Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Cl:46]Cl>O1CCOCC1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:46])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Reactant: ClCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A 1.0 g quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 10 ml of dioxane. To the solution was added 3 g of NaHCO3 and the mixture was stirred at room temperature. Into the reaction mixture was forced 1.5 equivalents of chlorine gas and the mixture was stirred for 2 hours. The same subsequent procedure as in Example 4 was conducted, giving 1.0 g of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C[Si]([C:21]#[N:22])(C)C>C(Cl)Cl.[I-].[Zn+2].[I-]>[NH2:22][CH2:21][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:7]
Reactant: C[Si](C)(C)C#N
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: NCC(O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound is prepared by combining 4,4′-dichlorobenzophenone (5 g, 20 mmol) and zinc iodide (480 mg, 1.49 mmol) in DCM (100 mL). Trimethylsilyl cyanide (2.17 g, 21.9 mmol) is added, and the reaction is stirred at room temperature for 18 hours. The reaction is washed with water (100 mL) and dried over magnesium sulfate, before filtering and removal of the solvent under reduced pressure. The residue is redissolved in dry THF (40 mL), 1.0M borane in THF (40 mL) is added, and the reaction is stirred at reflux for 24 hours. After cooling, the volatile components are removed under reduced pressure, the residue is taken up in methanol (100 mL). Concentrated hydrochloric acid is added, and the reaction is refluxed for a further 2 hours, before once more removing the volatile components under reduced pressure, to give the title compound as a hydrochloride salt.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:23](=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.6 g of 4-(2-dimethylamino-ethylamino)-nitrobenzene (according to Gabbay et al., J. Am. Chem. Soc. 91, 5136 (1969)) are dissolved in 50 ml of methylene chloride and 5.0 ml of triethylamine are added. 1.3 ml of acetyl chloride are slowly added dropwise to this mixture at room temperature and the mixture is stirred for 2 hours at room temperature. After this time another 5.0 ml of triethylamine and 1.3 ml of acetylchloride are added and the mixture is refluxed for another 2 hours. The solvent is removed, the residue is taken up in ethyl acetate and the organic phase is extracted twice with water. After drying over MgSO4 the solvent is removed and the residue dried in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](O)(=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.[OH-].[NH4+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: CCCCCCCC(=O)O
Reactant: COc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(OC)cc32)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 14.82 grams of 8-methoxy-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin in 50 milliliters of benzene was added 12.55 grams of caprylic acid (octanoic acid). The resulting reaction mixture was allowed to stand overnight and was then heated for 3 hours at a temperature of 60°C. After cooling, the mixture was shaken with 100 milliliters of water, 20 milliliters of concentrated aqueous ammonium hydroxide solution was then added thereto, and the mixture was extracted with a mixture of benzene and ethyl ether. The resulting extract was washed with water, dried over anhydrous potassium carbonate, and the solvent was evaporated therefrom. The residue was dissolved in 40 milliliters of acetone and added to a solution of 9.5 grams of maleic acid in 30 milliliters of acetone. On standing, 15.5 grams of crude 8-methoxy-10-]4-(3-octanoyloxypropyl)piperazino]-10,11-dihydrobenzo[b,f]thiepin di(hydrogen maleate) crystals separated therefrom. On purification by recrystallization from acetone, the di(hydrogen maleate) salt had a melting point of 130°C. The free base was recovered in the form of a viscous oil by adding the di(hydrogen maleate) to a dilute aqueous ammonium hydroxide solution and extracting the solution with benzene as described in Example 1 hereinbefore.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:17][C:18]1[NH:22][N:21]=[C:20]([NH2:23])[CH:19]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[C:4]([NH:23][C:20]2[CH:19]=[C:18]([CH3:17])[NH:22][N:21]=2)[N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CN(C)S(=O)(=O)N(C)c1cc(Cl)nc(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(N(C)S(=O)(=O)N(C)C)nc(Cl)n2)n[nH]1
Temperature: 70 °C
Yield: 9.7 %

