Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH3:8])[N:4]([CH3:9])[N:3]=1.[CH:10]([O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])=[O:15])([CH3:12])[CH3:11].ClCCCC>C(Cl)Cl>[CH3:9][N:4]1[C:5]([S:7][CH3:8])=[N:6][C:2]([NH:1][C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:14]([O:13][CH:10]([CH3:12])[CH3:11])=[O:15])(=[O:24])=[O:23])=[O:27])=[N:3]1
Reactant: CC(C)OC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CSc1nc(N)nn1C
Solvent: ClCCl
Solvent: CCCCCl
Product: CSc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC(C)C)nn1C

Procedure:
A mixture of 0.7 grams (0.00486 mole) of 3-amino-1-methyl-5-methylthio-1H-1,2,4-triazole and 4.0 grams of 2-(isopropoxycarbonyl)benzenesulfonylisocyanate was stirred in 12 ml of dry methylene chloride at ambient temperature overnight. After addition of 4 ml of 1-chlorobutane, a white solid precipitated which was filtered, washed with 1-chlorobutane and dried, yield 1.3 grams, m.p. 192°-194°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][N:22]([CH3:25])[C:21]3=[O:26])[N:17]2C(OC(C)(C)C)=O)[CH:13]=[CH:14][CH:15]=1.C([Cl:37])(C)=O>C(OCC)(=O)C.CO>[ClH:37].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][N:22]([CH3:25])[C:21]3=[O:26])[NH:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)Cl
Reactant: CN1CC[C@]2(CC[C@H](c3cccc(OCc4ccccc4F)c3)N2C(=O)OC(C)(C)C)C1=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CC[C@]2(CC[C@H](c3cccc(OCc4ccccc4F)c3)N2)C1=O
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl (2R,5R)-2-(3-{[(2-fluorophenyl)methyl]oxy}phenyl)-7-methyl-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D47, 60 mg, 0.13 mmol) in a mixture of ethyl acetate (1 mL) and methanol (0.2 mL) was added AcCl (58 μl, 0.82 mmol) at 0° C. The mixture was stirred for 1 hour at room temperature, solvent removal afforded the title compound. Despite a clean HPLC trace, the product did not become solid. The oil obtained was then submitted to a further purification by SCX column. The free base coming from the SCX (40 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL) and to this solution cooled at 0° C. HCl (0.15 mL of a 1M solution in diethyl ether, 0.15 mmol) was added. After 15 min the solvent was removed under reduced pressure and the solid obtained triturated with diethyl ether. The title compound was obtained as a white solid (40 mg, 80%); Rt (HPLC) 3.72 min; MS: (ES/+) m/z: 355 [MH+]; C21H23FN2O2 requires 354; 1H NMR (500 MHz, DMSO-d6) δ(ppm): 10.62 (br. s., 1H), 9.00 (br. s., 1H), 7.59 (dt, 1H); 7.42-7.48 (m, 1H); 7.39 (t, 1H), 7.34-7.37 (m, 1H); 7.22-7.31 (m, 2H); 7.18 (d, 1H), 7.11 (dd, 1H); 5.11-5.24 (m, 2H), 4.70-4.80 (m, 1H); 3.35-3.45 (m, 2H); 2.78-2.86 (m, 3H); 2.50-2.56 (m, 2H); 2.24-2.46 (m, 3H); 2.00-2.18 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].O[C:14](=[C:21]1[S:25][C:24](=[O:26])[NH:23][C:22]1=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NC(=O)C(=C(O)c2ccccc2)S1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)Oc1ccccc1C=C1SC(=O)NC1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
3,4-Dichlorophenylacetic acid was dissolved in SO2Cl2 followed by addition of a few drops of DMF. This resulting mixture was heated to 80 ° C for 15-30 min. followed by concentration of the reaction mixture under reduced pressure. The residue was dissolved in THF and slowly added to a solution of 5-(hydroxybenzylidene)thiazolidine-2,4-dione (1.5 eq.) and TEA (1.5 eq.) in THF. The resulting reaction was stirred for 1-2 h at which time the solid was filtered off and filtrate was concentrated under reduced pressure to yield light yellow solid. The solid was dissolved in EtOAc followed by washing with sat. aq. K2CO3. The organic phase was separated, and dried over Na2SO4 followed by concentration under reduced pressure to yield pure compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[CH:19]=[CH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C1COCC1.O.[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:28][CH:29]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccc(C=Cc2cc(Cl)ccc2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=[Pt]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCc2cc(Cl)ccc2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 84.8 %

