Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([NH2:19])=[C:9]([NH2:20])[N:8]=2)[CH:2]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>O1CCOCC1>[F:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]2[NH:20][C:9]3=[N:8][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[C:12]([C:13]4[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=4)[CH:11]=[C:10]3[N:19]=2)=[CH:24][CH:23]=1
Reactant: Nc1cc(-c2ccncc2)c(-c2cccnc2)nc1N
Reactant: O=Cc1ccc(F)cc1
Solvent: C1COCCO1
Product: Fc1ccc(-c2nc3cc(-c4ccncc4)c(-c4cccnc4)nc3[nH]2)cc1
Temperature: 100 °C
Reaction time: 96 h
Yield: 13.9 %

Procedure:
A sealed tube containing 3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 2,148 mg, 0.56 mmol), 4-fluorobenzaldehyde (57.0 μL, 0.53 mmol) and dioxane (3 mL) was filled with air and heated to 100° C. for 6 days. Then, the solvent was removed and CH3CN (2 mL) followed by Yb(OTf)3 were added, and the reaction mixture was stirred for 4 days at room temperature. Afterwards, the solvent was evaporated in vacuo and the residue was purified by flash column chromatography (CH2Cl2/EtOH/aq NH3 100:8:1) to afford the title compound as a white solid (27 mg, 13%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH:13]2[CH2:15][CH2:14]2)[N:10]=[C:9]([C:16]2[S:17][C:18]([S:21](=[O:28])(=[O:27])[NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:20]=2)[N:8]=1)(=O)=O.[NH2:31][C:32]1[N:36](C(OC(C)(C)C)=O)[N:35]=[C:34]([CH:44]2[CH2:46][CH2:45]2)[CH:33]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:23]([NH:22][S:21]([C:18]1[S:17][C:16]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:15][CH2:14]3)[CH:12]=[C:7]([NH:31][C:32]3[NH:36][N:35]=[C:34]([CH:44]4[CH2:46][CH2:45]4)[CH:33]=3)[N:8]=2)=[CH:20][CH:19]=1)(=[O:27])=[O:28])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)n1nc(C2CC2)cc1N
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc(C3CC3)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(Nc3cc(C4CC4)n[nH]3)cc(C3CC3)n2)s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 26.6 %

Procedure:
A mixture of crude 2-(5-(N-tert-butylsulfamoyl)thiophen-2-yl)-6 cyclopropylpyrimidin-4-yl trifluoromethanesulfonate 220 mg, 0.41 mmol, 1.0 equiv.), tert-butyl 5-amino-3-cyclopropyl-1H-pyrazole-1-carboxylate (138 mg, 0.62 mmol, 1.2 equiv.), Ph3P (33 mg, 0.12 mmol, 0.3 equiv.), Ph(Ph3P)4 (47 mg, 0.041 mmol, 0.1 equiv.) and K2CO3 (170 mg, 1.23 mmol, 3 equiv.) in dioxane (5 mL) was stirred at 100° C. for 3 h. The mixture was extracted with EtOAc. The combined organic phase was washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE/EtOAc/MeOH=1:1:0.1) to provide N-tert-butyl-5-(4-cyclopropyl-6-(3-cyclopropyl-1H-pyrazol-5-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (50 mg, 27%) as a white solid. LC-MS (m/z)=459.1 [M+H]+
Reaction SMILES: C(OC([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[CH:13][C:14]([C:20](=[O:22])[CH3:21])=[CH:15][C:16]=32)[CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:29]>>[ClH:29].[CH:17]12[CH2:19][CH:10]([CH2:9][NH:8][CH2:18]1)[C:11]1[CH:12]=[CH:13][C:14]([C:20](=[O:22])[CH3:21])=[CH:15][C:16]2=1
Reactant: CC(=O)c1ccc2c(c1)C1CC2CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(c1)C1CNCC2C1
Temperature: 70 °C

Procedure:
4-Acetyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (190 mg, 0.63 mmol) was treated with excess 3N HCl ethyl acetate and warmed to 70° C. for 1 hour then concentrated and dissolved in a minimum of methanol. The resulting solution was saturated with Et2O and stirred. After 18 hours the white crystalline product was collected by filtration (81 mg, 54%). 1H NMR (400 MHz, DMSO-d6)9.75 (br s, NH), 7.89 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.74 (br s, NH), 7.44 (d, J=8.0 Hz, 1H), 3.33 (br s, 2H), 3.22 (br s, 2H), 3.00 (br m, 2H), 2.54 (s, 3H), 2.17 (m, 1H), 2.02 (d, J=11.0 Hz, 1H). GCMS m/e 201 (M+). M.p. 198–202° C.
Reaction SMILES: [Cl:1][CH:2]([C:14](=[O:16])[CH3:15])[CH2:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH:11][C:12]#[N:13])=[N:9][CH3:10].[Cl:17][O-].[Na+].C(OCC)(=O)C>CO>[C:12]([NH:11][C:8]([NH:7][CH2:6][CH2:5][S:4][CH2:3][C:2]([Cl:17])([Cl:1])[C:14](=[O:16])[CH3:15])=[N:9][CH3:10])#[N:13]
Reactant: CN=C(NC#N)NCCSCC(Cl)C(C)=O
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN=C(NC#N)NCCSCC(Cl)(Cl)C(C)=O
Reaction time: 3 h
Yield: 25 %