Procedure:
To a solution of N-(2,6-dichloropyrimidin-4-yl)-N,N′,N′-trimethylsulfamide (Method 27, 1.72 g, 6.05 mmol) in n-BuOH (6 ml) was added 5-methyl-1H-pyrazol-3-amine (0.605 g, 6.05 mmol) and DIPEA (1.6 mL, 9.09 mmol). The mixture was heated at 70° C. overnight. The reaction mixture was filtered; the solid was washed by MeOH three times to give pure white solid. (0.205 g, 9.7% yield). LC-MS, 346 (M+1). NMR (DMSO-d6, 400 MHz, 80° C.) δ 11.89 (s, 1H), 9.82 (s, 1H), 7.22 (s, 1H), 5.97 (s, 1H), 3.32 (s, 3H), 2.87 (s, 6H), 2.21 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]([CH2:36][CH2:37][CH3:38])[CH2:34][NH2:35])[CH:30]=[CH:31][CH:32]=1>C1COCC1>[Cl:12][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([NH:35][CH2:34][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=1)[CH2:36][CH2:37][CH3:38])=[O:11]
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Reactant: CCCC(CN)c1cccc(OC)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCC(CNC(=O)Cc1c(Cl)cncc1Cl)c1cccc(OC)c1
Yield: 97 %

Procedure:
By working in a way similar to that described in example 4 but using (3,5-dichloro-pyridin-4-yl)-acetic acid (2.06 g, 10 mmoles), carbonyldiimidazole (1.78 g, 11 mmoles), THF (30 ml) and 2-(3-methoxy-phenyl)-pentylamine (1.93 g 10 mmoles), obtained as described in example 17, 3.7 g of the title compound were obtained (yield: 97%), m.p.: 97-98° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1>CN(C)C=O>[Br:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:23][C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1
Reactant: BrCCCCCCCBr
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(SCCCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.4 %

