Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Ce].[N+]([O-])(O)=O.[N+]([O-])([O-])=[O:7].[NH4+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[O:7])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(C)cc1
Agent: [Ce]
Agent: [NH4+]
Solvent: O=[N+]([O-])O
Product: COc1ccc(C=O)cc1
Yield: 94.8 %

Procedure:
The same procedure as in Example 1 is repeated except that the cerium salt is electrolyzed with 100 ml of 2 to 3% by weight aqueous solution of nitric acid placed into the cathode chamber in place of ammonium nitrate. p-Methyl anisole is oxidized with the solution withdrawn from the anode chamber to give anisaldehyde in a yield of 94.8%.
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29]O)=[N:27][CH:28]=1.CP(C)C>O1CCCC1.C(OCC)(=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[C:12]([CH3:13])[N:4]([CH:1]5[CH2:2][CH2:3]5)[N:5]=4)[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[N:27][CH:28]=1
Reactant: OCc1ccc(Cl)cn1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)ccc2nn1C1CC1
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (30 mg) in tetrahydrofuran (2 ml) were added (5-chloropyridin-2-yl)methanol (31 mg), bis(2-methoxyethyl)azodicarboxylate (55 mg) and trimethylphosphine (1 M tetrahydrofuran solution, 235 μl) at room temperature, and the mixture was stirred at the same temperature for 2 hr. The mixture was diluted with ethyl acetate, and washed with water, 1 M aqueous sodium hydroxide solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) and recrystallized from ethyl acetate to give the title compound (22 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:29][CH3:30])=[C:18]([O:21]CC4C=CC=CC=4)[CH:19]=3)[C:14]([OH:31])=[C:13]([C:32]([O:34][CH3:35])=[O:33])[C:12]=2[C:36]([O:38][CH3:39])=[O:37])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>O1CCCC1.CO.[H][H].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:29][CH3:30])=[C:18]([OH:21])[CH:19]=3)[C:14]([OH:31])=[C:13]([C:32]([O:34][CH3:35])=[O:33])[C:12]=2[C:36]([O:38][CH3:39])=[O:37])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2cc(OCc3ccccc3)c(OC)cc2c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2cc(O)c(OC)cc2c1O
Yield: 90.3 %

Procedure:
2 g of 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxy-carbonyl)-4-hydroxy-6-methoxy-7-benzyloxynaphthalene obtained in Example 6 are dissolved in a mixture of 200 ml of tetrahydrofuran and 50 ml of methanol. The solution is stirred in the presence of 2 g of 10% palladium-charcoal in hydrogen atomsphere at 40 psi for 2 hours. After the reaction, the catalyst is removed by filtration, and the filtrate is evaporated to dryness under reduced pressure. The resultant crude crystals are triturated with methanol, whereby 1.5 g of 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)4-hydroxy-6-methoxy-7-hydroxynaphthalene is obtained.
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[C:4]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:5]=2[NH:6][C:7](=[O:10])[C:8]=1[OH:9].[C:17]1([Sn](C)(C)C)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:4]2[C:3](=[O:16])[C:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:8]([OH:9])[C:7](=[O:10])[NH:6][C:5]=2[CH:11]=1
Reactant: C[Sn](C)(C)c1ccccc1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)c(Br)c1O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c(-c2ccccc2)c1O
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 4-Bromo-8-chloro-3-hydroxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (400 mg) in THF (10 mL) was added phenyltrimethylstannane (600 mg) and trans-Benzyl(chloro)bis (triphenyl-phosphinepalladium(II) (50 mg). The solution was heated to reflux for 5 hours at which time a dark gray precipitate formed. The reaction mixture was cooled to room temperature and diluted with an ether-tetrahydrofuran mixture (1:1). This mixture was washed with a 10% solution of potassium fluoride, dried (Na2SO4), and evaporated to dryness. Chromatography, with ethyl acetate as the eluent, yielded the title compound as a white solid (230 mg); mp 193-196 degrees C.; NMR: 7.18(m,2H), 7.31(m, 4H), 7.52(s, 1H), 7.87(d, 1H, J=8.7), 10.28(brs, 1H), 11.81(s, 1H). Analysis for C16H10ClNO3 -0.3H2O: Calculated: C, 62.98, H, 3.50, N, 4.59: Found: C, 62.82, H, 3.33, N, 4.67.
Reaction SMILES: O[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH2:7](N)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.N>>[CH2:18]([NH:6][C:4](=[O:5])[CH:3]=[CH2:2])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCCCCCCCCCCCN
Reactant: NC(=O)CCO
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: N
Product: C=CC(=O)NCCCCCCCCCCCC
Temperature: 160 °C

