Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][S:12][CH3:13])=[C:5]([Cl:7])[N:6]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[Cl:1][C:2]1[S:3][C:4]([N:8]([CH3:15])[C:9](=[O:14])[CH2:10][CH2:11][S:12][CH3:13])=[C:5]([Cl:7])[N:6]=1
Reactant: O=C([O-])[O-]
Reactant: CSCCC(=O)Nc1sc(Cl)nc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CSCCC(=O)N(C)c1sc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 43.5 %

Procedure:
To a solution of N-(2,4-dichloro-thiazol-5-yl)-3-methylsulfanyl-propionamide (596 mg, 2.2 mmol) in DMF (11 mL) stirring at 25° C. was added K2CO3 (365 mg, 2.64 mmol) and iodomethane (375 mg, 1.2 mmol), the solution was stirred at 25° C. for 20 h. The solution was diluted with 50 mL H2O and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with H2O (3×20 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a clear oil (273 mg, 44%): 1H NMR (300 MHz, CDCl3) δ 3.23 (s, 3H), 2.79 (t, J=7.2 Hz, 2H), 2.52 (t, J=7.2 Hz, 2H), 2.09 (s, 3H); ESIMS m/z 285.1 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Br[C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[F:22]>[Cu]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]2[C:13]([F:22])=[C:14]([F:21])[C:15]([F:20])=[C:16]([F:19])[C:17]=2[F:18])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Agent: [Cu]
Product: O=[N+]([O-])c1ccc(-c2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 190 °C
Yield: 63.4 %

Procedure:
A mixture of 4-iodonitrobenzene (15 g, 0.060 mol), bromopentafluorobenzene (14.9 g, 2.56 mL, 0.060 mol) and copper powder (30 g) was placed into a 50-mL J-Young glass tube and heated at 190° C. for 24 hours. The tube was cooled and the mixture was extracted exhaustively with dichloromethane. The solvent was removed and the residue was extracted with boiling hexane and filtered while hot. The solvent was removed and the resulting viscous solid was sublimed to obtain 4-nitro-2′,3′,4′,5′,6′-pentafluorobiphenyl as a yellow solid (11.0 g, 63% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[S:14][N:13]=[CH:12][C:11]=3[CH:15]=2)=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.C1(C)C=CC=CC=1.[CH3:29][N:30]=[C:31]=[O:32]>C(N(CC)CC)C>[CH3:29][NH:30][C:31]([NH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[S:14][N:13]=[CH:12][C:11]=3[CH:15]=2)=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1)=[O:32]
Reactant: CN=C=O
Reactant: Nc1ccc(Oc2ccc3sncc3c2)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(Oc2ccc3sncc3c2)c(C(F)(F)F)c1
Yield: 80 %

Procedure:
31 parts of 5-(4'-amino-2'-trifluoromethylphenoxy)-benzisothiazole, 400 parts of toluene, 1 part of triethylamine and 11.4 parts of methyl isocyanate were stirred for 12 hours at 80° C., after which the solvent was removed under reduced pressure and the residue was purified over silica gel, using chloroform as the mobile phase. 29.4 parts (80% of theory) of 5-(4'-methylaminocarbonylamino-2'-trifluoromethylphenoxy)-benzisothiazole of melting point 138° C. were obtained.
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18].Cl.CON.N1C=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:2]=[C:3]([NH2:18])[C:4]([NH2:15])=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: c1ccncc1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: CON
Agent: Cl
Solvent: CCO
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 25 mL round bottom flask was charged with a suspension of 1 (600 mg, 2.2 mmol), methoxyamine HCl (202 mg, 2.42 mmol), and pyridine (0.22 mL, 2.6 mmol) in ethanol (9 mL). The resulting reaction mixture was stirred at rt overnight. The crude product was concentrated, absorbed onto silica gel, and purified by flash chromatography (97:3 CH2Cl2/MeOH) to give 2 as an orange solid. LCMS m/z 303.2 (MH+), tR=2.40 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.C(OCCO)C.[Br:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].Cl.N1C=CC=CC=1>>[Br:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: N#Cc1cnc2c(sc3ccccc32)c1Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
A solution of 150 mg (0.61 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 3 mL of 2-ethoxyethanol containing 80 mg (0.74 mmol) of 3-bromoaniline and 71 mg of pyridine hydrochloride is heated at reflux temperature for 4 hours, then allowed to stir at room temperature for 3 days. The reaction mixture is partitioned between ethyl acetate and saturated sodium bicarbonate and the organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant solid is collected by filtration to give 139 mg (58%) of a white solid, mp 240–242° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32]C)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:12][C:11]1=2)[CH3:2].Br.[C:36](O)(=O)C>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:20]([O:22][CH2:23][CH3:36])=[O:21])[CH:13]=[CH:12][C:11]1=2)[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OC)C1CCCc2cc(C(=O)OC)ccc21
Agent: Br
Product: CCOC(=O)CCCCN(CCc1ccccc1O)C1CCCc2cc(C(=O)OCC)ccc21
Temperature: 135 °C

