Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-])=O)[C:3]=1[Cl:17].O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:14][C:4]1[C:3]([Cl:17])=[C:2]([Br:1])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2
Reactant: O=c1[nH]c2cc(Br)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)c(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A suspension of 7-bromo-6-chloro-5-nitro-1,4-dihydro-2,3-quinoxalinedione (50 mg, 0.16 mmol) and tin (II) chloride dihydrate (176 mg, 0.780 mmol, Aldrich, used as received) in ethanol (5 mL) was refluxed for 7 h. It was then cooled to r.t. and poured into ice (10 g). The suspension was then basified with 10% aq. NaHCO3 (25 mL) to pH 8-8.5 (pH paper) and extracted with ethyl acetate (50 mL). The ethyl acetate extract was washed with water and brine, dried over Na2SO4 and evaporated to give a solid which was dried under high vacuum to furnish 28 mg (62%) of pure title compound as a brown powder, m.p.>350° C.; 1H NMR (DMSO-d6) δ5.888 (br s, 2H), 6.075 (s, 1H), 11.286 (s, 1H), 11.827 (s, 1H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][C:15]1[S:19][C:18]2=[CH:20][N:21]=[CH:22][N:17]2[C:16]=1[CH3:23].[CH2:24]([O:27][C:28]([NH:30][S:31]([NH2:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH2:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.O1CCCC1>[CH2:24]([O:27][C:28]([N:30]([CH2:14][C:15]1[S:19][C:18]2=[CH:20][N:21]=[CH:22][N:17]2[C:16]=1[CH3:23])[S:31]([NH2:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH2:26]
Reactant: Cc1c(CO)sc2cncn12
Reactant: C=CCOC(=O)NS(N)(=O)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOC(=O)N(Cc1sc2cncn2c1C)S(N)(=O)=O
Reaction time: 1.83 h
Yield: 29.1 %

Procedure:
Under an argon atmosphere at -37° C., 0.51 ml of diethyl azodicarboxylate was added dropwise to 6.7 ml of an anhydrous tetrahydrofuran solution containing 365 mg of 2-hydroxymethyl-3-methylimidazo[5,1-b]thiazole, 586 mg of N-allyloxycarbonyl-N-aminosulfonylamine and 854 mg of triphenylphosphine, and the mixture was then stirred at -37° C. to -20° C. for 110 minutes. The solvent was evaporated under reduced pressure to obtain an oil, and this oil was then suspended in 50 ml of dichloromethane. Further, the suspension was extracted with 2N hydrochloric acid (15 ml×2), and the combined aqueous layer was then washed with 20 ml of dichloromethane. After alkalified with anhydrous potassium carbonate, the solution was further extracted with dichloromethane (30 ml×3). The combined organic layer was washed with a semi-saturated saline solution, dried (anhydrous magnesium sulfate:anhydrous potassium carbonate=1:1), and then filtered, and the solvent was evaporated under reduced pressure. Afterward, the resulting oil was purified by a silica gel column chromatograph and successively Cephadex LH-20 to obtain 208.5 mg of the title compound as a milky white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cc(F)ccc1OCc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(F)ccc1OCc1ccccc1Cl

Procedure:
10.0 g (34 mmol) of methyl 2-(2-chlorobenzyloxy)-5-fluorobenzoate are dissolved in 80 ml of methanol and 40 ml of 40% strength sodium hydroxide solution and stirred at RT for 12 h. The solvent is distilled out in vacuo, water is added to the residue until it has all dissolved, and the solution is then extracted with ethyl acetate. The aqueous phase is acidified with hydrochloric acid and extracted three times with ethyl acetate. The mixture is dried over magnesium sulfate, filtered, washed with ethyl acetate and concentrated. The residue is mixed with petroleum ether, and the crystals which have separated out are filtered off with suction and dried on a clay dish. 6.00 g (21.3 mmol, 63% of theory) of the title compound are obtained.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:36])/[CH:23]=[C:24](\[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)/[CH2:25][O:26][CH3:27])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[NH4+:47]>CO>[CH3:27][O:26][CH2:25]/[C:24](/[C:28]1[CH:29]=[C:30]([C:34]([NH2:35])=[NH:47])[CH:31]=[CH:32][CH:33]=1)=[CH:23]/[C:22](=[O:36])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:20][CH:19]=1
Reactant: COC/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC/C(=C/C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-4-methoxybut-2-enamide (150 mg, 0.298 mmol) in 10 ml 1:1 ethyl acetate:anhydrous methanol cooled to −78° C. was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (77 mg, 1 mmol) was added, and the reaction heated to reflux for 2 hours. The reaction was concentrated, treated with trifluoroacetic acid (10 ml) for 2 hrs, concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1E)-1-(methoxymethyl)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzenecarboxamidine (34 mg, (25%) as a fluffy off-white powder after lyophilization. ES-MS (M+H+): 465.15
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[C:43]([OH:50])[CH:42]=1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.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>[CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:44]5[CH:45]=[CH:46][C:41]([F:40])=[CH:42][C:43]=5[OH:50])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Reactant: OB(O)c1ccc(F)cc1O
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(-c5ccc(F)cc5O)c4)nn23)CC1
Temperature: 90 °C
Yield: 67.9 %

