Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1N
Yield: 105 %

Procedure:
Prepared from (4-benzoyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example D1) (280 mg, 0.82 mmol) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a yellow foam (269 mg).
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]([CH3:18])[C:4]=2[N:3]=1.C(OC([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[N:26]1([C:2]2[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]3[C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]([CH3:18])[C:4]=3[N:3]=2)[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=CCn1c(N2CCCNCC2)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8-Chloro-3-methyl-7-(3-methylbut-2-enyl)-3,7-dihydropurine-2,6-dione (40 mg) and 1-homopiperazine carboxylic acid tert-butyl ester (87 μl) were stirred at 140° C. for 1 hour, then trifluoroacetic acid (0.5 ml) was added thereto, and the reaction mixture was stirred at room temperature for 30 minutes. After removing the solvent by distillation at reduced pressure from the reaction mixture, the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as eluent to give 46.8 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:10][NH2:11])=O)=[CH:6][CH:5]=1.I.CS[C:19](=[NH:28])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]2[NH:28][C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:11][N:10]=2)=[CH:6][CH:5]=1
Reactant: CSC(=N)Nc1ccc(O)cc1
Reactant: NNC(=O)c1ccc(OC(F)(F)F)cc1
Agent: I
Solvent: c1ccncc1
Product: Oc1ccc(Nc2nnc(-c3ccc(OC(F)(F)F)cc3)[nH]2)cc1
Temperature: 25 °C
Yield: 40.7 %

Procedure:
4-trifluoromethoxybenzoic acid hydrazide (1.1 g, 5.0 mmol) and S-methyl N-[4-hydroxy-phenyl]isothiourea hydroiodide (1.55 g, 5.0 mmol) were suspended in 10 mL of anhydrous pyridine. The reaction mixture was refluxed for 24 hours, during which time it changed color from yellow into orange-red. Then it was cooled down to ambient temperature and poured with stirring into 150 mL of ice-water. The aqueous layer was decanted and the resulting residue was purified by silica gel chromatography using 1:1 mixture of ethyl acetate/hexane. Solvent was removed in vacuo to give the title product as a pinkish-grey solid (684.0 mg). 40.6% yield.
Reaction SMILES: [F:1][C:2]([N+:9]([O-:11])=[O:10])([N+:6]([O-:8])=[O:7])[CH2:3][CH2:4][OH:5].[F:12][S:13]([F:20])=[C:14](O)[C:15]([F:18])([F:17])[F:16]>>[F:12][S:13]([F:20])=[C:14]([O:5][CH2:4][CH2:3][C:2]([F:1])([N+:9]([O-:11])=[O:10])[N+:6]([O-:8])=[O:7])[C:15]([F:18])([F:17])[F:16]
Reactant: O=[N+]([O-])C(F)(CCO)[N+](=O)[O-]
Reactant: OC(=S(F)F)C(F)(F)F
Product: O=[N+]([O-])C(F)(CCOC(=S(F)F)C(F)(F)F)[N+](=O)[O-]
Yield: 83 %

Procedure:
Using a method similar to example 12, 3-fluoro-3,3-dinitropropanol and pentafluorothioacetic acid were reacted to form 3-fluoro-3,3-dinitropropyl pentafluorothioacetate (83% yield) mp 28° C.;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([CH3:8])=[N:6][CH:7]=1.[Cl-].[NH4+]>[Fe].C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ncc(Br)cc1N
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitropyridine (8.0 g, 37 mmol) in 4:1 ethanol/water (250 mL) was added iron (16.5 g, 295 mmol) and ammonium chloride (15.8 g, 295 mmol). The mixture was stirred at 80° C. for 3 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give 5-bromo-2-methylpyridin-3-amine (6.8 g, 99% crude yield), which was without further purification.
Reaction SMILES: P([O-])([O-])([O-])=O.[C:6]([OH:13])(=[O:12])/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10].[NH3:14]>>[NH2:14][C@H:7]([C:6]([OH:13])=[O:12])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: N
Agent: O=P([O-])([O-])[O-]
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
The culture of H-9183 strain as obtained in the controlled aeration condition in Example 1 was centrifuged to isolate the cells. The cells were suspended in a phosphate buffer (0.01 M potassium phosphate; pH 7.4), and homogenized along with glass beads to disrupt them into an extract. The extract was passed through a column filled with a resin, Duolite A-7 to thereby make the protein existing in the extract adsorbed by the resin. Then, an aqueous solution of fumaric acid (150 g/liter; adjusted the pH at 8.5 with aqueous ammonia) was passed through the column at 37° C. to thereby obtain a solution of L-aspartic acid (171 g/liter). The pH of the solution(1 liter) was adjusted to 2.7 with sulfuric acid, and 161 g of L-aspartic acid crystals was obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4](/[CH:5]=[CH:14]/[N+:11]([O-:13])=[O:12])[C:3]=1[CH3:10]
Reactant: C[N+](=O)[O-]
Reactant: Cc1c(F)cccc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1c(F)cccc1/C=C/[N+](=O)[O-]
Yield: 89 %

