Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[NH2:8].[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:17]([NH:25][C:26]([NH:8][C:7]1[C:6]([O:9][CH3:10])=[CH:5][N:4]=[C:3]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:2]=1[I:1])=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cnc(-c2ccccc2)c(I)c1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COc1cnc(-c2ccccc2)c(I)c1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a stirred solution of 159 g (4.88 mmol) 3-iodo-5-methoxy-2-phenyl-pyridin-4-ylamine in 30 ml acetone was added dropwise 0.98 ml (7.31 mmol) benzoyl isothiocyanate at room temperature. The reaction mixture then heated at reflux for 5 h before being cooled to room temperature concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) afforded 1.61 g (67%) 1-benzoyl-3-(3-iodo-5-methoxy-2-phenyl-pyridin-4-yl)-thiourea as a yellow crystalline solid. ES-MS m/e (%): 490 (M+H+, 100).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].Cl.[CH:7]1([NH2:11])[CH2:10][CH2:9][CH2:8]1>CC#N>[CH:7]1([NH:11][S:1]([Cl:5])(=[O:3])=[O:2])[CH2:10][CH2:9][CH2:8]1
Reactant: O=S(=O)(Cl)Cl
Reactant: NC1CCC1
Agent: Cl
Solvent: CC#N
Product: O=S(=O)(Cl)NC1CCC1
Temperature: 25 °C

Procedure:
Sulfuryl chloride (104 mmol) was dissolved in dry CH3CN (25 mL), added cyclobutylamine hydrochloride (31 mmol) and stirred at reflux for 16 h. The obtained reaction mixture was cooled to rt and concentrated in vacuo. The obtained residue was trituated with Et2O (2×25 mL). The combined Et2O-phases were concentrated in vacuo affording the title compound as oil.
Reaction SMILES: S(=O)(=O)(O)N.Cl([O-])=[O:7].[Na+].[C:10]1([C:16]2([CH2:21][CH:22]=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)(C)C>[C:10]1([C:16]2([CH2:21][C:22]([OH:7])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CCC1(c2ccccc2)CCCC1
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)CC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
1 ml of an aqueous solution of 39 mg (0.402 mmol) of sulfamic acid and then 1 ml of an aqueous solution of 37.6 mg (0.416 mmol) of sodium chlorite were added dropwise to a solution of 58.4 mg (0.310 mmol) of 2-(1-phenylcyclopentyl)acetaldehyde [prepared as described in step (v) above] in 1 ml of t-butanol at room temperature, and the resulting mixture was stirred for 1 hour at room temperature, after which it was extracted with methylene chloride. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give colorless crystals. These were recrystallized from a mixture of ethyl acetate and hexane, to give 57 mg (yield 90%) of the title compound as plate-like crystals.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][N:6]([O:22][CH3:23])[C:7]([NH:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:5][N:6]([O:22][CH3:23])[C:7]([N:9]([CH2:3][CH:2]=[CH2:1])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21])=[O:11])=[O:8]
Reactant: CON(C)C(=O)NC(=O)c1cnccc1C(F)(F)F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)c1cnccc1C(F)(F)F)C(=O)N(C)OC
Reaction time: 2 h

Procedure:
Allyl bromide (0.10 ml) was added to a suspension of 1-methyl-1-methoxy-3-(4-trifluoromethyl-3-pyridylcarbonyl)urea (0.25 g) and potassium carbonate (0.16 g) in N,N-dimethylformamide at 20° C., and stirred for 2 hours. Ethyl acetate and water were added and the organic phase dried (magnesium sulfate), evaporated and the residue purified by column chromatography on silica gel, eluting with n-hexane/ethyl acetate (2:1) to give 1-methyl-1-methoxy-3-allyl-3-(4-trifluoromethyl-3-pyridylcarbonyl)urea (0.26 g, Compound E-85).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30](C)(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:34]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH2:34])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(-c2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)ccc1F
Reactant: N
Product: Cc1cc(-c2c(-c3ccc(S(N)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)ccc1F

