Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])#[N:2].Br[CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[C:1]([C:3](=[C:29]1[CH2:28][CH2:27][CH2:26][O:30]1)[C:4]1[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:12])([F:13])[F:11])#[N:2]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CC#N)c1CC(C)C
Reactant: O=C(Cl)CCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2CCCO2)c1CC(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
To a solution of 5.0 g (14.3 mmol) of 5-(cyanomethyl)4-(2-methylpropyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylic acid, methyl ester, prepared as in Example d, above, 6.62 g (35.7 mmol) of 4-bromobutyryl chloride and 0.37 g of benzyltriethylammonium chloride in 160 mL dichloromethane was added 82 mL 50% NaOH. The solution turned red and was stirred for 15 min. Stirring was interrupted due to viscosity of solution; 0.5 mL additional 4-bromobutyryl chloride was added to enable stirring. The solution was poured into 175 mL of ice water and extracted with ethyl ether. The organic layer was washed with water, brine, and dried over magnesium sulfate. The solution was filtered through silica gel to give 5.8 g of the crude product as a dark red oil. Purification by chromatography using 30% ethyl acetate in hexanes yielded 1.4 g of the desired product as an oil, a 24% yield. nD25 1.4882.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NCCc1ccc(O)cc1
Solvent: CN(C)C=O
Product: Oc1ccc(CCNc2nccc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
2,4 dichloropyrimidine (1.49 g) was dissolved in DMF along with diisopropylethylmine (1.29 g) and tyramine (1.37 g.) The mixture was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water and the organic layer washed with 1 N HCl followed by saturated NaHCO3 and brine. The solvent was removed and the residue subjected to flash chromatography (ethyl acetate as eluent.) 4-[2-(4-Chloro-pyrimidin-2-ylamino)-ethyl]-phenol eluted first and was isolate as a minor product (15% yield.) LC-MS showed the product had the expected M+H+ of 250.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:11][O:12][CH3:13])[C:4](Br)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.S([O-])([O-])=O.[Na+].[Na+].CN(C)C=O.C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C>[Br:1][C:2]1[N:3]([CH2:11][O:12][CH3:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: COCn1c(Br)nc([N+](=O)[O-])c1Br
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCn1cc([N+](=O)[O-])nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Suspension of 2,5-dibromo-1-methoxymethyl-4-nitroimidazole (17.15 g), sodium sulfite (13.73 g), dimethylformamide (100 ml) and water (50 ml) was stirred at a room temperature for 8 hours. The reaction mixture was neutralized with an aqueous solution being saturated with sodium hydrogencarbonate, then ethyl acetate and water were added. The organic layer was washed with an aqueous solution being saturated with sodium chloride, and dried over anhydrous sodium sulfate, then concentrated under a reduced pressure to obtain 2-bromo-1-methoxymethyl-4-nitroimidazole (11.17 g, yield: 86.8%) of white powdery product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:19])=[N:4][C:5](Cl)=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:21][NH2:22]>>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:22][NH:21][C:13](=[O:14])[C:6]=2[CH:5]=[N:4][C:3]=1[CH3:19]
Reactant: CCOC(=O)c1c(Cl)nc(C)c(N)c1C(=O)OCC
Reactant: NN
Solvent: O
Product: Cc1ncc2c(=O)[nH][nH]c(=O)c2c1N
Temperature: 100 °C

Procedure:
To 57 mg of 3-amino-6-chloro-4,5-diethoxycarbonyl-2-methylpyridine was added 0.5 ml of hydrazine monohydrate, and the mixture was heated in a stream of nitrogen at 100° C. for 30 minutes. The solvent is distilled off, and the resultant crystals were collected by filtration with ethanol. After water was added to the crystals, the mixture was neutralized with 1N hydrochloric acid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19](=[N:25]O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[CH3:11][C:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2[O:10][N:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1noc(Cc2ccc(C)cc2)n1