Procedure:
A Knoevenagel condensation was carried out by stirring 3-fluoro-2-methyl-benzaldehyde (20.721 g, 150 mmol), nitromethane (48.75 ml, 900 mmol) and ammonium acetate (34.687 g, 450 mmol) in 300 ml of acetic acid at 115° C. for 3.5 h. The mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 250 ml of EA. The solution was washed with water (250 ml), three times with a 1 N sodium hydroxide solution (125 ml) and with brine (125 ml), dried over magnesium sulfate, filtered and evaporated to dryness. 24.18 g of the title compound were obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:29]1[CH2:33]OC[CH2:30]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:10][C:11]2([C:15]([O:17][CH3:18])=[O:16])[CH2:30][CH2:29][CH2:33][CH:12]2[C:13]1=[O:14]
Reactant: C1CCOC1
Reactant: COC(=O)C1CC(=O)N(c2c(C)cccc2C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)C12CCCC1C(=O)N(c1c(C)cccc1C)C2
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To methyl 1-(2,6-dimethylphenyl)-5-oxopyrrolidine-3-carboxylate (1.5 g, 6.1 mmol) dissolved in 5 mL anhydrous THF and cooled to −40° C., lithium bis(trimethylsily)amide (1.0 M in THF, 6.1 mL, 6.1 mmol) was added with a syringe. After stirring for 10 min, the bath was replaced with a 0° C. bath and stirring continued for another 10 min. The reaction mixture was then cooled to −40° C. and another 6.1 mL of lithium bis(trimethylsily)amide solution (6.1 mmol) was added. After stirring for 10 min at −40° C., the reaction mixture was allowed to gradually warm to room temperature, quenched with saturated ammonium chloride solution (15 ml) and the crude product was extracted with ether. The combined organic layer was dried over anhydrous Na2SO4, the solvent was evaporated and the residue purified by flash chromatography (SiO2, 10-100% EtOAc/hexanes) to yield 920 mg of methyl 2-(2,6-dimethylphenyl)-1-oxooctahydrocyclopenta[c]pyrrole-3a-carboxylate (32% yield). LC-MS Rt (retention time): 2.12 min, MS: (ES) m/z 288 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)Nc4ccccc4)cc3c2C1
Yield: 7 %

Procedure:
Beginning with 10.0 mg (0.0437 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 10.4 (0.0874 mMol) phenyl isocyanate, 1.0 mg (7%) of the title compound was recovered using the procedure described in detail in Example 12.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:21][C:16]2[C:15]([NH:14][CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: Nc1ccccc1NCC1CCN(c2ccncc2)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccccc2NCC2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 16.6 %