Procedure:
To 1,7-dibromoheptane (23 g) and potassium carbonate (10 g) in dry dimethylformamide (100 ml) was added 4-chlorothiophenol (4.3 g) dropwise with stirring at 25° C. After 6 h, the mixture was filtered and the solvent removed under reduced pressure. Chromatography of the residue on silica gel using hexane as eluent gave 1-bromo-7-(4-chlorophenylthio)heptane (9.6 g). 1H-NMR (CDCl3) δ 1.2-1.55 (6H, m), 1.55-1.75 (2H, m), 1.8-2.0 (2H, m), 2.89 (2H, t), 3.40 (2H, t) and 7.2-7.4 (4H, m).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].S(Cl)([Cl:13])=O>C(Cl)Cl>[CH2:1]([C:3]1[C:8]([CH2:9][Cl:13])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCc1ncccc1CCl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The 2-ethyl-3-hydroxymethylpyridine (2.3 g, 16.8 mmol) was dissolved in CH2Cl2 (100 mL) and cooled under nitrogen to 0° C. and thionyl chloride (7.0 mL) was slowly added and the reaction was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried with MgSO4, filtered, and the solvent removed under reduced pressure to give the desired 2-ethyl-3-chloromethylpyridine.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:22]([CH3:24])[CH3:23])[C:4]([N:6]1[CH2:11][CH2:10][C@@:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([OH:12])[C:8]([CH3:21])([CH3:20])[CH2:7]1)=[O:5].ClC1N=[C:30]([O:32]C)N=C(OC)N=1.C(O)=O.CN1CCOCC1>CN(C1C=CN=CC=1)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@@:9]2([OH:12])[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C@H:3]([NH:2][CH:30]=[O:32])[CH:22]([CH3:24])[CH3:23])[CH2:7][C:8]2([CH3:20])[CH3:21])=[CH:18][CH:17]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: COc1nc(Cl)nc(OC)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O=CO
Product: CC(C)[C@@H](NC=O)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (111 mg, 0.296 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (57.1 mg, 0.325 mmol), formic acid (0.012 mL, 0.325 mmol) and NMM (0.068 mL, 0.62 mmol) CH2Cl2 (10 mL), was added DMAP (3.61 mg, 0.03 mmol). The mixture was stirred at rt for 3 h. The reaction was filtered and the filtrate was washed with Na2CO3, 0.5N HCl, and brine. The organic layer was dried over Na2SO4 and Concentrated to give N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)formamide (76 mg, 0.207 mmol, 70.0% yield).
Reaction SMILES: [ClH:1].Cl.[C:3]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][C:32]([C:38](=[NH:40])[NH2:39])=[CH:33][CH:34]=4)[CH:29]=3)[S:20]([CH2:23][C:24]([OH:26])=[O:25])(=[O:22])=[O:21])=[CH:15][C:14]=2[F:41])[CH2:8][CH2:7]1)(=[NH:5])[CH3:4].Cl.O1CCO[CH2:45][CH2:44]1>C(O)C>[ClH:1].[ClH:1].[C:3]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][C:32]([C:38](=[NH:39])[NH2:40])=[CH:33][CH:34]=4)[CH:29]=3)[S:20]([CH2:23][C:24]([O:26][CH2:44][CH3:45])=[O:25])(=[O:22])=[O:21])=[CH:15][C:14]=2[F:41])[CH2:8][CH2:7]1)(=[NH:5])[CH3:4]
Reactant: C1COCCO1
Reactant: CC(=N)N1CCCN(c2ccc(N(Cc3ccc4ccc(C(=N)N)cc4c3)S(=O)(=O)CC(=O)O)cc2F)CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CS(=O)(=O)N(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(N2CCCN(C(C)=N)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
300 mg of [N-[4-(4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl)-3-fluorophenyl]-N-[(7-amidino-2-naphth-yl)methyl]sulfamoyl]acetic acid dihydrochloride obtained in Example 31 was dissolved in 10 ml of ethanol, to which was added 1 ml of a 4 N hydrochloric acid gas-dioxane solution, and stirred at room temperature for 22 hours. The reaction mixture was evaporated, and the resulting residue was dissolved in 20 ml of ethanol, to which was added 2 ml of a 4 N hydrochloric acid gas-dioxane solution, and stirred at room temperature for 7 hours. The reaction mixture was evaporated, and the resulting residue was purified through ODS column chromatography using an eluent solvent of ethanol. A s mall amount of 1 N hydrochloric acid was added to the thus-purified product, which was then freeze-dried to obtain 238 mg of ethyl [N-[4-(4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl)-3-fluorophenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]acetate dihydrochloride.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=3)[C:3]2=[O:19])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(-c2ccccc2)c2cc(F)ccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccccc2)c2cc(F)ccc2c1=O

Procedure:
The product from Example 35E and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.75 (s, 2H) 7.03-7.20 (m, 3H) 7.38 (dd, J=9.46, 2.44 Hz, 1H) 7.52-7.68 (m, 5H) 7.82 (d, J=2.44 Hz, 1H) 8.48 (d, J=3.36 Hz, 1H); MS (ESI) m/z 410 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[Br:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]>CCCCCC>[Br:9][C:10]1[CH:15]=[C:14]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1Br)N1Cc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Br)c2)n1
Reaction time: 0.67 h
Yield: 46.5 %

