Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2B(O)O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1c2ccccc2cc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: c1cncc(-c2c3ccccc3cc3ccccc23)c1

Procedure:
In a 200 mL three-neck flask, 5.2 g (23 mmol) of 9-anthrylboronic acid, 4.0 g (25 mmol) of 3-bromopyridine, 5.2 g (50 mmol) of sodium carbonate, 50 mL of toluene, 25 μL of ethanol, and 25 mL of water were placed. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. To the mixture, 0.28 g (0.25 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was stirred under nitrogen stream at 80° C. for 7 hours. After a certain period, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extracted solution and the organic layer were combined, washed with saturated saline, and dried with magnesium sulfate. The obtained mixture was gravity filtered, and the filtrate was condensed to give an oily substance. The oily substance was recrystallized with toluene/hexane, so that 2.8 g of target yellow powder was obtained in a yield of 46%.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)[C:11](=O)[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24][OH:25].[CH2:26]([OH:28])[CH3:27]>N1C=CC=CC=1>[CH2:26]([O:28][C:7](=[O:8])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:25]/[N:24]=[C:11]1\[CH:12]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]2[CH:22]=[CH:21][CH:20]=[CH:19][C:10]\1=2)[CH3:27]
Reactant: O=C1c2ccccc2OC(c2ccccc2)C1n1ccnc1
Reactant: NO
Reactant: CCO
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCCCCO/N=C1/c2ccccc2OC(c2ccccc2)C1n1ccnc1

Procedure:
As an example the intermediate oxime used as starting material can be prepared as follows: (+-)-2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-benzopyran-4-one[J. Het. Chem. 21,311,(1984)], (4 g.; 0.014 moles), is dissolved in pyridine, and hydroxylamine hydrochloride (2.4 g.; 0.034 moles) dissolved in ethanol (20 ml), is added at room temperature to the solution.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH2:21][CH2:22][OH:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:26][CH:27](Cl)[C:28]1[C:29]([CH3:34])=[CH:30][CH:31]=[CH:32][CH:33]=1.O>C1COCC1>[Cl:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][O:23][CH2:22][CH2:21][NH:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: ClCc1ccccc1COCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 2-(triphenylmethylamino)ethanol (5.00 g, 16.5 mmol) in THF (20 ml) was added dropwise to a suspension of NaH (60% in oil, 0.79 g, 19.8 mmol) in THF (30 ml) at room temperature and the mixture was stirred for 0.5 hour. α,α-Dichloro-o-xylene (1.56 g, 66.0 mmol) was added and the mixture was stirred for 24 h at reflux temperature. The mixture was poured into water (50 ml) and the whole was extracted with ether (50 ml×2). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=15/1 as eluent) to afford the titled compound as a colorless oil. (1.00 g, 14%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][C:28]1[O:37][C:36]2[C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[NH:33][CH2:32][CH2:31][C:30]=2[N:29]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:33]2[CH2:32][CH2:31][C:30]3[N:29]=[C:28]([CH3:27])[O:37][C:36]=3[C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]2=3)=[O:16])=[CH:12][C:11]=1[CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)O)ccc1CNC(=O)OC(C)(C)C
Reactant: Cc1nc2c(o1)-c1ccccc1NCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(C)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-3-methyl-benzoic acid from Example E2h (400 mg, 1.5 mmol) in dichloromethane (20 ml) and triethylamine (to pH9) was treated with WSCD (573 mg, 3.0 mmol) and DMAP (183 mg, 1.5 mmol). The solution was stirred for 30 min at room temperature then 2-methyl-5,6-dihydro-4H-1-oxa-3,6-diaza-benzo[e]azulene from Example E6 (300 mg, 1.5 mmol) was added and the mixture was heated at reflux for 3 days. WSCD (287 mg, 1.5 mmol) was added and the mixture was heated at reflux for another 24h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1N KHSO4, water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (62 mg, 9%).
Reaction SMILES: COC[CH2:4][CH2:5][NH2:6].[CH2:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]1[O:10][CH2:9]1.C([OH:30])C>>[CH2:12]([O:11][CH2:7][CH:8]([OH:10])[CH2:9][NH:6][CH2:5][CH2:4][OH:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COCCCN
Reactant: CCO
Reactant: CCCCCCCCCCCCCCCCOCC1CO1
Product: CCCCCCCCCCCCCCCCOCC(O)CNCCO
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a 2-l flask equipped with a stirrer, a dropping funnel, a nitrogen gas inlet tube and a distillation apparatus, 611 g (10.0 mol) of 2-aminoethanol (5-a) and 122 g of ethanol were charged, followed by the dropwise addition of 243 g (0.82 mol) of hexadecyl glycidyl ether (4-a) over 3 hours while stirring under heating to 80° C. in a nitrogen gas atmosphere. After the completion of the dropwise addition, stirring was conducted for further 2 hours at 80° C. From the reaction mixture, ethanol and excessive 2-aminoethanol were distilled off by heating under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby 262 g of the title compound (6-t) were obtained in the form of a white solid (yield: 90% relative to hexadecyl glycidyl ether).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]1[CH3:17]>C1COCC1.O=[Mn]=O>[CH3:17][C:12]1[N:11]([C:4]2[N:5]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:7][C:3]=2[CH:2]=[O:1])[C:15]([CH3:16])=[CH:14][CH:13]=1
Reactant: CCCc1nc(-n2c(C)ccc2C)c(CO)[nH]1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCCc1nc(-n2c(C)ccc2C)c(C=O)[nH]1
Yield: 74.8 %