Procedure:
8.7 g (18.6 mmol) of the compound from Example 2A were stirred in 90 ml of a 33% strength solution of hydrogen bromide in glacial acetic acid under reflux overnight. After addition of another 90 ml of hydrogen bromide solution, the mixture was stirred at a bath temperature of 135° C. for a further night. The mixture was then concentrated under reduced pressure, another 40 ml of the solution of hydrogen bromide in glacial acetic acid were added to the residue and the mixture was stirred at a bath temperature of 110° C. for another night. The mixture was then once more concentrated to dryness. The residue, which comprised 77% of the dicarboxylic acid compound 5-{(4-carboxybutyl) [2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid [LC-MS (Method 2): Rt=0.64 min; MS (ESIpos): m/z=412 [M+H]+], was subjected to incipient dissolution in 190 ml of ethanol, and 1.65 ml of thionyl chloride were added dropwise. The mixture was stirred at 70° C. overnight and then concentrated under reduced pressure. The residue (about 13 g) was taken up in ethyl acetate and washed twice with dilute aqueous sodium carbonate solution. The organic phase was dried over sodium sulphate and concentrated. The crude product (8.8 g) was purified by flash chromatography on silica gel using the mobile phase cyclohexane/ethyl acetate 5:1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]>CO.[Ni]>[NH2:14][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: CS(=O)(=O)c1cc(N)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
3-Methylsulfonyl-5-nitrobenzoic acid (D11) (7.5 g) was dissolved in methanol (250 ml) and Raney nickel was added. The mixture was stirred under hydrogen at atmospheric pressure and room temperature overnight. The mixture was heated to dissolve precipitated product and filtered hot. The filter cake was washed with hot MeOH and the combined filtrates were evaporated to give D12 (5.97 g) an off-white solid.
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:24]=[CH:23][N:22](OCC[Si](C)(C)C)[C:17]=4[N:18]=[C:19](C)[N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[CH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:24]=[CH:23][NH:22][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[CH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCC(C1CCCC1)n1cc(-c2nc(C)nc3c2ccn3OCC[Si](C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 4-[1-(1-cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidine (52 mg, 0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred for 2 hours. The solvents were removed in vacuo. The resulting residue was dissolved in THF (3 mL) and 6N NaOH (2 mL) was added. After stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded product (30 mg, 60%).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:8]=[C:9](CC(C)C)[N:10]=1)[C:5]([OH:7])=[O:6].C(B1OB(C(C)=C)OB(C(C)=C)O1)(C)=C>>[C:5]([OH:7])(=[O:6])[C:4]1[CH:8]=[CH:9][N:10]=[CH:2][CH:3]=1
Reactant: Cc1cc(C(=O)O)cc(CC(C)C)n1
Agent: C=C(C)B1OB(C(=C)C)OB(C(=C)C)O1
Product: O=C(O)c1ccncc1

Procedure:
The title compound is prepared in analogy to 2-methyl-6-(2-methyl-propyl)-isonicotinic acid using 2,4,6-triisopropenyl-cyclotriboroxane; LC-MS: tR=0.23 min; [M+1]+=180.44.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH:5]1[CH:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([C:28]1[CH:32]=[CH:31][NH:30][C:29]=1[CH2:33]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[F:1][C:2]([F:13])([F:14])[CH2:3][O:4][CH:5]1[CH:7]([C:8]([O:10][CH2:33][C:29]2[NH:30][CH:31]=[CH:32][C:28]=2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:9])[C:6]1([CH3:11])[CH3:12]
Reactant: BrCc1[nH]ccc1Cc1ccccc1
Reactant: CC1(C)C(OCC(F)(F)F)C1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(OCC(F)(F)F)C1C(=O)OCc1[nH]ccc1Cc1ccccc1
Reaction time: 15 h