Yield: 22.8 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-p-tolylacetic acid (0.568 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (12 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.2118 g (23%) of ethyl 5-(4-methylbenzyl)-1,2,4-oxadiazole-3-carboxylate as a yellow solid.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16](O)[C:17]3[CH:18]=[C:19]([Br:24])[CH:20]=[N:21][C:22]=3[CH:23]=2)=[CH:10][CH:9]=1>>[Cl:3][C:16]1[N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([Br:24])[CH:20]=[N:21]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc3ncc(Br)cc3c(O)n2)cc1
Product: COc1ccc(-c2cc3ncc(Br)cc3c(Cl)n2)cc1
Temperature: 100 °C
Yield: 94 %

Procedure:
POCl3 (3 mL) was added to 7-(4-methoxyphenyl)-3-bromo-[1,6]naphthyridin-5-ol (Example 22) (115 mg, 0.4 mmol). The mixture was heated at 100° C. for 3 hours. The excess POCl3 was concentrated under reduced pressure. The residue was diluted with CH2Cl2, washed with sat. NaHCO3, dried over Na2SO4, and concentrated giving 5-chloro-7-(4-methoxyphenyl)-3-bromo-[1,6]naphthyridine (115 mg, 94%) as a yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SH:65][C:66]1[CH:67]=[C:68]([NH:72][C:73](=[O:75])[CH3:74])[CH:69]=[CH:70][CH:71]=1.CC(C)([O-])C.[Na+]>COCCOC.C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:4]3[CH:3]=[C:2]([S:65][C:66]4[CH:67]=[C:68]([NH:72][C:73](=[O:75])[CH3:74])[CH:69]=[CH:70][CH:71]=4)[N:7]=[CH:6][C:5]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: CC(=O)Nc1cccc(S)c1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCn1c(-c2nonc2N)nc2cnc(Sc3cccc(NC(C)=O)c3)cc21
Temperature: 175 °C
Yield: 26.5 %

Procedure:
Under Ar, a suspension of the product from Example 9, Step 2 (50 mg, 162 μmol) in DME (1.4 mL) and toluene (2.8 mL) was treated with tris(dibenzylidene-acetone)dipalladium (15 mg, 16 μmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (20 mg, 32 μmol), N-(3-mercaptophenyl)acetamide (32.6 mg, 195 μmol), and sodium tert-butoxide (22 mg, 227 μmol). This mixture was then heated to 175° C. by microwave for 15 min. After cooling to rt, the reaction mixture was diluted with ethyl acetate (30 ml), filtered through a celite pad and the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (17 mg, 26%). MS (ES+) m/e 396 [M+H]+.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([Cl:34])[C:13]([N:16]2[CH2:33][CH2:32][C:19]3([C:23](=[O:24])[N:22]([C@H:25]4[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:14][CH:15]=1.[CH3:35][NH:36][C:37]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)=[O:38]>O.O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:34][C:12]1[CH:11]=[C:10]([C:43]2[CH:44]=[C:39]([CH:40]=[CH:41][CH:42]=2)[C:37]([NH:36][CH3:35])=[O:38])[CH:15]=[N:14][C:13]=1[N:16]1[CH2:33][CH2:32][C:19]2([C:23](=[O:24])[N:22]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)[CH2:18][CH2:17]1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCN(c1ncc(Br)cc1Cl)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1cccc(-c2cnc(N3CCC4(CC3)CCN([C@H]3CC[C@@H](O)CC3)C4=O)c(Cl)c2)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Potassium phosphate (0.017 g, 0.078 mmol) in water (0.10 mL) was added to a mixture of 8-(5-bromo-3-chloropyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (11.6 mg, 0.0262 mmol), 3-[(methylamino)carbonyl]phenylboronic acid (7.0 mg, 0.039 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.9 mg, 0.0008 mmol) in 1,4-dioxane (0.78 mL). The resulting mixture was heated and stirred at 120° C. for 2 h. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford the desired product. LCMS: (M+H)+=497.1/499.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.[Cs].Br[CH2:16]Cl>C(#N)C>[O:1]1[C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[O:12][CH2:16]1)[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]3
Reactant: O=C1CCCc2cc(O)c(O)cc21
Reactant: ClCBr
Agent: [Cs]
Solvent: CC#N
Product: O=C1CCCc2cc3c(cc21)OCO3
Reaction time: 4 h

Procedure:
A mixture of 6,7-dihydroxytetralone (1 g), cesium carbonated (2.75 g), bromochloromethane (0.549 cm3) and acetonitrile (20 cm3) was heated to reflux with continual stirring for 4 h. Upon cooling, the resulting suspension was filtered through a pad of Dicalite® which was then washed further with ethyl acetate (50 cm3). The crude product was then purified by column chromatography (silica, eluting with dichloromethane) to afford the title compound.