Procedure:
To a solution of 5-(hydroxy-methyl)-2-propyl-4-(2,5-dimethyl-1H-pyrrol-1-yl)imidazole (Example 48, 6.0 g, 0.026 mol) in dry THF (125 mL) was added MnO2 (11.2 g, 0.13 mol) and the reaction mixture refluxed for 4 hours under an atmosphere of nitrogen. The reaction mixture was cooled, filtered through celite, and the resulting filtrate evaporated under reduced pressure. Purification by flash chromatography (silica; 2:1 hexane ethyl acetate) gave the title compound 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-propylimidazole-5-carboxaldehyde (4.5 g, 75%), mp 119°-121° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([Cl:13])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Br)n1
Product: O=C(Cl)c1cccc(Br)n1

Procedure:
4 g of 6-bromopyridine-2-carboxylic acid and 25 g of thionyl chloride are refluxed for 1 hour. The excess thionyl chloride is removed in a vacuum and the residue is distilled on a bulb tube at 110° C. and 0.04 mbar. The 6-bromopyridine-2carboxylic acid chloride thus obtained is dissolved together with 3.32 g of 4-aminobutyric acid ethyl ester, hydrochloride in 40 ml of dioxane, mixed under ice cooling with 6 g of triethylamine and stirred for 5 hours at room temperature. The reaction mixture is added to water, extracted with diethyl ether, dried (sodium sulfate) and concentrated by evaporation. The residue is distilled on a bulb tube at 170° C. and 0.04 mbar and 3.2 g of 4-(6-bromo-2-pyridylcarbonylamino)-butyric acid ethyl ester is thus obtained as bright yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].[Cl:15][C:16]1[CH:17]=[C:18]([N:23]=[C:24]=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]>CC(C)=O>[F:10][C:7]([F:8])([F:9])[C:6]([NH:5][C:4]1[CH:3]=[C:2]([NH:1][C:24]([NH:23][C:18]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=2)=[O:25])[CH:14]=[CH:13][CH:12]=1)=[O:11]
Reactant: Nc1cccc(NC(=O)C(F)(F)F)c1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CC(C)=O
Product: O=C(Nc1cccc(NC(=O)C(F)(F)F)c1)Nc1ccc(Cl)c(Cl)c1