Procedure:
82 g of β-hydroxypropionamide and 195 g of dodecylamine were heated with 50 mg of 2,6-di-t-butyl-p-cresol for 4 hours in a temperature range of 130° C. to 190° C. unitl the evolution of ammonia was complete. After adding 5 g of polyphosphoric acid the reaction mixture was maintained at 160° C. for 1 hour and then distilled in an oil pump vacuum. The main run was taken off between 148° C. and 168° C. at 0.3 bar and crystallized in the receiver.
Reaction SMILES: [CH:1]1([N:4]([CH2:8][CH:9]2[CH2:14]CCCO2)[C:5]([Cl:7])=[O:6])[CH2:3][CH2:2]1.C1(NC2CC[O:22][CH2:21][CH2:20]2)CC1>C(Cl)Cl.CO>[CH:1]1([N:4]([CH:8]2[CH2:9][CH2:14][O:22][CH2:21][CH2:20]2)[C:5]([Cl:7])=[O:6])[CH2:2][CH2:3]1
Reactant: C1CC(NC2CC2)CCO1
Reactant: O=C(Cl)N(CC1CCCCO1)C1CC1
Solvent: CO
Solvent: ClCCl
Product: O=C(Cl)N(C1CCOCC1)C1CC1

Procedure:
The title compound is prepared analogously as described for cyclopropyl-(tetrahydro-pyran-2-ylmethyl)-carbamoyl chloride starting from commercially available cyclopropyl-(tetrahydro-pyran-4-yl)-amine. TLC, Rf (CH2Cl2/MeOH 95:5)=0.9.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)[CH3:2].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[C:7]=1[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:19])[CH3:2]
Reactant: CCc1cc2ccccc2o1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1oc2ccccc2c1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A stirring solution of 2-ethyl benzofuran (43.8 g; 0.3 mol) in methylene chloride (300 mL) was cooled in an ice bath. Benzoyl chloride (42.2 g; 0.3 mol) was added. Tin (IV) chloride (85 g; 0.33 mol) was then added dropwise. The mixture was stirred at room temperature for 30 minutes then at reflux for one hour. The mixture was then cooled to room temperature, poured over ice, and extracted with ether. The ethereal extract was washed with brine, dried over anhydrous magnesium sulfate, and solvent evaporated. The residue was purified by flash chromatography on silica gel using 1% ethyl acetate in hexane as an eluent. The product was obtained as an oil (26 g). Mass spectrum (ESI, [M+] m/z 250. 1HNMR (400 MHz, DMSO-d6): δ 1.21 (t, 3H, J=7.47 Hz), 2.76 (q, 2H, J=7.47 Hz), 7.21 (dt, 1H, J=7.25, 1.1 Hz), 7.3-7.38 (m, 2H), 7.52-7.56 (m, 2H), 7.61-7.69 (m, 2H), 7.73-7.76 (m, 2H). Elemental Analysis for C17H14O2: Calculated: C, 81.58; H, 5.64. Found: C, 81.73; H, 5.56.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.O.[CH:12]([CH:14]=O)=[O:13]>C(O)(=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[CH:14]/[CH:12]=[O:13])=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=CC=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C/C=N/Nc1ccc(F)cc1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of 1-(4-fluorophenyl)hydrazine hydrochloride (5.0 g, 30.75 mmol), water (20 mL), and acetic acid (20 mL) was added with stirring to a 40% aqueous solution of glyoxal (17.6 mL, 153.8 mmol) over 20 minutes. Stirring was continued for 2 hours and the mixture was then filtered. The precipitate washed with water and dried to afford 5.0 g (98%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 9.56 (d, 1H), 8.63 (br s, 1H), 7.24 (m, 1H), 7.16 (m, 2H), 7.06 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −120.3. LRMS (ESI pos) m/e 151.1 (M−16).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[CH2:22]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[CH2:23][CH2:24][CH3:25]>CO.C(Cl)Cl>[CH2:22]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][CH2:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]3[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:31][CH:32]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1ccc(N)cc1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1ccc(NCc2ccc3[nH]c(C(N)=O)c(Sc4ccccc4)c3c2)cc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 4-butylaniline (74 mg, 0.50 mmol) as described in General Procedure X to afford Iah (17 mg, 23.4%) as an ivory colored solid, tlc Rf=0.8 (5% MeOH/CH2Cl2-0.2% Et3N), m/z obs=430 (M+1).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[CH:5]2.N([O-])=O.[Na+].[ClH:20]>O.[Cu]Cl>[Cl:20][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: Cl
Reactant: Nc1ccc2cc(S(=O)(=O)O)ccc2c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1ccc2cc(Cl)ccc2c1
Reaction time: 8 h