Procedure:
In 1 ml of methanol was dissolved 131 mg of N-[2-(2-chloro-3-oxobutylthio)]ethyl-N'-cyano-N"-methylguanidine, and 0.63 ml of an aqueous solution of sodium hypochlorite was added to the solution and reaction was carried out at room temperature for 3 hours. Then, 15 ml of ethyl acetate was added to the reaction liquid and the organic layer was recovered. The obtained organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was refined by silica gel column chromatography (developing solvent: ethyl/ethanol=10/1) to obtain 37 mg of a colorless oily product (the yield was 25%).
Reaction SMILES: [CH2:1]([S:3]([O-])=[S:4])[CH3:2].S[CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10].[OH-].[Na+]>C(O)C.O>[CH2:1]([S:3][S:4][CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[CH3:2]
Reactant: CCS([O-])=S
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCSSCCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
A solution of ethylthiosulfinate (8.4 g) in ethanol (50 ml) is added to an aqueous solution of 3-mercaptopropanoyl-L-proline (10 g) maintained at pH 6-7 by careful addition of sodium hydroxide. The mixture is stirred vigorously at room temperature until negative thiol reaction. The mixture is diluted with water, adjusted to pH 8 and extracted with ethyl acetate, the aqueous phase is acidified to pH 3 and extracted again with ethyl acetate. This latter extract is washed with water, dried and concentrated to dryness to yield 1-[3-(ethyldithio)propanoyl]-L-proline.
Reaction SMILES: [H-].[Li+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[CH:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1.Br[CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1.O>CN(C)C=O>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[CH2:17][CH2:16][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([F:3])[CH:13]=2)[N:8]=[CH:9][C:10]1=[O:14]
Reactant: O=c1cnc2ccc(F)cc2[nH]1
Reactant: BrCCC1OCCO1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cnc2ccc(F)cc2n1CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
Lithium hydride (88 mg, 011 mmol) was added to a solution of 7-fluoroquinoxalin-2(1H)one (1.3 g, 7.8 mmol) in N,N-dimethylformamide (40 ml) under cooling on ice and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled on ice and 2-(2-bromoethyl)-1,3-dioxolane (1.33 ml, 11 mmol) was added thereto. The obtained mixture was stirred at room temperature for 24 hours, water was then gradually added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol) to yield 0.6 g (29%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19](=[O:27])[CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]1)[CH:6]=[CH:5]2.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[Cl:1][C:2]1[C:3]([NH:18][C:19](=[O:27])[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14]([O:17][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@@H](O)C3)ccc12
Product: CS(=O)(=O)O[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1

Procedure:
Prepared according to the method of example 33(a), using N-[6-chloro-2-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 28) (0.46 g) and methanesulphonyl chloride (0.183 mL) to afford the sub-title compound (0.47 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:29]([O:42][C:43]([NH:45][C:46]1[CH:51]=[CH:50][N:49]([CH2:52][C:53](O)=[O:54])[C:48](=[O:56])[N:47]=1)=[O:44])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:53](=[O:54])[CH2:52][N:49]1[CH:50]=[CH:51][C:46]([NH:45][C:43]([O:42][CH:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:44])=[N:47][C:48]1=[O:56])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of example 13. 1H NMR (400 MHz; DMSO-d6) δ 10.97 (s, 1H), 9.16 (brs, 1H), 8.40 (d, 0.6H), 8.38 (d, 0.4H), 8.06–7.94 (m, 2H), 7.91 (d, 0.6H), 7.85 (d, 0.4H), 7.45 (d, 4H), 7.37 (t, 4H), 7.29 (t, 2H), 6.96–6.93 (m, 1H), 6.80 (s, 1H), 4.81 (s, 1.2H), 4.63 (s, 0.8H), 4.36 (s, 0.8H), 4.18 (q, 0.8H), 4.07 (s, 1.2H), 4.06 (q, 1.2H), 3.61 (t, 1.2H), 3.48–3.40 (m, 2H), 3.27 (t, 0.8H), 1.25 (t, 1.2H), 1.17 (t, 1.8H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][CH:5]=1.N([O-])=[O:14].[Na+]>OS(O)(=O)=O>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([OH:14])=[CH:6][CH:5]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 70.2 %