Procedure:
Four and one-tenth grams of m-amino trifluoro acetanilide is dissolved in 100 ml of acetone and 3.8 g. of 3,4-dichlorophenyl isocyanate is added. The mixture is heated to reflux and crystallizes from acetone on cooling. Yield is 6.4 g., m.p. 221°-223° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([OH:11])=[CH:6][C:3]=1[CH:4]=O.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13]>CN(C=O)C.N1CCCCC1.C(O)(=O)C>[CH2:18]([O:17][C:15]([C:14]1[C:12](=[NH:13])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][C:7]([OH:11])=[C:8]([OH:10])[CH:9]=2)=[O:16])[CH3:19]
Reactant: O=Cc1cc(O)c(O)cc1O
Reactant: CCOC(=O)CC#N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cc(O)c(O)cc2oc1=N
Reaction time: 2 h

Procedure:
To a solution of 2,4,5-trihydroxybenzaldehyde (2.94 g) and ethyl cyanoacetate (1.62 g) in DMF (20 ml) were added 20 drops (Pasteur pipette) of piperidine and eight drops of acetic acid and the solution kept at 80° C. under nitrogen for two hours. The product was filtered and washed with DMF and ethyl ether. Yield: 2.00 g.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[N:16]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([B:43]2[O:47][C:46]([CH3:49])([CH3:48])[C:45]([CH3:51])([CH3:50])[O:44]2)=[CH:39][CH:38]=1>O1CCCC1>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[N:16]2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:36][C:37]2[CH:38]=[CH:39][C:40]([B:43]3[O:44][C:45]([CH3:51])([CH3:50])[C:46]([CH3:49])([CH3:48])[O:47]3)=[CH:41][CH:42]=2)=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc(CC(c3ccccc3)n3nnc4ccccc43)cc2)cc1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(CC(Cc3ccc(-c4ccccc4)cc3)(c3ccccc3)n3nnc4ccccc43)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
A solution of 4.26-A of Step 1 (450 mg, 1.2 mmol) in tetrahydrofuran (14 mL) was cooled to −78° C. and treated with n-butyllithium (0.62 mL, 2.5 M in hexanes) dropwise. The reaction mixture was stirred at −78° C. for 10 min and 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (410 mg, 1.4 mmol) in tetrahydrofuran (2 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h, quenched with sat. ammonium chloride (2 mL), and extracted with ethyl acetate (15 mL). The organic layer was separated and washed with brine (5 mL), dried with sodium sulfate, filtered, and concentrated to a crude residue which was purified by flash column chromatography to yield the desired product (350 mg, 50%). LCMS found for C39H38BN3O2Na (M+Na)+: m/z=614.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]([CH:49]([CH3:51])[CH3:50])[N:31](/[CH:40]=[CH:41]/[C@@H:42]([OH:48])[CH2:43][C:44](OC)=[O:45])[C:32]=2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:24][CH:23]=1>C1CCCCC1.C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:29]=[C:30]([CH:49]([CH3:51])[CH3:50])[N:31](/[CH:40]=[CH:41]/[C@@H:42]([OH:48])[CH2:43][C:44](=[O:45])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:32]=2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:26][CH:27]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C[C@H](O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)CC(=O)CC(=O)OC(C)(C)C