Procedure:
6-Amino-2-napthalenesulfonic acid (88.0 g, 0.4 mol) was suspended in 5 N HCl (200 mL) and water (150 mL) and cooled to 3° C. A solution of sodium nitrite (27.0 g, 0.4 mol) in water (50 mL) was added dropwise over two hours. After one additional hour, the mixture was poured in several portions into a stirred suspension of copper(I) chloride (39.6 g, 60.6 mmol) in 5 N HCl (200 mL). Considerable foaming occurred during this addition. After standing overnight at room temperature, the mixture was concentrated on a rotary evaporator to a brown solid that was then dried in a vacuum oven overnight at 100° C. to provide the acid (111.9 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]>>[CH3:15][O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: COCCCCCCl
Product: COCCCCCN1CCC(=O)CC1

Procedure:
1-(5-Methoxypentyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-5-methoxypentane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[CH2:29][CH2:28]2)[C:24]([CH3:40])=[CH:23][C:21]=1[NH2:22]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:22][C:21]2[CH:23]=[C:24]([CH3:40])[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:29][CH2:28]3)=[CH:26][C:20]=2[O:19][CH3:18])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(C)cc1N
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(C)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 26).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([NH:18][CH3:19])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([N:18]([CH3:19])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: Clc1ncnc2ccccc12
Reactant: CNc1ccc(OC)cc1
Product: COc1ccc(N(C)c2ncnc3ccccc23)cc1

Procedure:
The title compound was prepared from 4-chloroquinazoline and 4-methoxy-N-methylaniline by a procedure similar to Example 28 (79% yield). 1H NMR (CDCl3): 8.81 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.57 (ddd, J=8.1, 5.4 and 2.7 Hz, 1H), 7.09-7.14 (m, 2H), 7.03-7.06 (m, 2H), 6.9-6.93 (m, 2H).
Reaction SMILES: Cl.Cl.[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:11]=[CH:10][N:9]=1)[CH:4]([CH3:6])[CH3:5].[OH:20][C@H:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](O)=[O:23].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:20][C@H:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22]([N:17]1[CH2:18][CH2:19][N:14]([C:12]2[CH:13]=[C:8]([O:7][CH2:3][CH:4]([CH3:6])[CH3:5])[N:9]=[CH:10][N:11]=2)[CH2:15][CH2:16]1)=[O:23]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: CC(C)COc1cc(N2CCNCC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)COc1cc(N2CCN(C(=O)[C@H](O)c3ccccc3)CC2)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-isobutoxy-6-(piperazin-1-yl)pyrimidine dihydrochloride (30 mg, 0.097 mmol), (R)-2-hydroxy-2-phenylacetic acid (15 mg, 0.097 mmol), and triethylamine (0.07 mL, 0.49 mmol) in DMF was added HBTU (48 mg, 0.13 mmol), and the mixture was stirred at rt for 1 h. Then the mixture was poured onto water (3 mL), and the aqueous layer was extracted with dichloromethane (three times). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 7.2 mg (15% yields) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[S:15])[N:6]([CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[NH2:8].[CH:17](O)=O>>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[CH2:9][N:6]1[C:7]2[N:8]=[CH:17][NH:1][C:2]=2[C:3](=[O:16])[NH:4][C:5]1=[S:15]
Reactant: Nc1c(N)n(Cc2ccco2)c(=S)[nH]c1=O
Reactant: O=CO
Product: O=c1[nH]c(=S)n(Cc2ccco2)c2nc[nH]c12
Temperature: 70 °C