Reaction SMILES: C([C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CCC1=CC(=O)CC2)=C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[CH2:40]=[C:41]1[CH:58]([OH:59])[CH2:57][C@@:56]2([CH:60]=[CH2:61])[C:43]([CH2:44][CH2:45][C@@H:46]3[C@@H:55]2[CH2:54][CH2:53][C@@:51]2([CH3:52])[C@H:47]3[CH2:48][CH2:49][C:50]2=[O:62])=[CH:42]1.[BH4-].[Na+]>C(O)(=O)C.C1C=CC=CC=1>[CH2:40]=[C:41]1[C@@H:58]([OH:59])[CH2:57][C@@:56]2([CH:60]=[CH2:61])[C:43]([CH2:44][CH2:45][C@@H:46]3[C@@H:55]2[CH2:54][CH2:53][C@@:51]2([CH3:52])[C@H:47]3[CH2:48][CH2:49][C@@H:50]2[OH:62])=[CH:42]1
Reactant: C=C[C@]12CC(O)C(=C)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C=C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: C=C[C@]12C[C@H](O)C(=C)C=C1CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12

Procedure:
The compound 10β-vinyl-estra-4-ene-3,17-dione described by Halpern et al, cited above is converted to 10β-vinyl-estra-4-ene-2β-ol-3,17-dione acetate by reaction with a molar excess of lead tetraacetate at 60° to 120° C. in acetic acid or under reflux in benzene for a reaction period of from 6 to 15 hours. This can be converted to 3-methylene-10β-vinyl-estra-4-ene-2-ol-17-one, compound 44, by the Wittig reaction. The latter compound may be reduced with sodium borohydride to produce compound 38, 3-methylene-10β-vinyl-estra-4-ene-2β, 17β-diol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([N+:14]([O-])=O)[NH:12][CH:13]=2)[CH2:4][CH2:3]1.CO.C1COCC1.CO.[S:26]1[CH:30]=[C:29]([C:31]2[C:40]3[N:39]=[CH:38][CH:37]=[N:36][C:35]=3[C:34]([C:41](O)=[O:42])=[CH:33][CH:32]=2)[C:28]2[CH:44]=[CH:45][CH:46]=[CH:47][C:27]1=2>[Ni].C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([NH:14][C:41]([C:34]3[C:35]4[N:36]=[CH:37][CH:38]=[N:39][C:40]=4[C:31]([C:29]4[C:28]5[CH:44]=[CH:45][CH:46]=[CH:47][C:27]=5[S:26][CH:30]=4)=[CH:32][CH:33]=3)=[O:42])[NH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(-c2csc3ccccc23)c2nccnc12
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2c[nH]c(NC(=O)c3ccc(-c4csc5ccccc45)c4nccnc34)n2)CC1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture for 20 h at 65° C., using 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3, Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 8-benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid (Example 59) in Step 14.1. Title compound: ESI-MS: 484.0 [M+H]+; tR=3.36 min (System 1); TLC: Rf=0.10 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH:14]1(C(O)=O)[CH2:18][CH2:17][CH2:16][CH2:15]1>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)C1CCCC1
Reactant: Clc1ccc(Cl)nn1
Agent: O=S(=O)(O)O
Solvent: O
Product: Clc1cc(C2CCCC2)c(Cl)nn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
3,6-Dichloropyridazine (10 g) was suspe n ded in water (200 ml), conc. H2SO4 (19.7 g) and cyclopentane carboxylic acid (32.7 g) was added and the reaction degassed under N2 at 70° C. Silver nitrate (2.28 g) was added followed by dropwise a ddition of ammonium persulfate (45.9 g) in water (120 ml). After ail additional one hour heating at 70° C., the reaction was poured onto ice, basfied to pH 8-9 with aqueous ammonium hydroxide and extracted into ethyl acetate (3×500 ml), dried (MgSO4) and evaporated to dryness. Purified with hexane-ethyl acetate mixtures to obtain pure product (13.4 g). 1H NMR (360 MHz, CDCl3) δ1.57 (2 H, m), 1.82 (4 H, m), 2.20 (1 H, m), 3.30 (1 H, m), 7.38 (1 H, s); MS (ES+) m/e 217 [MH]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]2[N:6]=[CH:7][CH:8]=[C:2]12.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O>[N+:9]([C:8]1[CH:7]=[N:6][N:3]2[CH2:4][CH2:5][NH:1][C:2]=12)([O-:11])=[O:10]