Procedure:
A solution of dry diisopropylamine (0.77 ml) in dry cyclohexane (15.6 ml) at 3° under nitrogen was treated dropwise with n-butyl lithium solution (1.55M in hexanes, 3.54 ml). After 15 min t-butyl acetate (0.74 ml) was added dropwise. After 30 min the mixture was cannulated into a solution of methyl(3S,E)-5-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3-hydroxy-4-pentenoate (334 mg) in dry THF (7.8 ml) at 3° under nitrogen over 15 min. After 1 h the mixture was quenched with saturated aqueous ammonium chloride solution (3.5 ml) and then diluted with water. The mixture was then and extracted with ethyl acetate (3×20 ml). The combined extracts were dried and evaporated to a gummy solid (518 mg) which was treated with ether (4 ml) and then cyclohexane (4 ml) and cooled in an ice bath. The solid was collected, washed and dried to give the title compound (239 mg) as a white powder; δ(CDCl3) 1.41 (d, J 7.5 Hz, 6H, CH(CH3)2), 1.46 (s, 9H, C(CH3)3), 2.59 (d, J 7.5 Hz, 2H, C(OH)CH2CO), 3.02 (bs, 1H, OH), 3.14 (septet, J 7.5 Hz, 1H, --CH(CH3)2), 3.35 (s, 2H, CH2CO2R), 4.63 (m, 1H, CHOH), 5.39 (dd, J 14 and 7 Hz, 1H, N--CH=CH--C), 6.70 (d, J 14 Hz, 1H, N--CH=CH--C), 6.90 and 7.10 (2 t, J 9 Hz, each 2H, C-3 and C-5 protons of 4-fluorophenyls), 7.17-7.47 (m, 4H, C-2 and C-6 protons of 4-fluorophenyls). Also present was a trace of the enol form, δ values include 1.52 (s, --C(CH3)3), 4.51 (m, CHOH), 4.89 (s, C(OH)=CHCO2), 5.38 (dd, J 14 and 7 Hz, --N--CH=CH), 6.64 (d, J 14 Hz, NCH=CH). Chiral hplc detected none of the other enantiomer. A second crop of title compound (56 mg) was also obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:6]([O:7][Si](C(C)(C)C)(C)C)[CH2:5][C:4](=[O:15])[CH:3]=1.O1CCCC1.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CCOCC>[Cl:1][C:2]1[CH:6]([OH:7])[CH2:5][C:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([OH:15])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)C=C1Cl
Reactant: CCCCCCCC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCC1(O)C=C(Cl)C(O)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
108 mg of 3-chloro-4-t-butyldimethylsilyloxy-2-cyclopentenone was dissolved in 4 ml of ether, and the solution was cooled to -78° C. Then, 0.79 ml of a 0.72 M tetrahydrofuran solution of octyl magnesium bromide was added. The mixture was stirred for 10 minutes, and water was added. The mixture was extracted with ether, and the extract was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting oily product was dissolved in 6 ml of tetrahydrofuran, and 1.1 ml of a 1 M tetrahydrofuran solution of tetrabutyl ammonium fluoride was added. The mixture was stirred for 2 days. A saturated aqueous solution of sodium chloride was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was chromatographed on a silica gel column to give 92 mg (yield 83%) of 2-chloro-4-octylcyclopent-2-ene-1,4-diol.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:9]=[CH2:10])[CH:7]=1
Reactant: Cc1ccnc(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(C)ccn1
Temperature: 100 °C
Yield: 52.3 %

Procedure:
A yellow mixture of 2-bromo-4-methyl-pyridine (Aldrich, 5.2 9, 30.5 mmol, 1.0 eq), 2,6-di-tert-butyl-4-methyl-phenol (Aldrich, 67 mg, 0.3 mmol, 1 mol %), tributyl-vinyl-stannane (Aldrich, 26.8 mL, 91.5 mmol, 3.0 eq) and tetrakis(triphenylphosphine) palladium (0) (Strem, 1.8 9, 1.5 mmol, 5 mol %) in toluene (100 mL) was degassed and purged with argon. An amber solution was obtained after the mixture was warmed to 100° C. The reaction mixture was quenched after 18 hours by the addition of 1.0 M HCl. The acidic extract was washed with ether, adjusted to pH 9 with solid sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product (3.7 g of a brown oil) was purified by flash chromatography (silica) and eluted with 0–5% ethyl acetate-dichloromethane, which gave a clear oil (1.9 g, 53%). 1H NMR (DMSO-d6, 300 MHz) δ 8.39 (1H, d, J=4.9 Hz), 7.33 (1H, s), 7.10 (1H, dd, J=5.0, 0.8 Hz), 6.77 (1H, dd, 17.5, 10.8 Hz), 6.20 (1H, dd, J=17.5, 1.7 Hz), 5.44 (1H, dd, J=10.8, 1.8 Hz), 2.31 (3H, s). ESIMS m/z 120 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH3:20].[CH2:21]([Li])CCC.CN(CCN(C)C)C.IC>C1COCC1.O>[CH3:20][O:19][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[C:2]=1[CH3:21]
Reactant: [Li]CCCC
Reactant: COc1ccc(-c2cc3c(Br)c(OC)ccc3o2)cc1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COc1ccc(-c2cc3c(C)c(OC)ccc3o2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4-Bromo-5-methoxy-2-(4-methoxyphenyl)-benzofuran 133 (0.282 g, 0.85 mmol) was taken into 20 mL of THF and cooled to 0° C. Then butyllithium (0.68 mL of a 2.5M solution in THF, 1.7 mmol) was added dropwise and allowed to stir for 20 minutes. Then TMEDA (0.256 mL, 1.7 mmol) was added followed by iodomethane (1.06 mL, 17 mmol). The reaction was allowed to stir overnight at room temperature. The reaction was poured into water and extracted with ethyl acetate. The combined organics was washed with water (2×), brine (1×), dried over magnesium sulfate filtered and concentrated. The resulting material was purified by column chromatography on silica gel, using a gradient of 1% to 3% ethyl acetate in hexane. The first fractions contained the product and another side product. This fraction was added to another synthesis of this compound (starting with 0.250 g 4-Bromo-5-methoxy-2-(4-methoxyphenyl)-benzofuran) for the final cleavage reaction.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1(C(O)=O)[CH2:5][CH2:4]1.C1C=CC(OP([O:23][C:24]2C=CC=CC=2)(N=[N+]=[N-])=O)=CC=1.C([N:32](CC)CC)C>C1(C)C=CC=CC=1>[N:32]([C:3]1([C:2]([F:1])([F:9])[F:10])[CH2:4][CH2:5]1)=[C:24]=[O:23]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C=NC1(C(F)(F)F)CC1