Procedure:
To a solution of 4-[2-[2-(4-chlorophenyl)sulfonylamino-5-chlorophenyl]vinyl]benzoic acid (54 mg; prepared in Example 5.) in THF (4 ml), platinum oxide hydrate (3 mg) was added. The mixture was stirred for 2 hours at room temperature in a stream of hydrogen. The reaction mixture was filtered and the filtrate was concentrated under the reduced pressure. To the residue, methylene chloride was added. The mixture was stirred. The precipitate was collected by filter to give the title compound (46 mg) having the following physical data.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=1)[C:25]([N:27]=[S:28]([CH3:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:20]3[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=3)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[CH:8][CH:7]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: CS(=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1ccc(NC(=O)c2ccc(F)cc2)cc1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(NC(=O)c3ccc(F)cc3)cc2)c1)c1ccccc1
Yield: 72.2 %

Procedure:
In a manner similar to that described in Example 449, N-(4-ethynyl-phenyl)-4-fluoro-benzamide (0.106 g, 0.443 mmol) and 5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (106 mg, 72%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1.[Na].O>C(O)CCC>[NH:1]1[CH2:6][CH2:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH2:2]1
Reactant: c1ccc2c(CCc3ccncc3)c[nH]c2c1
Agent: [Na]
Solvent: CCCCO
Solvent: O
Product: C1=C(CCc2c[nH]c3ccccc23)CCNC1
Yield: 24.8 %

Procedure:
A solution of 10.3 g of 3-[2-(4-pyridyl)-ethyl]-indole (prepared according to U.S. Pat. No. 3,300,506) in 400 ml n-butanol was heated, under nitrogen, at a temperature of approximately 90° C. Thereafter, 8 g of sodium were added portionwise while agitating magnetically and the temperature was raised to and maintained at about 110° C. until the sodium disappeared. Once the ambient temperature had been restored, the solution was poured into 400 ml water, the organic phase washed with water until it became neutral and then was dried over sodium sulfate and evaporated under vacuum. The evaporation residue was mixed with 25 ml absolute ethanol and purified by means of chromatography over silica gel, (eluant: ethanol-diethylamine=40-1). Following two processes of crystallization in methanol, 2.6 g of 3-[2-(1,2,5,6-tetrahydro-4-pyridyl)-ethyl]-indole were obtained, which melted at 155° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)CC)C.Cl.[CH3:34][C:35]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:36]=1[NH2:37].C(P(C#N)(CC)=O)C>ClCCl>[CH3:34][C:35]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:36]=1[NH:37][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:25][CH:24]=1
Reactant: Cc1cccc(N)c1C
Reactant: O=C(O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)c1C
Yield: 25.4 %

Procedure:
A mixture of 0.332 g of 4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid, 0.222 g of triethylamine, 0.157 g of 2,3-dimethylaniline hydrochloride, 0.15 ml of diethylphosphoryl cyanide in 20 ml of dichloromethane is heated on a steam bath for 3 hours. The mixture is washed with H2O, 1M NaHCO3, H2O, 1N HCl, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated to dryness under vacuum and the residue crystallized from dichloromethane-hexane to give 0.11 g of crystals, m.p. 239°-240° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][C:38]=3[F:51])[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]4[NH:3][C:4](=[O:7])[O:5][N:50]=4)=[CH:39][C:38]=3[F:51])[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.9 g), sodium hydrogencarbonate (1.37 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.9 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (20 mL). N,N′-Carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.4 g, 40%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH2:17])=[CH:11][C:10]=1[O:18][CH3:19])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:11][C:10]=1[O:18][CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)c(OC)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)c(OC)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a ice-cooled solution of (4-amino-2-methoxy-5-vinyl-benzyl)-carbamic acid tert-butyl ester (220 mg, 0.79 mmol) in methylene chloride was added triethylamine (132 L) followed by methanesulfonyl chloride (72 L). The mixture was warmed up to room temperature and stirred for 4 hrs. The reaction was quenched with water, and the reaction solution was extracted with methylenechloride, washed with water and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The resulting residue was treated with 1N NaOH/MeOH/THF (1/2/1) for 2 hrs, and then neutralized by adding 1N HCl. After evaporating methanol, water was added to the residue. The resulting mixture was extracted with EtOAc, and the combined organic layer was washed with brine, dried over anhyd. MgSO4, filtered, and concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate=1/1) to yield a white solid (260 mg, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(Br)nc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(F)cc1)c1ccc(Br)nc1
Reaction time: 12 h
Yield: 71.8 %

