Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]1[CH:14]2[CH2:15][CH:11]([CH2:12][CH:13]2[C:16]([OH:18])=[O:17])[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH:9]1[CH:14]2[CH2:15][CH:11]([CH2:12][CH:13]2[C:16]([OH:18])=[O:17])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CC2CC(C(=O)O)C1C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CC2CC(C(=O)O)C1C2
Reaction time: 0.5 h

Procedure:
A solution of 6-(tert-butoxycarbonylamino)norbornane-2-carboxylic acid, 72g, in dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL) for 1 hour at room temperature. The solvent was evaporated under reduced pressure and the resulting product was dissolved in 2 mL TFA and added to a stirring 1N HCl in Et2O solution. After stirring the mixture for 0.5 hour, the resulting precipitate was filtered and washed with dry Et2O to give 6-aminobicyclo[2.2.1]heptane-2-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCOCC.CCCCC>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:11][C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Agent: NN
Solvent: CCOCC
Solvent: CCCCC
Solvent: O
Product: O=C1Cc2ccccc2N1Cc1ccccc1
Temperature: 125 °C
Yield: 78.2 %

Procedure:
Prepared according to literature procedure (C. Martin and E. M. Carreira, J. Am. Chem. Soc., 2005, 127, 11505-11515). A stirred solution of isatin (10.0 g, 68 mmol) in dry DMF (125 mL) was cooled in an ice bath before addition of sodium hydride (60 wt % in mineral oil, 2.86 g, 71.5 mmol) in 10 portions, the orange solution turning quickly purple. When no further evolution of gas was observed, benzyl bromide (13.4 g, 78.0 mmol) was added by syringe. A colour change back to orange was observed within 20 min Water (300 mL) was added with stirring, and the resulting orange-red precipitate collected by filtration and washed with water and a little cold ethanol. The solid was then recrystallized from boiling ethanol (300 mL) to afford N-benzylisatin (13.7 g, 85%) as long, red needles. N-benzylisatin (13.0 g, 55 mmol) was mixed with hydrazine hydrate (60 mL) and placed in an oil bath. The mixture was heated in stages to 125° C., becoming first a green sludge, then yellow with clumps of a sticky solid. After a total of 5 h at 125° C., the mixture was cooled and extracted with EtOAc (2×100 mL). The combined organic portions were washed twice with 1.0 M aq. H2SO4, and once each with half-saturated brine then brine, dried over MgSO4, filtered and concentrated to afford a pale yellow solid. Re-precipitation from ether/pentane gave the title compound as an off-white solid (9.6 g, 75%). Spectral data matches literature values (C. Martin and E. M. Carreira, J. Am. Chem. Soc., 2005, 127, 11505-11515).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[NH:7][CH3:8].[Cl-].[NH4+]>CCO.O.[Fe]>[Br:1][C:2]1[CH:9]=[C:6]([NH:7][CH3:8])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CNc1cc(Br)ccc1N
Temperature: 60 °C
Yield: 90 %

Procedure:
To a solution of 5-bromo-N-methyl-2-nitroaniline (10 g, 43.5 mmol) in EtOH/H2O (700 mL) was added Fe (14.6 g, 261 mmol), ammonium chloride (14 g, 261 mmol) and the reaction mixture was heated at 60° C. for 4 h. The crude reaction mixture was filtered, concentrated, dissolved in ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was used in next reaction without further purification. (7.9 g, yield 90%) MS (ESI+) e/z: 202.1.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].Cl.[CH3:38][N:39]([CH2:41][C:42](Cl)=[O:43])[CH3:40]>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:42](=[O:43])[CH2:41][N:39]([CH3:40])[CH3:38])[CH2:7]1)#[N:2]
Reactant: CN(C)CC(=O)Cl
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Agent: Cl
Product: CN(C)CC(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 73, Step 4 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and dimethylaminoacetyl chloride hydrochloride (Lancaster and Cat. No. L18475). LCMS (M+H)+: m/z=581.3.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:20]#[N:21])([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1>>[C:20]([C:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][CH2:2][N:23]([CH3:22])[CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)#[N:21]
Reactant: CNCCc1ccc(C(=O)OC)cc1
Reactant: COC(=O)C(C#N)(CCCBr)c1ccc(OC)c(OC)c1
Product: COC(=O)c1ccc(CCN(C)CCCC(C#N)(C(=O)OC)c2ccc(OC)c(OC)c2)cc1

Procedure:
Reaction of 1b with 2b produced 3i. MS found M+H=469. The oxalate salt of 3i was recrystallized from ethyl acetate; mp 80-83° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:26])[NH2:25])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C#N)c1
Reaction time: 0.02 h
Yield: 112.1 %