Procedure:
A mixture of 1-(trifluoromethyl)cyclopropanecarboxylic acid (13 mg, 0.084 mmol) (Oakwood, Cat. #013181), diphenylphosphonic azide (36 uL, 0.17 mmol) and triethylamine (18 uL, 0.13 mmol) in toluene (0.5 mL) was refluxed overnight. The mixture was concentrated under reduced pressure to afford the crude product which was used directly for next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[N:19]O)[NH2:18])=[N:15][CH:16]=1>>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]1[O:9][N:19]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][N:15]=2)[N:18]=1
Reactant: NC(=NO)c1ccc(Cl)cn1
Reactant: O=C(O)c1occc1Br
Product: Clc1ccc(-c2noc(-c3occc3Br)n2)nc1

Procedure:
The title compound was prepared from 3-bromo-furan-2-carboxylic acid (381.7 mg, 2.00 mmol) and 5-chloro-pyridine-2-amidoxime (343 mg, 2.00 mmol), similar to Example 70, and yielded 353 mg (54%) of white solid.
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[O-:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+].O>CN1C(=O)CCC1>[O:13]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [O-]c1ccccc1
Reactant: Nc1nnc2ccc(Cl)nn12
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1nnc2ccc(Oc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001; 200 mg) were initially charged dissolved in NMP (4 ml). Thereafter, sodium phenoxide (185 mg) was introduced at RT. After stirring at RT for one hour, the reaction was completed by heating to 55° C. for 2 h. Subsequently, the mixture was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The crude product was purified using silica gel with a dichloromethane/methanol gradient. 38 mg of the title compound were obtained in solid form. LC-MS rt: 0.80 min [M+H]+: 228.1 (met. a)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([Cl:20])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>CN(C)C=O>[ClH:20].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16]([NH:25][CH:21]([CH2:23][CH3:24])[CH3:22])=[N:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Reactant: CCC(C)N
Solvent: CN(C)C=O
Product: CCC(C)Nc1cc2n(c(=O)n1)CCc1cc(OC)c(OC)cc1-2
Product: Cl

Procedure:
A solution of 9,10-dimethoxy-6,7-dihydro-2-chloro-4H-pyrimido(6,1-a)isoquinolin-4-one (2.5 g), sec-butylamine (10 ml) and dimethylformamide (2 ml) is heated under reflux for 5 hours. The solvent and excess amine are distilled under reduced pressure. The residue is treated with water. A white solid precicipitates and is collected by filtration. The precipitate is crystallized from methylene chloride-ether mixture, yield 2.10 g. The crystals are dissolved in dichloromethane and treated with a solution of etheral hydrochloric acid. The hydrochloride is crystallized from ethanol-ether mixture, m.p. 218°-225° C.