Procedure:
To a suspension of 6-bromonicotinoyl chloride (0.5 g, 2.5 mmol) in dry chloroform (10 mL) was added 4-fluoroaniline (0.33 mL, 3.5 mmol) and 2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, (0.85 g, 3.5 mmol). The mixture was stirred for 12 h, diluted with hexanes and the solids isolated by filtration. Purification by trituration using ethyl acetate/hexanes gave 0.53 g (73%) of the desired product as a white solid. 1H NMR (300 MHz, DMSO-d6) a 10.51 (s, 1H), 8.87 (m, 1H), 8.20 (m, 1H), 7.82 (m, 1H), 7.74 (m, 2H), 7.19 (m, 2H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([CH:9]2[CH2:12][C:11](=C)[CH2:10]2)=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5]1)([CH3:3])[CH3:2].[OH2:19]>CC#N.[O-]S([O-])(=S)=O.[Na+].[Na+].C(Cl)Cl>[CH:1]([N:4]1[C:8]([CH:9]2[CH2:12][C:11](=[O:19])[CH2:10]2)=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5]1)([CH3:3])[CH3:2]
Reactant: O
Reactant: C=C1CC(c2cc(C(=O)OCC)nn2C(C)C)C1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1cc(C2CC(=O)C2)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Compound 8c (6.45 g, 26.0 mmol) was dissolved in a mixture of MeCN (77 mL) and water (13 mL) and cooled in an ice-bath. To this solution RuCl3×H2O (0.19 g, 0.86 mmol) was added, followed by portion-wise addition of NaIO4 (19.35 g, 90.9 mmol). An exotherm was observed during this addition. The obtained thick slurry was stirred at rt for 45 min. The reaction mixture was diluted with Na2S2O3 aq. sol. (10%, 260 mL), water (50 mL) and DCM (100 mL). The phases were separated and the aq. phase was extracted with DCM (2×70 mL). The combined organic phases were washed with Na2S2O3 aq. sol. (10%, 50 mL), water (100 mL), brine (100 mL) and dried over anh. Na2SO4. The crude product (6.5 g) was purified on silica, eluting with hexanes/MTBE to give pure product as an oil that solidified upon storage at −20° C. Yield: 5.8 g (78% over two steps). 1H-NMR (DMSO-d6), δ (ppm): 6.78 (s, 1H), 4.57 (h, J=8.0 Hz, 1H), 4.26 (q, J=8.0 Hz, 2H), 3.85-3.75 (m, 1H), 3.58-3.45 (m, 2H), 3.35-3.25 (m, 2H), 1.39 (d, J=8.0 Hz, 6H), 1.28 (t, J=8.0 Hz, 3H).
Reaction SMILES: NN.[N+:3]([C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][NH:18][CH:17]3[CH2:21][S:22](=[O:25])(=[O:24])[CH2:23][CH:16]23)[C:9]2O[CH:12]=[CH:11][C:10]=2[CH:14]=1)([O-])=O.CC#N.C1C[O:32]CC1>CCO.[Ni]>[O:25]=[S:22]1(=[O:24])[CH2:21][CH:17]2[CH:16]([N:15]([C:8]3[O:32][C:11]4[CH:12]=[CH:7][C:6]([NH2:3])=[CH:14][C:10]=4[CH:9]=3)[CH2:20][CH2:19][NH:18]2)[CH2:23]1
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1cc(N2CCNC3CS(=O)(=O)CC32)c2occc2c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: CC#N
Product: Nc1ccc2oc(N3CCNC4CS(=O)(=O)CC43)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (204 mL, 4.20 mmol) were added to 1-(5-nitro-1-benzofuran-7-yl)octahydrothieno[3,4-b]pyrazine 6,6-dioxide (0.354 g, 1.05 mmol; Intermediate 35) in a mixture of THF (20 mL) and EtOH (80 mL). The resulting mixture was stirred at room temperature overnight and then more Raney-nickel (slurry in ethanol; 2 mL) and hydrazine (204 mL, 4.20 mmol) were added and stirring was continued overnight. The mixture was filtered through Celite and the solvent was removed in vacuo to afford 0.338 g (quantitative). HPLC 90%, RT: 0.782 (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, methanol-d4) δ ppm 2.79 (dd, J=12.49, 7.30 Hz, 1H) 2.90-3.25 (m, 4H) 3.43-3.64 (m, 3H) 3.91-3.94 (m, 1H) 5.01-5.07 (m, 1H) 6.33 (d, J=1.98 Hz, 1H) 6.61 (dd, J=12.99, 2.10 Hz, 2H) 7.62 (d, J=1.98 Hz, 1H). LC-MS 308 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O1CCCC1.Cl[C:13]1[C:18]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:17][C:16]([N+:24]([O-:26])=[O:25])=[CH:15][N:14]=1>O>[O:4]1[CH2:5][CH2:6][N:1]([C:13]2[C:18]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:17][C:16]([N+:24]([O-:26])=[O:25])=[CH:15][N:14]=2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)c(-n2cccn2)c1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cnc(N2CCOCC2)c(-n2cccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Morpholine (50 μl) was added to a tetrahydrofuran solution (1 ml) containing 2-chloro-5-nitro-3-(1H-pyrazol-1-yl)pyridine (30 mg), followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a yellow solid of 2-morpholino-5-nitro-3-(1H-pyrazol-1-yl)pyridine (37 mg) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]>>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:8](=[O:9])[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1nccs1
Reactant: O=C(Cl)Oc1ccccc1
Product: O=C(Nc1nccs1)Oc1ccccc1