Procedure:
A solution of N1-[1-(4-pyridyl)piperidin-4-ylmethyl]-1,2-benzenediamine (212 mg, 0.75 mmol) and pyridine (4 mL) in chloroform (2 mL) at 0° C. was treated with a solution of 4-methoxybenzoyl chloride (128 mg, 0.75 mmol) in chloroform. The mixture was allowed to warm to room temperature and stir for 17 h. The mixture was concentrated and the residue was dissolved in EtOAc. The organic layer was washed with 1 N NaOH (2×), water (3×), brine (1×), dried (K2CO3), and concentrated. The residue was purified by RPHPLC, yielding 52 mg (17%) of the title compound as a hydrochloride salt.
Reaction SMILES: I[Si](C)(C)C.[NH2:6][C:7]1[C:8]([C:15](/[N:17]=[C:18]2\[NH:19][CH2:20][C:21]3([CH2:28][CH:27]4[N:29](C(OC(C)(C)C)=O)[CH:24]([CH2:25][CH2:26]4)[CH2:23]3)[NH:22]\2)=[O:16])=[N:9][C:10]([Cl:14])=[C:11]([NH2:13])[N:12]=1.CN(C=O)C>C(Cl)Cl>[NH2:6][C:7]1[C:8]([C:15](/[N:17]=[C:18]2\[NH:19][CH2:20][C:21]3([CH2:28][CH:27]4[NH:29][CH:24]([CH2:25][CH2:26]4)[CH2:23]3)[NH:22]\2)=[O:16])=[N:9][C:10]([Cl:14])=[C:11]([NH2:13])[N:12]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC1(CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N1)C2
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4)N2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodotrimethylsilane (0.23 ml, 1.66 mmol) is added to a suspension of (E)-tert-Butyl 2′-(3,5-diamino-6-chloropyrazine-2-carbonylimino)-8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-8-carboxylate (Ex. 251) (500 mg, 1.11 mmol) in DCM (10 ml). DMF (5 ml) is then added and the reaction is stirred at room temperature overnight. Iodotrimethylsilane (0.5 ml) is added and the reaction mixture is concentrated in vacuo. The yellow solid is suspended in DCM and collected by filtration. The solid is dissolved in 1:1 MeOH/DCM and loaded onto an SCX-2 cartridge eluted with DCM followed by MeOH and NH3/MeOH. The methanolic ammonia fractions are concentrated in vacuo to afford (E)-3,5-diamino-6-chloro-N-(8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-2′-ylidene)pyrazine-2-carboxamide as a yellow gum; [M+H]+ 351
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][N:4]([CH2:8]CC#N)[C:3]1=[O:12].Cl.[C:14]([OH:17])(=[O:16])[CH3:15]>>[CH3:1][N:2]1[C:6](=[O:7])[CH2:5][N:4]([CH2:8][CH2:15][C:14]([OH:17])=[O:16])[C:3]1=[O:12]
Reactant: CC(=O)O
Reactant: CN1C(=O)CN(CCC#N)C1=O
Agent: Cl
Product: CN1C(=O)CN(CCC(=O)O)C1=O
Yield: 49.4 %