Procedure:
Sodium hydride (60% suspension in oil, 1.2 g, 30.15 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (110 mL). Neat 3-methylpyrazole (2.47 g, 30.15 mmol) was added dropwise at 0° C. After the gas evolution subsided the cooling bath was removed and stirring was continued at room temperature. The [2-bromo-4-fluorophenyl]-(5,11-dihydro-pyrido [2,3-b][1,5]benzodiazepin-6-yl)-methanone of Step B (6 g, 18.07 mmol) was added in one portion to the clear solution. The mixture was placed in an oil bath (preheated at 130° C.) for 40 minutes, cooled and partitioned between water and ethyl acetate. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with a hexane-ethyl acetate gradient (from 95:5 to 75:25) provided the less polar title compound (3.87 g) along with a mixture of 3- and 5-methylpyrazole regioisomers (0.860 g). The title compound (3.5 g, 51%) crystallized by sonication from hexane-ethanol, m.p. 208-209° C. (dec).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[CH:22]=[C:21]2[C:16]([N:17]=[C:18]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C:19]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[C:20]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:15]1)C1C=CC=CC=1.C(O)=O>CCO.[Pd]>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[C:21]3[C:16](=[N:15][N:14]([CH2:13][CH:9]4[CH2:10][CH2:11][CH2:12][NH:8]4)[CH:22]=3)[N:17]=[C:18]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[C:19]=2[C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(-c2nc3nn(CC4CCCN4Cc4ccccc4)cc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: Fc1ccc(-c2nc3nn(CC4CCCN4)cc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Yield: 85.6 %

Procedure:
To a solution of 2-(1-benzylpyrrolidin-2-ylmethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (83 mg, 0.1 mmol, obtained in example 259) in EtOH (6.9 mL), 10% Pd/C (8 mg) and formic acid (0.34 mL) were added and heated a reflux for 2 h. It was allowed to cool and filtered through celite, washed with EtOH and concentrated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc-MeOH—NH3 of increasing polarity as eluent, to afford 40 mg of the title compound (yield: 57%)
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:8][N:7]([C:9]([NH:11][CH2:12][CH3:13])=[NH:10])[N:6]=[CH:5]1)[CH3:3].CCN(C(C)C)C(C)C.[N:23]1[S:27][N:26]=[C:25]2[C:28]([S:32](Cl)(=[O:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:24]=12>C(Cl)Cl>[CH2:12]([NH:11][C:9]([N:7]1[CH2:8][CH:4]([CH2:2][CH3:3])[CH:5]=[N:6]1)=[N:10][S:32]([C:28]1[C:25]2=[N:26][S:27][N:23]=[C:24]2[CH:31]=[CH:30][CH:29]=1)(=[O:34])=[O:33])[CH3:13]
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: CCNC(=N)N1CC(CC)C=N1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1cccc2nsnc12)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
300 mg 4,N-Diethyl-4,5-dihydro-pyrazole-1-carboxamidine hydrochloride was suspended in 10 mL DCM. 0.53 mL DiPEA and 310 mg benzo[1,2,5]thiadiazole-4-sulfonylchloride were added and the mixture was stirred overnight at room temperature. The mixture was washed with 5% NaHCO3 and 2 M NaOH, the organic layer dried over Na2SO4 and the solvent evaporated in vacuo to yield 410 mg of a red/brown oil. The crude product was purified by flash chromatography (DCM:aceton=98:2, Rf=0.18) to yield 350 mg (65%) of an orange oil. 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=7.5 Hz, 3H), 1.16 (br t, J=7 Hz, 3H), 1.41-1.66 (m, 2H), 3.01-3.16 (m, 1H), 3.39-3.55 (m, 2H), 3.59-3.74 (m, 1H), 3.95-4.15 (m, 1H), 6.94 (br s, 1H), 6.95 (br s, 1H), 7.68 (dd, J=9 and 7 Hz, 1H), 8.15 (br d, J=9 Hz, 1H), 8.31 (br d, J=7 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=[O:39])[NH:16][CH:17]([C:25]2[S:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][CH:31]=3)[CH:29]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:48])C(=O)C1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=[O:39])[NH:16][CH:17]([C:25]2[S:26][C:27]([Cl:48])=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][CH:31]=3)[CH:29]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(Cc2ccccc2)c2cc(-c3ccc(C(N)=O)cc3)cs2)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(Cc2ccccc2)c2cc(-c3ccc(C(N)=O)cc3)c(Cl)s2)CC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1C (336 mg, 0.6 mmol) and NCS (104 mg, 0.78 mmol) in chloroform (20 mL) was stirred at 60° C. under N2. After 1.5 h, the mixture was cooled to rt and concentrated. Reverse-phase HPLC purification gave ID as a light yellow solid. LC/MS m/z 596.2 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([CH3:21])([CH3:20])[O:16][C:17](=[O:19])[NH:18][C:13]=2[CH:12]=1)(=O)=O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:23]=[CH:22][C:14]3[C:15]([CH3:20])([CH3:21])[O:16][C:17](=[O:19])[NH:18][C:13]=3[CH:12]=2)=[CH:27][CH:26]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCOS(C)(=O)=O)ccc21
Product: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccc(Cl)cc3)ccc21

