C)C)(C)C>ClCCl>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)(=[O:31])=[O:30]
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1F

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 2-fluorophenylsulfonyl chloride in presence of N,N-diisopropyl ethyl amine in dichloromethane to give 2-fluoro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless oil. MS: 499.3 ([M+NH4]+)
Reaction SMILES: [S:1]1[CH:5]=[C:4](B(O)O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].O.O=[CH:23][C:24]([OH:26])=[O:25]>C(#N)C>[S:1]1[CH:5]=[C:4]([CH:23]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([F:13])[CH:15]=2)[C:24]([OH:26])=[O:25])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: Nc1cccc(F)c1
Reactant: O=CC(=O)O
Solvent: CC#N
Solvent: O
Product: O=C(O)C(Nc1cccc(F)c1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of benzo[b]thiophen-3-ylboronic acid (400 mg, 2.25 mmol), 3-fluoroaniline (217 μl, 2.25 mmol), and 2-oxoacetic acid hydrate (207 mg, 2.25 mmol) in acetonitrile (20 ml) was stirred at room temperature for 4 hours. The solvent was removed under vacuum and the crude was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(O[C:19]([S-])=[S:20])C.[K+].C(O)C>O>[S:20]=[C:19]1[NH:1][C:2]2[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: CCOC(=S)[S-]
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc2oc(=S)[nH]c2c1

Procedure:
A stirred mixture of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (8.4 g.), potassium ethylxanthate (6.33 g.), ethanol (38 ml.) and water (6.5 ml.) was heated under reflux for 4 hours. The solution was evaporated to half volume and diluted with water (65 ml.). The mixture was acidified with 2N-hydrochloric acid and extracted several times with ether. The ethereal solution was washed with water, then dried with anhydrous sodium sulphate, and evaporated to give ethyl 2-(2-thioxo-2,3-dihydrobenzoxazol-5-yl)propionate as an oil. Dry chlorine was passed into a solution of the thione (9 g.) in freshly dried and distilled chloroform (150 ml.) with stirring for 4 hours. The solution was then washed with water, N-sodium hydroxide solution, then water (3x). The dried (Na2SO4) organic solution was evaporated to yield ethyl 2-(2-chloro-5-benzoxazolyl)propionate as a brown oil which was shown to be a single compound by thin layer chromatography.