Procedure:
40% Methanolic Triton B (0.06 mL, 0.13 mM) was added to a solution of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (34.1 mg, 0.1 mM) in 5 mL DMF at room temperature. After 1 minute, tert-butyl bromoacetate (40 mg, 0.2 mM) was added and the resultant mixture stirred at room temperature for 24 h. The mixture was diluted with ethyl. acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with hexane to afford 51 mg (100%) of the {9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (CDCl3) δ7.55 (d, 1H, J=8 Hz), 7.5-7.2 (m, 7H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.5 (s, 2H), 4.8 (s, 2H), and 1.5 (s, 9H). IR (KBr, cm−1) 2228, 1748, and 1669. MS (ES) m/e 455, 456.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:15])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:16](=[O:23])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH2:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:17][C:16](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: Cc1ncccc1Oc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1ncccc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 83.7 %

Procedure:
3-(2-Chloropyridin-4-yloxy)-2-methylpyridine (4.8 g, 21.8 mmol), tert-butyl carbamate (6.37 g, 54.4 mmol), and potassium phosphate (5.08 g, 23.9 mmol) were added to degassed toluene (100 mL). 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.944 g, 1.63 mmol), tris(dibenzylideneacetone)-dipalladium (0.996 g, 1.09 mmol) and degassed water (25 mL) were added, and the reaction was stirred at 90° C. for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried, concentrated, and flash chromatographed (10-50% ethyl acetate/hexanes) to give the title compound (5.5 g, 59% yield) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[H-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39]Cl)=[CH:34][CH:33]=1.[Cl-].[NH4+]>CN(C=O)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:23]2([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20][N:19]3[C:15]([C:5]4[CH:6]=[CH:7][C:8]([C:9]5[O:13][C:12]([CH3:14])=[N:11][CH:10]=5)=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:16][N:17]=[C:18]23)=[CH:34][CH:33]=1
Reactant: ClCOc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2ccc(Cl)cc2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
Under ice-cooling and an argon stream, to a mixture of ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1000 mg) in DMF (15 mL) was added sodium hydride (60%, 115 mg), and the mixture was stirred at 0° C. for 30 min. 1-Chloro-4-(chloromethoxy)benzene (694 mg) was added, and the mixture was stirred at 0° C. for 1 hr. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (440 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:27]([O-:29])=[O:28])[C:5]([O:9][CH2:10][N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])=[C:6]([F:8])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1COc1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)N1COc1c(F)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-fluoro-5-(phthalimido)methoxybenzene (5.0 g, 16.4 mmol) was slowly added to a stirred mixture of con. sulfuric acid-con. nitric acid (10:1, 20 ml) at −20° C. Solution was then warmed to ambient temperature and allowed to stir for 1 hr. Addition to ice-water resulted in a light yellow precipitate which was separated by filtration. Column chromatography on silica gel in hexane-methylene chloride (3:7) furnished the title compound (3.2 g); 1H NMR (CDCl3, 300 MHz) 4.06 (3H, s), 7.54 (1H, d, J=8.5 Hz), 7.84 (2H, m), 7.97 (2H, m) ppm.
Reaction SMILES: O.[O:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:12][CH:13]([OH:16])[CH2:14][OH:15])[CH:6]=[CH:5][C:4]1=2>[Pd].COCCOCCOC>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH:13]([OH:16])[CH2:14][OH:15]
Reactant: O=C1CCCc2c1ccn2CC(O)CO
Agent: [Pd]
Solvent: COCCOCCOC
Solvent: O
Product: OCC(O)Cn1ccc2c(O)cccc21
Yield: 45.1 %

Procedure:
3.8 g of palladium on carbon at 5% by weight and containing 50% of water were introduced into a solution of 9.4 g of 4-oxo-4,5,6,7-tetrahydro-1-N-(β,γ-dihydroxypropyl)-indole, obtained in the preceding stage, in 50 cm3 of diglyme. The temperature of the reaction medium was raised to the reflux temperature of diglyme and the water was distilled off by azeotropy. After 23 hours of reaction, the catalyst was filtered off on celite and then the diglyme was evaporated off under vacuum. The crude product obtained was chromatographed on silica gel (ethyl acetate/heptane=9/1 ). 4.2 g of 4-hydroxy-1-N-(β,γ-dihydroxypropyl)indole were obtained in the form of a very viscous oil whose analysis by 1H and 13C nuclear magnetic resonance was in conformity with the expected product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([C:23]6[CH:24]=[CH:25][C:26]([N:29]7[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]7)=[N:27][CH:28]=6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:29]1([C:26]2[N:27]=[CH:28][C:23]([C:20]3[CH:21]=[N:22][C:17]4[N:18]([C:14]([C:11]5([C:7]6[CH:6]=[C:5]7[C:10](=[CH:9][CH:8]=6)[N:1]=[CH:2][CH:3]=[CH:4]7)[CH2:13][CH2:12]5)=[CH:15][N:16]=4)[CH:19]=3)=[CH:24][CH:25]=2)[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2ccc(C3(c4cnc5ncc(-c6ccc(N7CCNCC7)nc6)cn45)CC3)cc2c1
Yield: 191.3 %