Procedure:
p-Trifluromethoxy aniline (49.60g) was added rapidly dropwise to vigorously stirred 9N aqueous H2SO4 (500 mL) at 40° C. The mixture was heated to dissolve the solid, then cooled to 0° C. To the fine white suspension, a solution of sodium nitrite (19.46 g in 50 mL of H2) was added portionwise until an immediate positive KI/starch test result was obtained. This cold solution of diazonium salt was added rapidly dropwise to 9N aqueous H2SO4 (500 mL) at 110° C. Stirring and heating was continued for 2.5 hours. The mixture was cooled to 10° C. and extracted with diethyl ether (3×500 mL). The combined organic layers were dried (MgSO4), filtered and evaporated in vacuo, then flash chromatographed on SiO2 using diethyl ether as eluant to give 35.0 g of the desired phenol as a light brown oil was distilled (b.p.=75°-80° C. at 20 torr.) to afford a yellow liquid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:19][CH2:18][CH:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:16][OH:17]
Reactant: OCC(CO)NC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCC(CO)NC1CCNCC1
Yield: 99.8 %

Procedure:
34.5 g of 1-benzyl-4-(1,3-dihydroxyprop-2-ylamino)-piperidine are dissolved in 400 ml of methanol, combined with 3.4 g of 20% palladium-charcoal and hydrogenated with hydrogen at 24-28° C. under 2.2 bar. Then the catalyst is filtered off and the solvent is eliminated in vacuo. 22.7 g of 4-(1,3-dihydroxyprop-2-ylamino)-piperidine are obtained as an oil, which is used for the next reaction without any further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>O>[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: Clc1ccncc1Cl
Reactant: O=Cc1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=Cc1cccn1-c1ccncc1Cl
Temperature: 120 °C
Reaction time: 25 h
Yield: 70.4 %

Procedure:
A mixture of 2.0 g of 2-pyrrole carbaldehyde, 3.0 g of 3,4-dichloropyridine, 8.0 g of cesium carbonate and 30 ml of N-methylpyrrolidone was stirred at 120° C. for 25 hours. The reaction mixture was allowed to cool room temperature, and water was poured into the mixture. The mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 2.95 g of 1-(3-chloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [SH:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[NH:4][N:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(O)C.[OH-].[Na+]>O>[CH2:29]([S:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[NH:4][N:3]=1)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: CC(C)(C)c1ccc(-c2nc(S)n[nH]2)cc1
Reactant: CCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCSc1n[nH]c(-c2ccc(C(C)(C)C)cc2)n1
Temperature: 20 °C
Yield: 59 %

Procedure:
A mixture of 11.7 parts of 3-mercapto-5-(4-tert.-butylphenyl)-1,2,4-triazole, 12.5 parts of 1-bromododecane and 100 parts by volume of ethyl alcohol was heated at reflux temperature for four hours. After cooling to 20° C., a four percent weight/volume aqueous sodium hydroxide solution was added followed by 100 parts by volume of water. The precipitated product was filtered and dried yielding 59 percent of 3-(n-dodecylthio)-5-(4-tert.butylphenyl)-1,2,4-triazole which had a melting point of 87°-92° and the following elemental analysis:
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Li+].[OH-]>CO>[C:12]([O:11][C:9]([NH:8][CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:24])=[O:2])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:16])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
t-Boc-gly-phe-OCH3, 6a (9.2 g, 2.7×10-2 mole), 1M aqueous LiOH (30 ml, 3.0×10-2 mole), and methanol (100 ml) are stirred at room temperature for 2 hours. Most of the methanol is evaporated. The concentrate is diluted with water (10 ml) and transferred to a separatory funnel. The mixture is then acidified with 1M aqueous HCl (50 ml) and the aqueous acidic mixture subsequently extracted with CHCl3 (4 times). The combined CHCl3 extracts are washed with saturated aqueous NaCl before being dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate gives a foam which when triturated with Et2O/hexane affords 7a as a colorless solid which crystallizes from ethyl acetate/hexane as colorless needles: 6.3 g (71%), m.p. 138°-141° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[K].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:12]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
A mixture of o-nitrophenol (2.08 g, 15.0 mmol), 1-[bromo(phenyl)methyl]benzene (3.70 g, 15.0 mmol) and potassium carbonated (K2CO3) (4.14 g, 30.0 mmol) in acetone (60 mL) was kept at reflux temperature for 5 h. The reaction mixture was cooled to room temperature, concentrated in vacuo. The residue was partitioned between dichloromethane (CH2Cl2) and water (H2O), organic layer dried over sodium sulphate (Na2SO4), filtered, concentrated. The residue was purified by silica gel flash chromatography to give subtitled compound (1.81 g).
Reaction SMILES: C(O)C.C(O[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)=[O:8])C.CC[O-].[Na+].[CH2:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(=O)N2
Agent: CC[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C1CCc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Yield: 9.5 %