Procedure:
To (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.38 g, 0.63 mmol, 1 equiv), (4-fluoro-2-hydroxyphenyl)boronic acid (148 mg, 0.95 mmol, 1.5 equiv), and Pd(PPh3)4 (73 mg, 0.063 mmol, 0.1 equiv) was added DMF (6.3 mL that had been degassed by sparging with nitrogen for 10 min) Na2CO3 (0.63 mL of a 2 M aqueous solution, 1.27 mmol, 2 equiv) was added and the reaction was heated to 90° C. for 18 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc and washed with water. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc in hexane) to provide the product as a yellow glass (0.27 g, 68%). LCMS (M+1)=631.4.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:7]1[CH:8]=[C:9]([S:16]([NH2:19])(=[O:18])=[O:17])[S:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13])[CH3:6])(=O)[CH3:2].Cl>O1CCCC1>[CH2:1]([NH:4][CH:5]([C:7]1[CH:8]=[C:9]([S:16]([NH2:19])(=[O:18])=[O:17])[S:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13])[CH3:6])[CH3:2]
Reactant: CC(=O)NC(C)c1cc(S(N)(=O)=O)sc1S(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCNC(C)c1cc(S(N)(=O)=O)sc1S(C)(=O)=O
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To a stirred refluxing solution of 4-(1-acetamidoethyl)-5-methylsulfonylthiophene-2-sulfonamide (2.52 g, 0.0077 mol) in dry tetrahydrofuran (25 ml) under nitrogen atmosphere was added dropwise a solution of borane dimethylsulfide complex (2.3 ml, 0.023 mol) in THF (10 ml) over 1/2 hour. Reflux was continued for 1 hour. The solution was cooled in ice and acidified with 6N HCl (10 ml). The acidified solution was concentrated in vacuo. The residue was basified with saturated NaHCO3 solution and was extracted with ethyl acetate. The product was extracted into 3N HCl. This was again basified with saturated NaHCO3 solution, extracted with ethyl acetate, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. A white solid was obtained (1.33 g) (55%), m.p. 162.5-165° C. Recrystallization from ethyl acetate gave 1.23 g of product, m.p. 164-165.5° C. HPLC and TLC confirmed the purity and NMR confirmed the structure.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[C:10]1([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N:25]3[CH2:30][CH2:29][N:28](C)[CH2:27][CH2:26]3)=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CS(C)=O>[C:10]1([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N:25]3[CH2:30][CH2:29][N:28]([C:2]#[N:1])[CH2:27][CH2:26]3)=[N:17]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To a stirred mixture of 1.5 g of cyanogen bromide 2.0 g of potassium carbonate and 30 ml of dimethylsulfoxide was added, dropwise, a solution of 2.8 g of 1-phenyl-3-(4-methyl-1-piperazinyl)-1H-indazole in 30 ml of dimethylsulfoxide. The reaction mixture was stirred at ambient temperature for 1.5 hours and then poured into water. The aqueous mixture was extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by flash chromatography on silica gel, utilizing ethyl acetate-hexane (1:1) as the eluent, followed by recrystallization from isopropyl alcohol-water to yield 2.3 g (59%) of 4-(1-phenyl-1H-indazol-3-yl)-1-piperazine carbonitrile, m.p. 118°-120°.
Reaction SMILES: [CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[CH:13]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33].[Al].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[C:13]3[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1ccc2cc(NC(=O)OC3CCCC3)ccc21
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C([O-])O
Agent: [Al]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 44.7 %