Procedure:
tert-butyl 4-{5-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-yl}piperazine-1-carboxylate (80.0 mg, 0.146 mmol) in methylene chloride (1.0 mL) was treated with trifluoroacetic acid (1.0 mL) at RT for 2 h. The volatiles were evaporated and the residue was co-evaporated with acetonitrile to give the desired product (125 mg) as a TFA salt which was directly used in next step without further purification. LCMS: (M+H)=448.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.O>CCCCCC>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)=[O:10])[CH3:12]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: COc1cc(CO)ccc1O
Solvent: O
Solvent: CCCCCC
Product: COc1cc(COC(=O)CCCCCCC(C)C)ccc1O
Temperature: 50 °C
Reaction time: 20 h
Yield: 97.5 %

Procedure:
8-Methylnonanoic acid (1.00 g, 5.80 mmol), vanillyl alcohol (851 mg, 5.52 mmol), and Novozym 435 (50 mg) were measured and placed in a flask (25 ml). The mixture in the flask free of a plug was heated with stirring in an oil bath at 50° C. for 20 hours. After 2 to 3 hours of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The reaction mixture was returned to room temperature, hexane (25 ml) was added, and Novozym 435 and a small amount of precipitated vanillyl alcohol were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml) and saturated brine (25 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a mixture (1.66 g) of dihydrocapsiate and 8-methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 89.7%, and the purity was 99.5 area % by HPLC. The mixture contained 8.0 wt % of 8-methylnonanoic acid relative to dihydrocapsiate.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1C=CC=C[CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5].F[B-](F)(F)F.CN(C)C(C(OCC)=O)=CC=[N+](C)C.CC[O-].[Na+].C(SCC(OCC)=O)C>C(O)C>[CH3:23][N:2]([CH3:1])[C:3](=[CH:9][CH:10]=[C:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5]
Reactant: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)CSCC
Agent: CC[O-]
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)CC

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (21 cc) and ethyl (ethylthio)acetate (5.2 g) in ethanol (100 cc). Diethyl 2-dimethylamino-5-ethylthio-2,4-hexadienedioate (8.5 g) is thereby obtained in the form of a red oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.CO.O.C(OCC)(=O)C.[CH3:20][N:21](C)C=O>C(Cl)Cl.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1)#[N:21]
Reactant: CN(C)C=O
Reactant: NS(=O)(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(S(N)(=O)=O)s1
Reaction time: 0.25 h

Procedure:
A mixture of 5-bromothiophene-2-sulfonamide (0.50 g, 2.1 mmol), zinc cyanide (0.25 g, 2.1 mmol), tetrakis(triphenylphosphine)palladium(0) (0.072 g, 0.06 mmol) in dimethylformamide (5 mL, anhydrous) is placed under microwave radiation (under nitrogen atmosphere, 160° C.) for 15 min. Thin layer chromatography (5% methyl alcohol in methylene chloride) demonstrates the reaction is incomplete. Additional tetrakis-(triphenylphosphine)palladium(0) (0.24 g, 0.2 mmol) and dimethylformamide (10 mL) are added to the reaction mixture and placed under microwave radiation (under nitrogen atmosphere at 160° C.) for 37 min. 10 mL of water and 20 mL of ethyl acetate are added to the reaction mixture. The organic phase is separated and the aqueous layer is extracted with 20 mL ethyl acetate. The combined organic layers are dried over sodium sulfate, concentrated in vacuo, and then chromatographed on silica (0-5% methyl alcohol in methylene chloride) to give the title compound, as a white solid (0.22 g, 57% yield).
Reaction SMILES: [N+](=[CH2:3])=[N-].C(=O)(O)[O-].[Na+].[CH3:9][N:10]1[C:14]([OH:15])=[C:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[Cl:26])[C:12]([CH3:28])=[N:11]1>C(OCC)C.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:9][N:10]1[C:14]([O:15][CH3:3])=[C:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[Cl:26])[C:12]([CH3:28])=[N:11]1
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: C=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1c(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c(C)nn1C
Temperature: 0 °C