Procedure:
Prepared analogously to Example 210 from 7-(4-methanesulfonyloxy-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-chlorothiophenol.
Reaction SMILES: [NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH2:15][CH2:16][OH:17])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.S(=O)(=O)(O)O.[C:23](O)(=[O:25])[CH3:24]>>[NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH2:15][CH2:16][O:17][C:23](=[O:25])[CH3:24])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1
Reactant: NN1NC=C(c2ncc([N+](=O)[O-])n2CCO)S1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: CC(=O)OCCn1c([N+](=O)[O-])cnc1C1=CNN(N)S1

Procedure:
The sample (0.1 g.) of 2-amino-5-[1-(2-hydroxyethyl)-5-nitro- 2-imidazolyl]thiadiazole is dissolved in 2 ml. of hot glacial acetic acid and a drop of concentrated sulfuric acid is added. The solution is refluxed for 45 minutes, cooled and poured on ice to give a yellow solid. This solid is collected, washed with water and dried; the yield is 0.1 g., melting point 159°-162° C. (turbid). A purified sample of the 2-amino-5-[1-(2-acetoxyethyl)- 5-nitro-2-imidazolyl]thiadiazole, melts at 164°-165.5° C.
Reaction SMILES: [OH-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH3:12][C:13]1[CH:21]=[CH:20]C(C(Cl)=O)=[CH:15][CH:14]=1>O.C1(C)C=CC=CC=1>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[C:7]1[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][CH:15]=1)[CH3:11]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(C)cc1
Yield: 34.9 %

Procedure:
Sodium hydroxide solution (33%, 32.5 ml) was added to ethyl acetoacetate (97.5 g, 750 mmol) in a mixture of water (250 ml) and toluene (12 ml) at 0–5° C. under stirring (pH 11). After 30 minutes 4-methylbenzoylchloride (127.46 g, 825 mmol) and sodium hydroxide solution (33%, 135 ml) was added simultaneously over a period two hours. The reaction mixture was stirred for 15 minutes at 0° C. and for 1 hour at 35° C. Aqueous layer was separated, ammonium chloride (40 g) was added and stirred slowly over night. The reaction mixture was saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulphate and concentrated to dryness in vacuum. The crude product thus obtained was purified by column chromatography to yield the title compound as viscous oil (54 g, 35%). MS m/z: 207.1 (M+). Preparation 2 Synthesis of ethyl(4-chloro)benzoylacetate
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH3:17]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89 %

Procedure:
4-Chloro-3,5-dinitrobenzoic acid (25.0 gm.) is dissolved in a cooled solution of methanol (125 ml.) and concentrated sulfuric acid (3.0 ml.). The reaction mixture is allowed to warm to room temperature and then heated to reflux for 18 hours. The product precipitated as light yellow needles on cooling, which are collected by filtration and washed with 15 ml. of methanol (24.0 gm., m. p. 102°-104.5°). Recrystallization from methanol gives light yellow needles (23.6 g., m.p. 104°-105.5°, 89% yield).