Reactant: c1cc2n(n1)CCN2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnn2c1NCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a solution of 2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (1 g, 9.17 mmol) in conc. H2SO4 (aq.) at 0° C. was added conc. HNO3 (aq.) portion-wise over 15 min. The reaction was warmed to room temperature and the mixture was stirred for 18 h. The mixture was poured into ice water (200 mL) with stirring. The product was extracted into DCM and the combined organics were washed with saturated aqueous NaHCO3. The organic layer was separated, passed through a phase separator cartridge and concentrated under reduced pressure. The crude residue was triturated with diethyl ether to yield 7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole as a pale brown solid (0.52 g, 34%). Sodium hydride (60% dispersion in mineral oil, 0.065 g, 1.62 mmol) was added in 2 portions to a stirred solution of 7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (0.21 g, 1.35 mmol) in anhydrous DMF (10 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred for 10 min. before di-tert-butyl dicarbonate (0.68 mL, 2.75 mmol) was added. The reaction was stirred for 45 min. Water (5 mL) was added dropwise and the mixture concentrated under reduced pressure. The residue was diluted with water and the product extracted into diethyl ether. The combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/isohexane) to give tert-butyl 7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole-1-carboxylate as a grey solid (0.22 g, 63%). 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 4.60-4.53 (m, 2H), 4.38-4.30 (m, 2H), 1.50 (s, 9H)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.CCO.CCOC(C)=O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[C:20]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[N:19]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1cnc(Cl)nc1Oc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1cnc(-c2cccnc2)nc1Oc1ccc(NC(=O)OCc2ccccc2)cc1
Yield: 64.5 %

Procedure:
To a teflon-lined septum sealed Schlenk tube, a mixture of Compound 11a (1.0 g; 2.7 mmol), pyridin-3-yl boronic acid (0.83 g; 6.75 mmol), Cs2CO3 (2.60 g; 8.1 mmol) and [1,1-Bis(diphenylphosphino)-ferrocene]dichloro-palladium(11) (0.49 g; 0.6 mmol) in a mixture of dioxane (15 mL) and EtOH (1 mL) was irradiated in a microwave reactor at 150° C. for 55 min. The reaction mixture was poured into water, diluted with EtOAc and the solid was collected by filtration. The organic phase was isolated and dried over MgSO4. and the reaction mixture was concentrated under reduced pressure. The resultant residue was purified by reverse phase HPLC, eluting with a CH3CN—H2O (0.5% TFA) gradient to afford Compound 11b (0.72 g; 42% yield based on di-TFA). 1H-NMR (300 MHz, MeOH-d4): δ 9.2 (s, 1H), 8.9 (d, 1H), 8.7 (d, 1H), 8.2 (s, 1H), 8.0 (m, 1H), 7.5 (d, 2H), 7.5-7.3 (m, 6H), 7.2 (m, 2H), 5.2 (s, 2H); MS: m/z 414.2 (M+H)+.