Procedure:
To 100 ml of ethanol was added 2.0 g of 6-ethoxycarbonyl-3,4-dihydrocarbostyril, 0.5 g of sodium ethylate and 1.6 g of benzylpiperazine, the mixture was reacted in an autoclave under 110 atmospheric pressure at 140°-150° C. for 6 hours. After the reaction was completed, the reaction mixture was cooled and concentrated under a reduced pressure. The residue thus obtained was dissolved in 200 ml of chloroform and the chloroform solution was washed with 1%-potassium carbonate aqueous solution, a diluted hydrochloric acid and water in this order, then dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was treated by means of a silica gel column chromatography (Silica gel: Wako C-200, eluate:chloroform:methanol (volume/volume)=20:1) and the crude crystals were recrystallized from ethanol to obtain 300 mg of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 198°-200° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1([C:11]2O[C:13]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].BrN1C(=O)CCC1=O.[NH2:31][NH2:32]>C1COCC1.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1([C:11]2[N:31]=[N:32][C:13]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)o2)cn1
Reactant: NN
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)nn2)cn1
Temperature: -35 °C
Reaction time: 20 h
Yield: 21.7 %

Procedure:
In a round bottom flask, {1-[5-(1-methyl-1H-pyrazol-4-yl)-furan-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (226 mg, 0.745 mmol) was dissolved in a mixture of THF (12.4 mL) and water (1.3 mL). The flask was cooled to −35° C. in a dry ice/acetone bath (the mixture becomes a thick slurry) and then N-bromosuccinimide (146 mg, 0.819 mmol) was added as a solid in one portion. The reaction immediately turned a bright yellow color. The reaction was stirred for 15 min at this temperature after which time anhydrous hydrazine (0.21 mL, 6.7 mmol) was added in one portion via syringe. The ice bath was removed and the reaction was allowed to stir at room temperature for 20 h. The volatiles were removed at 50° C. under a stream of N2. The resulting residue was purified by flash chromatography (silica, 90→100% EtOAc/hexanes) to give 51 mg of {1-[6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-cyclopropyl}-carbamic acid tert-butyl ester as a bright yellow solid, m/z 316.6 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:49][C:50]([C:52]1[C:53]2[CH:54]=[CH:55][N:56]=[CH:57][C:58]=2[CH:59]=[CH:60][CH:61]=1)=[NH:51]>CN(C)C=O>[CH3:4][C:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]2[O:12][N:51]=[C:50]([C:52]3[CH:61]=[CH:60][CH:59]=[C:58]4[C:53]=3[CH:54]=[CH:55][N:56]=[CH:57]4)[N:49]=2)=[CH:13][CH:14]=1)([CH3:1])[CH3:3]
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
A mixture of 4-[(1,1-dimethylethyl)oxy]benzoic acid (Apin chemicals) (117 mg, 0.603 mmol), HATU (232 mg, 0.610 mmol), Hunig's base (0.263 mL, 1.506 mmol) in N,N-Dimethylformamide (DMF) (1 ml) was stirred for 1 hr before the addition of N-hydroxy-5-isoquinolinecarboximidamide (D1; 94 mg, 0.502 mmol) in N,N-dimethylformamide (DMF) (1 ml). The reaction was left to stir at room temperature for 2 hrs and then heated to 120° C. for 2 hr in the microwave. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Waters Sunfire C18 column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN+0.1% Formic acid)) to give the title compound (31.5 mg)
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:18]=[C:17]([N:19]4[CH2:20][CH2:21][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:23][CH2:24]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3noc(N4CCNCC4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3noc(N4CCN(CCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 20 mg (0.06 mmol) of 1-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,4-oxadiazol-5-yl]piperazine and 13 μl (0.09 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:12].Cl[O-].[Na+]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:12])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(CC=O)cc1
Agent: [Na+]
Agent: [O-]Cl
Product: Cc1ccc(CC(=O)O)cc1

Procedure:
In the like manner as Example 1, 26.4 g of p-methylphenylacetaldehyde as an aldehyde and 2.3 g of sulfuric acid were used. The oxidation was done by using 125 g of 12% aqueous solution of sodium hypochlorite at temperatures of -10° to -12° C., which was followed by the hydrogenation to obtain p-methylphenylacetic acid.