Procedure:
5,6-Diamino-1-(2-furyl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.12 g, 0.51 mmol) in formic acid (0.5 mL) was stirred at ambient temperature for 0.5 h. The excess of formic acid was evaporated off and the resulting solid dissolved in 10% sodium hydroxide solution (3 mL). This solution was heated at 70° C. for 0.5 h. The reaction mixture was neutralized with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, and dried. Yield: (0.047 g, 37%).
Reaction SMILES: [N: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][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.[OH:23][C:24]1([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N: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][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:23][C:24]2([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25]2)=[O:21])=[CH:15][CH:14]=1
Reactant: COC(=O)C1(O)CC1
Reactant: O=C(Cl)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1(OC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Reaction time: 14 h
Yield: 77.9 %

Procedure:
To a stirred solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetyl chloride (2.0 g, 6.557 mmol) in DCM (50 mL), DMAP (1.4 g, 13.114 mmol) was added followed by methyl 1-hydroxycyclopropanecarboxylate (1.1 g, 9.836 mmol) under a nitrogen atmosphere at RT and the mixture was stirred for 14 h. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with a saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude methyl 1-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetoxy)cyclopropanecarboxylate (2.0 g,) as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([N:5]1[C:9]([CH2:16][CH2:17][NH:18][S:19]([CH:22]=[CH2:23])(=[O:21])=[O:20])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][C:7]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:6]1)=[O:4].[CH2:33]([NH2:35])[CH3:34]>C(#N)C>[CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([N:5]1[C:9]([CH2:16][CH2:17][NH:18][S:19]([CH2:22][CH2:23][NH:35][CH2:33][CH3:34])(=[O:21])=[O:20])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][C:7]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:6]1)=[O:4]
Reactant: CCN
Reactant: C=CS(=O)(=O)NCCC1(c2ccccc2)SC(NC(=O)C(C)(C)C)=NN1C(=O)C(C)(C)C
Solvent: CC#N
Product: CCNCCS(=O)(=O)NCCC1(c2ccccc2)SC(NC(=O)C(C)(C)C)=NN1C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
N-[4-(2,2-Dimethylpropionyl)-5-(2-ethenesulfonylaminoethyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (0.16 g, 0.33 mmol) obtained in Step 4 mentioned above was dissolved in acetonitrile (10 mL), and 70% aqueous ethylamine (1.0 mL, 12 mmol) was added, then the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (chloroform/methanol/concentrated aqueous ammonia=100/10/1) to give N-{4-(2,2-dimethylpropionyl)-5-[2-(2-ethylaminoethanesulfonyl-amino)ethyl]-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl}-2,2-dimethylpropanamide} (0.15 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([CH:14]=[C:15](OCC)[NH:16][CH3:17])#[N:13]>N1C=CC=CC=1>[C:12]([CH:14]=[C:15]([NH:16][CH3:17])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CCOC(=CC#N)NC
Solvent: c1ccncc1
Product: CNC(=CC#N)NCCSCc1[nH]cnc1C
Reaction time: 5 h

Procedure:
4-Methyl-5-[(2-aminoethyl)thiomethyl]imidazole (3.5 g) was added to a solution of 1-cyano-2-ethoxy-2-methylaminoethylene in pyridine (3.1 g) and the solution was stirred for 5 hours at 100°. The product was chromatographed on a column of neutral alumina with elution by chloroform/ethyl acetate (1:1) to give the title compound as a glass.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.C(N(CC)CC)C.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](Cl)=[O:24]>C(O)C.[Pd]>[NH:6]1[CH:5]=[C:4]([NH:1][C:23](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: O=C(Cl)c1ccccn1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1cn[nH]c1)c1ccccn1
Reaction time: 3 h