Procedure:
To 10 ml DMF is added 0.88 g 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylic acid (4.14 mmol) and 1.146 g potassium carbonate (8.29 mmol), after which is added 4.00 mmol of 3-benzylpyrrolylmethyl bromide. This mixture is stirred under nitrogen for 15 hours. The reaction mixture is extracted with ether and the ether phase is washed with water (3X) and brine, and dried over sodium sulfate. The solvent is then removed to yield 3-benzylpyrrolylmethyl 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7]([N+:16]([O-])=O)[C:8]([F:15])=[C:9]([F:14])[C:10]=2[O:12][CH3:13])[C:5](=[O:19])[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3]1>CC(O)=O.[Fe]>[NH2:16][C:7]1[C:8]([F:15])=[C:9]([F:14])[C:10]([O:12][CH3:13])=[C:11]2[C:6]=1[C:5](=[O:19])[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][N:2]2[CH3:1]
Reactant: CCOC(=O)c1cn(C)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C)c2c(OC)c(F)c(F)c(N)c2c1=O
Yield: 32 %

Procedure:
A solution of ethyl 1-methyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (735 mg, 2.15 mmol) and iron powder (600 mg, 10.7 mmol) in AcOH (5 mL) was stirred e at 80° C. for 8 h. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. The residue was diluted with water and basified with aq. NaOH. The mixture was filtrated over celite and washed with CH2Cl2. The resulting solution was extracted with CH2Cl2. The organic layer washed with water, brine, and then dried. The solvent was removed and the resulting solid washed with EtOH, dried to yield ethyl 5-amino-1-methyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (215 mg, 32%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([Cl:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:37][CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([Cl:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3Cl)c(=O)n(C)c2n1
Reactant: CN
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3Cl)c(=O)n(C)c2n1
Yield: 50 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea and methylamine were combined to provide 1-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (88 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6): δ10.5 (brs, 1H), 9.00 (brs, 1H), 8.61 (s, 1H), 8.11 (d, J=9 Hz, 1H), 7.88 (brs, 1H), 7.76 (s, 1H), 7.57 (d, J=12 Hz, 1H), 6.00 (s, 1H), 3.58 (s, 3H), 2.89 (d, J=5 Hz, 3H), 1.21 (s, 9H); MS (ESI) m/z: 500.3 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:13]Br>CCOCC>[Br:13][CH2:2][C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1ccsc1
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
3-Acetylthiophene (6.3 g, 50 mmol) was dissolved in anhydrous ether (100 ml) and aluminium chloride (catalytic amount) added. Bromine (2.55 ml, 50 mmol) was added dropwise and then stirred for 10 min. The ether was removed under reduced pressure and the residue washed with water. The crude product was recrystallised from petroleum-ether (60°-80° C.) to yield 3-bromoacetylthiophene m.p. 54°-56° C. (8.76 g, 85%), δH (CDCl3) 8.15 (1H, dd, H2), 7.55 (1H, dd, H4'), 7.35 (1H, dd, H5').
Reaction SMILES: [N+](C1C=CC(C([N:10]2[C:16]3OC=C[C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=O)=CC=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[CH:11]1[C:12]2[N:13]([CH:20]=[CH:21][CH:22]=2)[CH2:14][CH:15]=[CH:16][N:10]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccoc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C1=CN=Cc2cccn2C1
Reaction time: 5 h

Procedure:
A mixture of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[C:13]([N+:19]([O-])=O)[CH:12]=3)[N:10]=2)[N:7]=1.CC(O)=O>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[C:13]([CH:12]=3)[NH2:19])[N:10]=2)[N:7]=1
Reactant: CCc1ccc(-c2cn3nc(Cl)ccc3n2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1ccc(-c2cn3nc(Cl)ccc3n2)cc1N
Temperature: 80 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
Iron powder (4.61 g, 0.0825 mol) is added to a mixture of 6-chloro-2-(4-ethyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (5.0 g, 0.0165 mol) in EtOH—H2O (150 mL, 4:1)containing AcOH (5.66 mL, 0.099 mol) at 80° C. The mixture is stirred at 80° C. for 4 hrs. The reaction mixture is cooled to room temp, filtered through celite, washed with EtOAc and concentrated. The oily residue is dissolved in EtOAc (200 mL) and washed twice with 100 mL Sat. NaHCO3. Compound is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound (4.02 g, 89%). LCMS m/z=273.3, 275.3 [M+H]+, tR=1.93 min.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH:9]1([C:15](O)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:16])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C1CCCCC1
Reactant: Nc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(NC(=O)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A mixture of m-phenylenediamine (2.00 g), cyclohexanecarboxylic acid (2.37 g), HOBt (2.75 g) and EDCI (3.9 g) in DMF (20 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and the resulting solid was collected by filtration. The solid was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/2 v/v) to give N-(3-aminophenyl)cyclohexanecarboxamide (2.2 g) as a white powder.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([C:34](O)=O)[CH2:29]1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][CH:10]([C:17]2[N:18]=[C:34]([CH:30]3[CH2:31][CH2:32][CH2:33][N:28]([CH3:27])[CH2:29]3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CN1CCCC(C(=O)O)C1
Product: CON=C1CC(c2noc(C3CCCN(C)C3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 72 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 1-methyl-3-piperidinecarboxylic acid, the title compound was obtained in 72% yield (99.2% purity by HPLC).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1>C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Clc1cnccn1
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(-c2cnccn2)c1
Temperature: 80 °C