Procedure:
Using analogous procedures to those described in Example 49, the appropriate 2-amino-1,3-thiazole was reacted with phenyl chloroformate and the phenyl N-(1,3-thiazol-2-yl)carbamate so obtained was reacted with the appropriate alkylamine to give the compounds described in Table II.
Reaction SMILES: [CH2:1]1CCCC[CH2:2]1.[C:7]([O:10][CH2:11][CH3:12])(=[O:9])[CH3:8].[CH:13](Cl)(Cl)Cl>>[CH3:12][CH2:11][O:10][CH:7]([O:9][CH2:1][CH3:2])[CH:8]=[CH2:13]
Reactant: C1CCCCC1
Reactant: ClC(Cl)Cl
Reactant: CCOC(C)=O
Product: C=CC(OCC)OCC

Procedure:
Formula: C11H18O5 (MM=230.3) Rf: (cyclohexane/ethyl acetate: 85/15): 0.16 mp=35° C. {α}D20+23.18° (c 1.005, CHCl3) IR (film): 3089, 2977, 2933, 2871, 2822, 1464, 1441, 1424, 1382, 1323, 1282, 1262, 1232, 1168, 1144, 1107, 1045, 1028, 1002, 942, 912 cm−1 MS (m/z): 55 (83), 71 (100), 85 (38), 101 (31) 1H-NMR (500 MHz, CDCl3) 3.22 (2H, m), 3.31 (3H, m), 3.49 (3H, s), 3.50 (1H, t, J=10.2 Hz), 3.63 (3H, s), 4.06 (1H, dd, J=11.1 Hz, J=4.9 Hz), 4.18 (1H, dd, J=4.9 Hz, J=10.4 Hz), 4.97 (1H, d, J=4.1 Hz), 5.32 (1H, d, J=10.8 Hz), 5.48 (1H, d, J=17.4 Hz), 5.86 (1H, ddd, J=4.1 Hz, J=10.8 Hz, J=17.4 Hz) 13C-NMR (500 MHz, CDCl3) 59.2 (CH3), 60.9 (CH3), 68.5 (CH2), 68.5 (CH2), 71.3 (CH), 79.6 (CH), 81.5 (CH), 83.8 (CH), 100.5 (CH), 119.0 (CH2), 133.7 (CH)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH2:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]([O:26]C)=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:28])[CH:16]=2)[CH3:13])=[O:11])=[CH:4][CH:3]=1.O1CCCC1.[Li+].[OH-]>CO.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([N:12]([CH2:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]([OH:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:28])[CH:16]=2)[CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c(CN(C)C(=O)/C=C/c3ccc(N)nc3)cn(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(Cc1cn(C)c2c(C(=O)O)cccc12)C(=O)C=Cc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.3 %