Procedure:
A solution of 5-(cyclopentyloxycarbonyl)amino-1-methylindole (AA) (1.3 g.) and methyl 4-bromomethyl-3-methoxybenzoate (B) (1.3 g.) in N,N-dimethylformamide (25 ml.) was stirred and heated at 100° C., under a nitrogen atmosphere, while protecting the reaction vessel from light with aluminum foil, for 24 hours. The cooled mixture was poured onto saturated aqueous sodium bicarbonate solution (300 ml.), extracted with ethyl acetate (3×100 ml.), the combined extracts washed with brine (50 ml.), dried (MgSO4), and evaporated. The product was isolated by flash chromatography on silica gel (3.5 cm. diameter column) to give the title compound (P) (0.98 g., 45%), identical with that obtained in Example 8.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:32])=[CH:14][C:15]([C:26]4[CH2:27][CH2:28][O:29][CH2:30][CH:31]=4)=[CH:16][C:17]=3[C:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>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.CN(C=O)C>[O:29]1[CH2:30][CH:31]=[C:26]([C:15]2[CH:14]=[C:13]([F:32])[C:12]3[O:11][C:10]4[C:19](=[CH:20][C:7]([C:37]5[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=5)=[CH:8][CH:9]=4)[C@:18]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:17]=3[CH:16]=2)[CH2:27][CH2:28]1
Reactant: OB(O)c1cccnc1
Reactant: NC1=NC2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
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: [K+]
Solvent: CN(C)C=O
Product: NC1=N[C@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Temperature: 75 °C

Procedure:
A vial was charged with 2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (150 mg, 0.300 mmol), pyridin-3-ylboronic acid (111 mg, 0.899 mmol), and Pd(PPh3)4 (34.6 mg, 0.030 mmol). The vial was purged with Ar (g), then DMF (2 mL) and potassium carbonate (0.749 mL, 1.499 mmol) (as a 2.0 M aq. solution) were added in sequence. The vial was capped and heated in a Biotage Initiator microwave reactor for 1.5 h at 75° C. The product was purified via Gilson HPLC (gradient elution 20-90% MeCN/H2O, 0.1% TFA) to afford (R)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off white solid. Found MS: MH+=430.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:43]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccccc2Cl)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.13 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-2-chlorobenzene (0.44 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.6 g, 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[Sn](CCCC)(CCCC)CCCC.Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:33]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1(C)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>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:33]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cccc1F
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cncc(-c2c(F)cccc2F)c1
Yield: 81 %

Procedure:
A mixture of (2,6-difluorophenyl)tributyltin (1.18 g, 2.9 mol), ethyl 5-bromonicotinate (0.69 g, 3 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.10 g) in xylene (10 mL) was heated under reflux for 24 h, then cooled, filtered and evaporated. The residue was chromatographed on silica gel eluted with 20% ethyl acetate/petrol to give the title compound (0.64 g, 84%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][C:12]1[N:13]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:14]=[CH:15][N:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 112.5 %

Procedure:
A mixture of 50.0 g of p-fluoronitrobenzene, 85.93 g of 2-methylimidazole and 44.9 g of potassium carbonate in 860 ml of dimethylsulfoxide is heated at 120° C. for 24 hours. The mixture is poured into 2.5 liter of water and stored in a refrigerator for two days. The mixture is filtered and cake washed with copious volumes of water and vacuum dried. The cake is dissolved in 1500 ml of ethyl acetate, filtered through hydrous magnesium silicate and the filtrate reduced to about 500 ml, cooled and the resulting solid, filtered, and air dried to give 81.0 g of the desired product as brown crystals, m.p. 135°-137° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8](N(OC)C)=[O:9])=[C:4]([O:16][CH3:17])[CH:3]=1.[CH:18]1([Mg]Br)[CH2:20][CH2:19]1.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([CH:18]2[CH2:20][CH2:19]2)=[O:9])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: COc1cc(Br)ccc1OCC(=O)N(C)OC
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1OCC(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 2-(4-bromo-2-methoxyphenoxy)-N-methoxy-N-methylacetamide Part A (2 g, 6.58 mmol) in THF (25 mL) was slowly added cyclopropylmagnesium bromide (39.5 mL, 19.73 mmol). After stirring for 1 hour at RT, the reaction mixture was added to a sat. NH4Cl solution which was subsequently extracted with EtOAc, dried (Na2SO4), and concentrated. The crude product was purified using ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 50:50 gradient) to afford the desired product 2-(4-bromo-2-methoxyphenoxy)-1-cyclopropylethanone 16B (1.72 g, 6.03 mmol, 92% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.01 (2H, dddd), 6.65 (1H, d, J=8.53 Hz), 4.72 (2H, s), 3.89 (3H, s), 2.24-2.35 (1H, m), 1.15 (2H, quin, J=3.83 Hz), 0.98 (2H, dq, J=7.56, 3.67 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][S:11][C:10]2=[S:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:16]([O:19][C:20](=O)[CH3:21])(=O)[CH3:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:16]([O:19][CH2:20][CH3:21])[CH2:17][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[S:11][C:10]2=[S:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CSC(=S)N1c1ccc(Cl)c(Cl)c1
Product: CCOC(Cc1ccccc1)=C1SC(=S)N(c2ccc(Cl)c(Cl)c2)C1=O