Procedure:
To a solution of commercial 3-isopropyl-benzene boronic acid (1.0 g) in a 2:2:1 mixture of toluene/1M Na2CO3/EtOH (122 mL), at r.t.,2-chloropyrazine (599 μL) and the bis[1.2-bis(diphenylphosphino)ethane]-palladium(0) catalyst (110 mg) were added. The reaction mixture was heated at 80° C. for 3 hr. It was then cooled down and partitioned between AcOEt/sat.aq. NaCl. The phases were separated and the organic layer was dried. The solids were filtered and the solvent evaporated. The crude oil was purified by flash chromatography (CH/AcOEt 7:3) obtaining the title compound as a clear oil (468 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.C(N(CC)CC)C.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].Cl>O1CCCC1.CN(C)C1C=CN=CC=1>[O:7]([CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1)[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C=CC(O)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (191 g, 1.95 mol, prepared in example 1) and triethylamine (430 mL, 3.09 mol) in anhydrous tetrahydrofuran (1 L) is treated with 4-dimethylaminopyridine (4.90 g, 40.0 mmol). The solution is cooled to 0° C. and treated portionwise, over 10 minutes, with tert-butyldimethylsilyl chloride (278 g, 1.84 mol) maintaining the temperature at or below 10° C. The reaction is then allowed to stir overnight at room temperature. It is then poured into aqueous HCl (0.5N, 1 L). The phases are separated and the aqueous phase is extracted with heptane (2×1 L). The organic phase and organic extracts are combined, washed with aqueous HCl (0.5N, 2×500 mL), then 5% sodium bicarbonate (500 mL), then brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum (40° C., 20 mmHg) to provide the title compound (325 g). This is purified by Kugelrohr distillation (70°-80° C., 1 mmHg) to provide the title compound (282 g, 72% yield) as a light yellow oil, Rf =0.55, 20% ethyl acetate/hexane, GC retention time is 14.97 minutes; 1H NMR (CDCl3) δ 7.48 (dd, J=5.7, 2.4 Hz, 1 H), 6.20 (d, J=5.7 Hz, 1 H), 4.95-4.99 (m, 1 H), 2.72 (dd, J=18.2, 6.0 Hz, 1 H), 2.25 (dd, J=18.2, 2.3 Hz, 1 H), 0.88 (s, 9 H), 0.11 (s, 6 H); 13 C NMR (CDCl3) δ 206.4, 163.8, 134.4, 70.8, 44.9, 25.7, 25.6, 18.0; IR (neat) νmax 2957, 2931, 2887, 2858, 1725 cm-1 ; MS (EI) m/e (% relative intensity) 212 (M+, 5), 155 (M+ -57, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Reaction time: 2 h
Yield: 93.5 %

Procedure:
In a stream of argon, 1.50 g of 4-chloro-2-methoxybenzoic acid was added to 10 ml of sulfuric acid under ice-cooling, and 0.85 g of potassium nitrate was added to the solution in small portions, followed by 2 hours of stirring. After completion of the reaction, the reaction solution was poured on crushed ice, and the thus precipitated product of interest was collected by filtration, washed with methanol and then dried under a reduced pressure to give 1.74 g of 4-chloro-2-methoxy-5-nitrobenzoic acid.
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6](=[S:24])[CH:7]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[CH3:2].[CH2:25](N(C(C)C)C(C)C)[CH3:26].BrCC>O1CCOCC1>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6]([S:24][CH2:25][CH3:26])=[C:7]2[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=S)SC12
Solvent: CCBr
Solvent: C1COCCO1
Product: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(CC)C2S1

Procedure:
To a solution of 0.5 g of 4-nitrobenzyl 6-ethyl-7-oxo-3-thioxo-4-thia-1-azabicyclo[3,2,0]heptane 2-carboxylate in 2 ml of dioxane was added, in one batch, 0.57 ml of N-ethyldiisopropylamine, then 0.10 ml of bromoethane. When the reaction was complete, the solution was evaporated in vacuo and chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures to give the title product. (Yield 0.300 g)