Procedure:
A solution of (E)-3-(6-aminopyridin-3-yl)-N-(7-methoxycarbonyl-1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (76 mg, 0.2 mmole) in methanol (4 mL), water (2 mL), and tetrahydrofuran (2 mL) was treated with LiOH (39 mg, 1.6 mmole), and the reaction was stirred at ambient temperature for 48 h. The mixture was filtered, and the filtrate was acidified to pH 4.0-4.5 with 1.0 N HCl. The precipitate was collected, washed with water and dried giving the title compound (25 mg, 35%) as a white solid: MS (ES) m/e 365.2 (M+H)+. Anal. Calcd for C20H20N4O3.0.25H2O: C, 65.11: H, 5.60; N, 15.18. Found: C, 64.83; H, 5.52; N, 15.07.
Reaction SMILES: CN1CCCC1=O.C(N(C(C)C)CC)(C)C.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([O-:19])=[O:18].[CH3:27][O:28][C:29]([C:31]1[O:40][C:34]2=[N:35][CH:36]=[CH:37][C:38](Cl)=[C:33]2[CH:32]=1)=[O:30]>O>[CH3:27][O:28][C:29]([C:31]1[O:40][C:34]2=[N:35][CH:36]=[CH:37][C:38]([O:26][C:23]3[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)=[C:33]2[CH:32]=1)=[O:30]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)c1cc2c(Cl)ccnc2o1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2o1
Temperature: 140 °C
Reaction time: 5 h
Yield: 4.7 %

Procedure:
After adding N-methylpyrrolidone (4.0 ml), diisopropylethylamine (1.3 ml) and para-nitrophenol (822 mg) to 4-chlorofuro[2.3-b]pyridine-2-carboxylic acid methyl ester (1.0 g), the mixture was heated and stirred at 140° C. for 5 hours. After cooling, water was added, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Tetrahydrofuran was used for recrystallization to obtain the title compound (70 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>>[C:16]([NH:20][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 74.2 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88 mmol), tert-butylamine (503 mg, 6.88mmol) and triethylamine(l.43 mL, 10.32 mmol) were reacted to form the desired product (1.67 g, 75%). 1H NMR (MeOD-d4): δ 7.91 (d, 1H), 7.78 (d, 1H), 1.25 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:6]2[N:7]=[C:8]([N:10]=[C:11]=[O:12])[S:9][C:5]=2[CH:4]([CH3:14])[CH2:3]1.C[CH:17]([NH2:20])[CH:18]=[O:19].[C:21]1(C)C=CC=CC=1>>[CH3:21][N:20]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]([CH3:14])[CH2:3][C:2]([CH3:15])([CH3:1])[CH2:13][C:6]=2[N:7]=1)=[O:12]
Reactant: Cc1ccccc1
Reactant: CC1CC(C)(C)Cc2nc(N=C=O)sc21
Reactant: CC(N)C=O
Product: CC1CC(C)(C)Cc2nc(NC(=O)N(C)CC=O)sc21
Reaction time: 1 h

Procedure:
5,5,7-Trimethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl isocyanate dimer (7.5 grams), the dimethyl acetal of 2-methyl-aminoacetaldehyde (5 grams) and toluene (15 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture was then heated, with stirring for a period of about 1 hour. After this time the mixture was cooled and filtered. The filtrate was washed with water, dried and evaporated, leaving the desired product dimethyl acetal of 2-[1-methyl-3-(5,5,7-trimethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl)ureido]acetaldehyde as a brown oil.