Procedure:
In a four necked flask, 1.4 g of 1,3-dimethyl-4-(2-chloro-4-nitrobenzoyl)-5-hydroxypyrazole was dissolved in 10 ml of ethyl ether. The solution was cooled with ice-water and an ether solution of diazomethane was added and the reaction was carried out until ceasing nitrogen gas. Diazomethane and ether were distilled off from the reaction mixture to obtain the precipitate of the reaction product. The precipitate was dissolved in methylene chloride. The solution was mixed with a saturated aqueous solution of sodium bicarbonate. The organic phase was separated and methylene chloride was distilled off to obtain a solid product. The solid product was dissolved in toluene and adsorbed on a silica gel column and eluted with methylene chloride to obtain 0.8 g of 1,3-dimethyl-4-(2-chloro-4-nitrobenzoyl)-5-methoxy pyrazole having a melting point of 97° to 98° C.
Reaction SMILES: ClC1C(CC2C=CC(OCC)=CC=2)=CC([C@H]2[C@H](OCC3C=CC=CC=3)[C@@H](OCC3C=CC=CC=3)[C@H](OCC3C=CC=CC=3)[C@@H](COCC3C=CC=CC=3)O2)=CC=1O.[CH2:58]([O:65][C@H:66]1[C@H:71]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[C@@H:70]([O:80][CH2:81][C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[C@H:69]([C:88]2[CH:93]=[C:92]([CH2:94][C:95]3[CH:100]=[CH:99][C:98]([O:101][CH2:102][CH3:103])=[CH:97][CH:96]=3)[C:91]([Cl:104])=[C:90]([O:105]C)[C:89]=2[O:107][CH3:108])[O:68][C@@H:67]1[CH2:109][O:110][CH2:111][C:112]1[CH:117]=[CH:116][CH:115]=[CH:114][CH:113]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>>[Cl:104][C:91]1[C:92]([CH2:94][C:95]2[CH:96]=[CH:97][C:98]([O:101][CH2:102][CH3:103])=[CH:99][CH:100]=2)=[CH:93][C:88]([C@H:69]2[C@H:70]([O:80][CH2:81][C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)[C@@H:71]([O:72][CH2:73][C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[C@H:66]([O:65][CH2:58][C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[C@@H:67]([CH2:109][O:110][CH2:111][C:112]3[CH:113]=[CH:114][CH:115]=[CH:116][CH:117]=3)[O:68]2)=[C:89]([O:107][CH3:108])[C:90]=1[OH:105]
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OC)c(OC)c2Cl)cc1
Agent: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc(O)c2Cl)cc1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OC)c(O)c2Cl)cc1

Procedure:
Similar procedure with preparation of 77 proceeded except for using compound 162 to obtain the compound 163.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:14]=[C:13]([CH2:15]OS(C)(=O)=O)[CH:12]=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[N+:21]([C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+].[I-]>CC(C)=O>[CH3:3][C:4]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:15][N:26]3[CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:28]=[N:27]3)[N:14]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cccc(COS(C)(=O)=O)n2)OCCO1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CC1(c2cccc(Cn3cc([N+](=O)[O-])cn3)n2)OCCO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 6-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl ester (273 mg, 1.00 mmol) in acetone (4.0 mL) was added, under inert atmosphere (N2) to a solution of 4-nitro-1H-pyrazole (115 mg, 1.00 mmol) in acetone (4.0 mL). K2CO3 (698 mg, 5.00 mmol) and TBA iodide (64 mg, 0.20 mmol) were added and the reaction mixture was stirred at rt for 5 h. The solvent was removed under reduced pressure. Water (10 mL) and EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (30:10 to 50:50 hept-EA) gave the title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.87 min; [M+H]+=291.27.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]([C:12](OC)=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][C:5]2=[N:4][O:3]1.[BH4-].[Li+]>C1COCC1>[OH:13][CH2:12][CH:7]1[N:6]2[C:2](=[O:1])[O:3][N:4]=[C:5]2[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)C1CCCCc2noc(=O)n21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1onc2n1C(CO)CCCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ex-5) To a solution of the product of Example 4 in anhydrous THF was added lithium borohydride (21.5 mL, 43 mmol). This solution was stirred for 16 hours at 25° C. The lithium borohydride was quenched with methanol and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed twice with potassium hydrogen sulfate and twice with brine. The organic phase was dried over magnesium sulfate and all solvent was removed under reduced pressure to yield the title compound.