Procedure:
334.33 g (2.0 mol) of 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionitrile, prepared as described in Example 5, are hydrolysed for 5 hours and 30 minutes at 96°-107° C. in a mixture of 1482.7 g (13.0 mol) of aqueous 32% hydrochloric acid and 288.3 g (4.8 mol) of acetic acid. The reaction solution is then evaporated at 90° C. under reduced pressure in a rotary evaporator and dried at 120° C./0.1 mbar to constant weight, giving 354.1 g (95.1% of theory) of crude product, which is purified by recrystallization from 1 liter of ethyl acetate, giving 184 g (50.4% of theory) of crystalline 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionic acid having a melting point of 109° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]#[C:9][CH2:10][CH3:11]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)#[C:9][CH2:10][CH3:11]
Reactant: Brc1ccccn1
Reactant: C#CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCC#Cc1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
After dissolving 2-bromopyridine (50 g) in diethylamine (500 mL) and adding dichlorobis(triphenylphosphine)palladium (II) (2.2 g) and copper iodide (0.3 g), the mixture was stirred at room temperature for 4 hours while introducing 1-butyne (100 g) as a gas. After bubbling in nitrogen, extraction was performed with ethyl acetate. The insoluble portion was filtered out with celite, and then the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (35 g) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a brown oil.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:6]2[C:12]([C:13]#[N:14])=[C:11]([F:15])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].[NH2:22][C:23]1[N:28]=[C:27](Cl)[C:26]([C:30]#[N:31])=[C:25]([CH3:32])[N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[N:28]=[C:27]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]3[C:12]([C:13]#[N:14])=[C:11]([F:15])[CH:10]=[CH:9][C:7]=3[N:8]=2)[CH3:3])[C:26]([C:30]#[N:31])=[C:25]([CH3:32])[N:24]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccc(F)c(C#N)c2n1-c1ccccn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccc(F)c(C#N)c3n2-c2ccccn2)c1C#N
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 2-((S)-1-aminoethyl)-5-fluoro-3-pyridin-2-yl-3H-benzoimidazole-4-carbonitrile (0.085 g, 0.240 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.057 g, 0.335 mmol) and DIPEA (0.17 mL, 0.960 mmol) in IPA (1.5 mL) was stirred at 80° C. in a sealed microwave tube for 16 hours. After cooling, the mixture was concentrated in vacuo and the residue was purified by chromatography (Si—PPC, gradient 0-8% 2M NH3/MeOH in DCM) to give 368 as an off white solid (0.064 g, 64%). LCMS (Method K): RT 2.87 min [M+H]+ 414.1. 1H NMR (DMSO, 400 MHz): δ 8.76-8.74 (1H, d), 8.02-7.97 (1H, t), 7.96-7.92 (1H, m), 7.58-7.54 (1H, m), 7.47-7.44 (1H, d), 7.15-7.10 (1H, t), 6.06-6.02 (1H, d), 5.42-5.35 (1H, m), 5.15-5.11 (2H, s), 2.32 (3H, s), 1.61-1.59 (3H, d)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[CH2:12]=O.[ClH:14]>>[ClH:14].[S:1]1[C:2]2[CH2:6][C@H:7]([C:9]([OH:11])=[O:10])[NH:8][CH2:12][C:3]=2[CH:4]=[CH:5]1
Reactant: N[C@H](Cc1cccs1)C(=O)O
Reactant: C=O
Agent: Cl
Product: O=C(O)[C@H]1Cc2sccc2CN1
Temperature: 110 °C

Procedure:
A mixture containing 87 mmol of β-2-thienyl-D-alanine, 11 ml of formaldehyde at 40% in aqueous medium, and 88 ml of 1N hydrochloric acid is heated for 2 h 30 min at 110° C., with stirring, and then at 60° C. overnight. After evaporation, the residue is taken up in ethanol and then evaporated and the expected product is recovered in the form of a solid in diethyl ether.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]=[O:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.[CH3:22][Mg]Br>O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]([OH:13])[CH3:22])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1
Reactant: C[Mg]Br
Reactant: C[Si](C)(C)CCOCn1nc(Br)c2cc(Cl)cc(C=O)c21
Solvent: C1CCOC1
Product: CC(O)c1cc(Cl)cc2c(Br)nn(COCC[Si](C)(C)C)c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-Bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carbaldehyde (1.35 g, 3.46 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to −78° C. and treated with methylmagnesium bromide (3.0 M in diethyl ether, 1.7 mL, 5.20 mmol) over several minutes. After 1 h, the ice bath was removed and stirring continued for 1 h at room temperature. The reaction was cooled to 0° C., treated with saturated ammonium chloride and diluted with ethyl acetate. The layers were separated. The organic layer was washed with water (2×), brine (2×), dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel (30% ethyl acetate/hexanes) afforded 1.29 g (92%) as a brown oil. 1H-NMR (CDCl3, 300 MHz) δ 7.51-7.53 (m, 2H), 5.91 (qAB, JAB=11.7 Hz, 2H), 5.52-5.54 (m, 1H), 3.49-3.54 (m, 2H), 1.63 (d, J=6.6 Hz, 3H), 0.78-0.83 (m, 2H), 0.09 (s, 9H). Mass spec.: 429.18 (MNa)+.
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].[CH2:24]([O:26][C@H:27]1[CH2:44][C@@:43]2([CH3:45])[C@@H:30]([CH2:31][CH2:32][C@@H:33]3[C@@H:42]2[C:41](=[O:46])[CH2:40][C@@:38]2([CH3:39])[C@H:34]3[CH2:35][CH2:36][C:37]2=O)[CH2:29][C@@H:28]1[OH:48])[CH3:25]>O1CCCC1>[CH2:24]([O:26][C@H:27]1[CH2:44][C@@:43]2([CH3:45])[C@@H:30]([CH2:31][CH2:32][C@@H:33]3[C@@H:42]2[C:41](=[O:46])[CH2:40][C@@:38]2([CH3:39])[C@H:34]3[CH2:35][CH2:36][C:37]2=[CH2:2])[CH2:29][C@@H:28]1[OH:48])[CH3:25]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]32)C[C@@H]1O
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.2 %