Procedure:
The rhodanine is reacted as described in Examples 1 and 3 with triethylorthophenylacetate in acetic anhydride to yield 3-(3',4'-dichlorophenyl)-5-(1'-ethoxy-2'-phenylethylidene)-rhodanine which is similarly hydrolyzed to 3-(3',4'-dichlorophenyl)-5-(1'-hydroxy-2'-phenylethylidene)-rhodanine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][CH:13]2[CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: NC1CC1
Solvent: CN(C)C=O
Product: Cc1csc2c(NC3CC3)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 428 mg (7.5 mmol) of cyclopropylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/6) to give 780 mg (yield: 95.4%) of the title compound.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8]2[C:10]3[C@@H:11]4[CH2:20][C@H:14]([C:15]=3[C:16]([O:18][CH3:19])=[CH:17][C:7]=2[CH2:6]1)[CH2:13][CH2:12]4)=[N+]=[N-]>[Pd]>[CH3:19][O:18][C:16]1[CH:17]=[C:7]2[C:8](=[C:10]3[C:15]=1[CH:14]1[CH2:20][CH:11]3[CH2:12][CH2:13]1)[O:9][CH:5]([CH2:4][NH2:1])[CH2:6]2
Reactant: COc1cc2c(c3c1[C@@H]1CC[C@H]3C1)O[C@@H](CN=[N+]=[N-])C2
Agent: [Pd]
Product: COc1cc2c(c3c1C1CCC3C1)OC(CN)C2
Yield: 53 %

Procedure:
Treatment of [(2R*,6R*,9S*)-5-methoxy-2,3,6,7,8,9-hexahydro-6,9-methanonaphtho[1,2-b]furan-2-yl]methyl 4-methylbenzenesulfonate (1.2 g, 2.30 mmol) with sodium azide (0.78 g, 11.99 mmol) generally according to the procedure described for Intermediate 24 gave (2R*,6R*,9S*)-2-(azidomethyl)-5-methoxy-2,3,6,7,8,9-hexahydro-6,9-methanonaphtho[1,2-b]furan. Treatment of the azide with palladium on carbon (10 wt. %, 0.10 g) generally according to the procedure described for Example 2 gave 0.45 g (53%) of (9-methoxy-4-oxatetracyclo[9.2.1.02,10.03,7]tetradeca-2,7,9-trien-5-yl)methylamine as a white solid, hydrochloride salt. mp>200° C. (dec); Anal. calcd. for C16H21NO2HCl: C, 63.94; H, 7.15; N, 4.97. Found: C, 64.68; H, 7.63; N, 4.5. Separation of the stereoisomers of (9-methoxy-4-oxatetracyclo[9.2.1.02,10.03,7]tetradeca-2,7,9-trien-5-yl)methylamine provided three compounds with >99% optical purity.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([Cl:20])=[CH:14][C:13]=2[F:21])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:21])=[CH:14][C:15]([Cl:20])=[C:16]([O:18][CH3:19])[C:17]=2[N+:27]([O-:29])=[O:28])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Agent: O=S(=O)(O)O
Product: COc1c(Cl)cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole (1.2 g, 3.5 mmol) was slurried with 4 ml of conc. sulfuric acid and was slowly added to a stirred 4 ml of conc. sulfuric acid-con. nitric acid (9:1) at −15° C. Solution was allowed to stir at ambient temperature for 2 hr and then added to ice water. Extraction with ethyl acetate and removal of the solvent afforded a crude product which was chromatographed on silica gel. Elution of the column with hexane-methylene chloride (4:6) furnished the title compound (0.72 g).