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.CO.C[C:17]([O:19][CH2:20][C:21]1[CH2:30][S:29][C@@H:24]2[C@H:25]([NH2:28])[C:26](=[O:27])[N:23]2[C:22]=1[C:31]([OH:33])=[O:32])=O>O1CCOCC1>[NH2:28][CH:25]1[C:26](=[O:27])[N:23]2[C:22]([C:31]([OH:33])=[O:32])=[C:21]([CH2:20][O:19][CH3:17])[CH2:30][S:29][C@H:24]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
17.94 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 1), 0.31 g of trimethyl borate and 2.31 g of methanol were added to 10 ml of dioxane. The mixture was cooled to 0° C., and 2.74 g of 7-ACA were added thereto, followed by stirring at 0° C. for 5 hours. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2. 2.09 g (yield 85%) of the desired compound with a high purity were thereby obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.[O-]CC.[Na+].[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.II>C(O)C.C1(C)C(C)=CC=CC=1>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH:38][C:37]2[CH:40]=[CH:41][C:34]([Br:33])=[CH:35][CH:36]=2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: CC[O-]
Agent: II
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: Brc1ccc(C=Cc2ccc(Br)cc2)cc1
Temperature: 48 °C
Reaction time: 8 h

Procedure:
Into a reaction flask equipped with a mechanical stirrer, condenser, drying tube and thermometer was charged 76.8 grams (0.15 moles) of the triphenylphosphine salt of p-bromobenzyl bromide prepared in Part A and 11.1 grams (0.159 mole) of sodium ethoxide in 150 milliliters of absolute ethanol. Over a ten minute period, 30.0 grams (0.162 mole, Aldrich, 99 percent) of 4-bromobenzaldehyde in 30 milliliters of absolute ethanol was added to the reaction mixture at a reaction temperature of from 30° C. to 43° C. The 4-bromobenzaldehyde was washed into the reaction flask with 10 milliliters of absolute ethanol. The reaction mixture was then heated to a temperature of 48° C. and maintained at this temperature with continuous stirring overnight. The reaction was quenched by adding 140 milliliters of distilled water to the reaction flask. A soft cream colored precipitate formed in the reaction flask which was filtered and the collected solids dried to give 15.5 grams of a crude product fraction. This crude product fraction was heated to a temperature of 122° C.-128° C. in xylene with a small crystal of iodine, cooled to ambient temperature, filtered and the collected solids were dried in a vacuum oven to give 11.2 grams of 4,4'-dibromostilbene having a melting point of from 211° -213° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.[C:19](=[O:21])=[O:20].Cl>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH2:10][CH2:11][O:12][CH3:13])[C:3]=1[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: COCCOc1ccc(F)c(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOc1ccc(F)c(F)c1C(=O)O
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a suspension of 3,4-difluorophenol (2 g) and cesium carbonate (7.51 g) in N,N-dimethylformamide (15 mL) was added 2-methoxyethyl bromide (2.14 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 3,4-difluoro-1-(2-methoxyethoxy)-benzene (2.49 g). To the solution of the obtained 3,4-difluoro-1-(2-methoxyethoxy)benzene (1.47 g) in tetrahydrofuran (39 mL) was added n-butyllithium (2.64 mol/L n-hexane solution, 3.25 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dry ice (10 g), and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. To the reaction mixture was added 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.48 g).
Reaction SMILES: CCC([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12]C(=O)C)[O:9][C@@H:8]([N:16]2[CH:30]=[C:20]3[NH:21][C:22](=[O:29])[C:23]4[C:24](=[O:28])[NH:25][N:26]=[CH:27][C:18]([C:19]=43)=[N:17]2)[C@@H:7]1[O:31]C(=O)C)=O.N.[CH3:36]O>>[CH3:36][C@@:7]1([OH:31])[C@H:6]([OH:5])[C@@H:10]([CH2:11][OH:12])[O:9][C@H:8]1[N:16]1[CH:30]=[C:20]2[NH:21][C:22](=[O:29])[C:23]3[C:24](=[O:28])[NH:25][N:26]=[CH:27][C:18]([C:19]=32)=[N:17]1
Reactant: CO
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc3[nH]c(=O)c4c(=O)[nH]ncc(n2)c34)O[C@@H]1COC(C)=O
Agent: N
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2[nH]c(=O)c3c(=O)[nH]ncc(n1)c23
Temperature: 25 °C

Procedure:
To the product from Step 8 is added 7N NH3 in MeOH and the mixture is stirred at ambient temperature until deacetylation is sufficiently complete as determined by TLC. The mixture is concentrated in vacuo and the crude material is taken up and purified by Phenomenex-C18 reverse phase HPLC (Buffer A=H2O, Buffer B=acetonitrile) to afford the title compound.