Procedure:
Triphenylmethyl phosphonium bromide (7.5 g) was added to a suspension of sodium hydride (500 mg) in dry tetrahydrofuran (100 ml). The mixture was stirred at room temperature for 1.5 hours and then treated with 2β-ethoxy-3α-hydroxy-5α-androstane-11,17-dione (2.43 g). The mixture was refluxed for 1.5 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (Na2SO4) and evaporated in vacuo. Purification of the residue by chromatography over silica in ethyl acetate-petroleum ether (1:2) and crystallization from ether-petroleum ether afforded the titled compound (850 mg), m.p. 103°-108°, [α]D +25.5°.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[Br-:12].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:12][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[N:2]([CH3:11])[CH3:1])[CH:7]=[O:8]
Reactant: [Br-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CN(C)c1ccc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 4-(dimethylamino)-benzaldehyde (10.0 g, 67.03 mmol) in dichloromethane (250 mL) was added pyridinium tribromide (21.4 g, 67.03 mmol). The reaction mixture was stirred at room temperature overnight. The solution was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. Chromatography on silica gel (15% EtOAc in hexane) afforded 14.06 g of 3-bromo-4-(dimethylamino)-benzaldehyde (92%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SC)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[N:17][C:16]3=[O:22])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3Cl)c2)S1
Reactant: CN1CCNCC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(S(C)(=O)=O)cc4Cl)c3)S2)CC1

Procedure:
5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([N:1]([S:31]([CH3:30])(=[O:33])=[O:32])[C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1)(=[O:33])=[O:32]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cl)cc2F)c1=O
Yield: 131.4 %

Procedure:
To a mixture of 1.00 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)pyrimidinedione, 0.63 g of triethylamine and 10 ml of dichloromethane, 0.48 g of methanesulfonylchloride was added at a temperature of not more than 5° C. The resultant mixture was stirred overnight. After washing twice the reaction mixture with water, the reaction mixture was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dichloromethane was distilled off to obtain a crude product. The obtained product was washed with diisopropylether to obtain 1.36 g of the objective product as white crystals.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:10]12[CH2:15][CH:14]1[C:13](=[O:16])[O:12][C:11]2=O>>[C:1]1([CH2:7][CH2:8][N:9]2[C:11](=[O:12])[CH:10]3[CH:14]([CH2:15]3)[C:13]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: NCCC1=CCCCC1
Reactant: O=C1OC(=O)C2CC12
Product: O=C1C2CC2C(=O)N1CCC1=CCCCC1
Temperature: 180 °C

Procedure:
A mixture of 2-(cyclohexen-1-yl)ethylamine (0.59 g) and 3-oxabicyclo[3.1.0]hexane-2,4-dione (0.5 g) was heated at 180° C. for 3 hours. The resulting mixture was cooled to room temperature to give the title compound as a yellow solid, m.p. 60-61° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:45])[NH2:44])[CH:39]=2)[CH:34]=1)(=O)=O>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([O:12][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:44])[NH2:45])[CH:39]=3)[CH:34]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)CCCc3ccccc3)ccc2c1
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a solution of 2.9 g of 4-phenylbutyric acid in 50 ml of anhydrous pyridine, while being cooled in ice and stirred, was added 4.4 g of DCC. After 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added and the mixture was stirred for 24 hours at room temperature and removed of insolubles. Ethyl ether was added to the filtrate and the precipitate was collected by filtration. The precipitate was recrystallized from a DMF-ethyl ether mixture to obtain 2.3 g of a white powder of 6-amidino-2-naphthyl 4-phenylbutyrate methanesulfonate.