Procedure:
A solution of 4-nitro-1H-pyrazole (2.5 g, 22 mmol) in ethanol (80 mL) was added to a Parr vessel under an argon atmosphere. Carefully into the vessel, 10% Pd/C (0.2 g) was added. The vessel was sealed and H2 was added to a pressure of 40 psi. The vessel was shaken for 3 hours and then the catalyst removed by filtration. The catalyst was washed with ethanol and the combined filtrates where evaporated to dryness under reduced pressure. The residue was dissolved in THF (350 mL), treated with triethyl amine (6.9 mL, 49 mmol) and cooled on an ice bath under an argon atmosphere. Picolinoyl chloride hydrochloride (3.94 g, 22.3 mmol) was added in one portion. When the reaction was complete, the solvent was removed under reduced pressure and the residue dissolved in dichloromethane. The solution was extracted with water, NaHCO3 sat, dried, and the solvent removed under reduced pressure. The crude residue was re-crystallized from ethyl acetate to afford N-(1H-pyrazol-4-yl)picolinamide. (2.19 g, 52%). 1H NMR (DMSO-d6) δ 10.88 (s, 1 H), 8.7 (s, 1 H), 8.12 (m, 2 H), 8.04 (m, 1 H,), 7.96 (s, 1 H), 7.65 (m, 1 H). MS: m/z=189[M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:16][C:17]3[CH:31]=[CH:30][C:20]([CH2:21][S:22][CH2:23][CH2:24][N:25]4[CH:29]=[CH:28][N:27]=[N:26]4)=[CH:19][CH:18]=3)[N:14]=2)=[C:4]([F:32])[CH:3]=1.ClC1C=C(C(OO)=[O:41])C=CC=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:16][C:17]3[CH:31]=[CH:30][C:20]([CH2:21][S:22]([CH2:23][CH2:24][N:25]4[CH:29]=[CH:28][N:27]=[N:26]4)=[O:41])=[CH:19][CH:18]=3)[N:14]=2)=[C:4]([F:32])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1/C=C/c1nc(COc2ccc(CSCCn3ccnn3)cc2)co1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(Cl)cc3F)n2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of 320 mg (0.68 mmol) 1-[2-(4-{2-[2-(E)-(4-chloro-2-fluoro-phenyl)vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 9 ml dichloromethane at −30° C. were added dropwise during 20 min 197 mg (0.88 mmol) 3-chloro-benzenecarboperoxoic acid dissolved in 9 ml ethyl acetate. After 1 hour stirring at 30° C. the mixture was allowed to warm up over night, stirred another 48 hours at room temperature, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate/methanol 20:1 furnished as the second fraction 171 mg (51%) title compound as white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C)C=O.[CH2:12]([O:14][C:15]([C:17]1[N:18]=[CH:19][N:20]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH:31]([CH3:33])[CH3:32])[CH:26]=C3)[CH:21]=1)=[O:16])[CH3:13]>ClCCl>[CH2:12]([O:14][C:15]([C:17]1[N:18]=[CH:19][N:20]([C:22]2[CH:30]=[C:29]3[C:28](=[CH:24][CH:23]=2)[N:27]([CH:31]([CH3:32])[CH3:33])[CH:26]=[C:2]3[CH:1]=[O:5])[CH:21]=1)=[O:16])[CH3:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cn(-c2ccc3c(ccn3C(C)C)c2)cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)c(C=O)cn3C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To anhydrous dichloromethane (30 mL) was added oxalyl chloride (0.03 mL, 0.36 mmol). N,N-dimethylformamide (0.03 mL, 0.36 mmol) was added at 0° C., which was then stirred for 30 min at 0° C. To this solution was added 1-(1-isopropylindol-5-yl)-imidazole-4-carboxylic acid ethyl ester (0.09 g, 0.3 mmol) obtained in Preparation 27, and the mixture was stirred for 1 h at room temperature. The solvent was removed, tetrahydrofuran (30 mL) and 20% aqueous ammonium acetate solution (30 mL) were added to the residue, and the mixture was heated for 30 min while being stirred under reflux. The reaction solution was cooled, ethyl acetate was added, and washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was filtered, washed with ethyl acetate and dried to give the title compound (0.09 g, 92% Yield).