Procedure:
The title compound was prepared according to the method of procedure Example 384, substituting 2-(3,4-difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 105 mg, 27%). mp 243-245° C. 1H NMR (300 MHz, DMSO-d6) δ 2.2 (s, 3H), 7.01 (m, 2H), 7.25 (m, 1H), 7.45 (s, 1H), 7.47 (bs, 2H), 7.6 (m, 2H), 7.77 (d, J=9 Hz, 2H), 7.85 (m, 1H), 8.26 (s, 2H). MS (DCI/NH3) m/z 472 (M+H)+, 489 (M+NH4)+. Anal. calc. for C24H17F3N2O3S.0.5H2O: C, 58.59; H, 3.42; N, 8.91. Found: C, 57; H, 4.23; N, 8.89.
Reaction SMILES: [Se](=O)=O.[O:4]1CCOCC1.O.[C:11]([CH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[CH:24][C:25]3[S:29][C:28]([CH3:30])=[N:27][C:26]=3[CH:31]=2)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([CH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:23]=[CH:24][C:25]3[S:29][C:28]([CH:30]=[O:4])=[N:27][C:26]=3[CH:31]=2)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1nc2cc(OC3CCC(C(C)(C)C)CC3)ccc2s1
Reactant: C1COCCO1
Agent: O=[Se]=O
Solvent: O
Product: CC(C)(C)C1CCC(Oc2ccc3sc(C=O)nc3c2)CC1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
Selenium dioxide (180 mg, 1.6 mmol) was combined with 1,4-Dioxane (5 mL, 60 mmol) and Water (0.5 mL, 30 mmol) at room, temperature open to the atmosphere. The mixture was then treated with 5-(4-tert-Butyl-cyclohexyloxy)-2-methyl-benzothiazole (250 mg, 0.82 mmol) and resulting mixture was heated to 65° C. for 2 hours. The heat was increased to 90° C. and 4 additional eq. of SeO2 were added. Reaction was stirred for additional 5 hours. LCMS shows nearly complete conversion. Reaction become dark and solids formed in reaction mixture. Reaction was cooled to RT and allowed to stand over night. Solids were removed via filtration. Concentrated to dryness then purified directly via column chromatography using a gradient of 0-40% Ethylacetate/hexane to give the title compound as a dark solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.[CH2:32]([O:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][C:40]([CH2:46]Cl)=[CH:41][CH:42]=2)[CH:37]=1)[CH:33]=[CH2:34]>>[CH2:32]([O:35][C:36]1[CH:37]=[C:38]2[C:43]([CH:42]=[CH:41][C:40]([CH2:46][O:1][CH:2]3[CH:7]([C:8]4[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:24]=[CH:23][S:22][CH:21]=5)=[CH:12][CH:13]=4)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]3)=[CH:39]2)=[CH:44][CH:45]=1)[CH:33]=[CH2:34]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccsc3)cc2)C(O)C1
Reactant: C=CCOc1ccc2ccc(CCl)cc2c1
Product: C=CCOc1ccc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccsc4)cc3)cc2c1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate with 2-allyloxy-7-chloromethyl-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(7-allyloxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate, from which after cleavage of the allyl group by means of bis-(triphenylphosphine)-palladium(II) diacetate analogously to Example 152 (e) there was obtained tert-butyl (3RS,4RS)-3-(7-hydroxy-naphthalen-2-ylmethoxy)-4-{4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a yellowish, viscous oil; MS: 604 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:25][CH2:24]1
Reactant: OCCN1CCNCC1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(CCO)CC3)ncc2c1=O
Yield: 68 %

Procedure:
5.6 g. of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine, 5.2 g. of 1-β-hydroxyethyl piperazine and 50 cm3 of toluene are heated under reflux for 2 hours. After cooling, the solution is filtered to remove the hydrochloride which has precipitated, and the organic solution is diluted with its own volume of chloroform, is washed with water and dried (MgSO4). After evaporation, the residue is recrystallised from 40 cm3 of a mixture of isopropanol (1 volume) and isopropyl ether (2 volumes). 5.14 g. (68%) of 2-(4'-β-hydroxyethyl-piperazino)-5-oxo-6-carbethoxy-8-ethylpyrido(2,3-d)pyrimidine are obtained; melting point 172° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15]Cl)[CH:6]=[C:5]2[CH:19]=[O:20].C([O-])(=[O:23])C.[K+].[CH:26]1([NH:29][C:30](=[O:48])[C:31]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[C:34]([CH3:46])=[C:33]([F:47])[CH:32]=2)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O.CO>[CH:26]1([NH:29][C:30](=[O:48])[C:31]2[CH:36]=[C:35]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:23])[CH:6]=[C:5]4[CH:19]=[O:20])[C:34]([CH3:46])=[C:33]([F:47])[CH:32]=2)[CH2:27][CH2:28]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)[O-]
Reactant: CC(C)(CCl)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(C=O)c2c1
Temperature: 130 °C
Reaction time: 20 h
Yield: 87.1 %

Procedure:
A solution of 6-bromo-2-(3-chloro-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Example 2b, 0.50 g) dissolved in NMP (5 mL) was treated with potassium acetate (0.17 g) under nitrogen. The resulting mixture was stirred at 130° C. for 20 h. The mixture was then treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.63 g), Pd-118 (0.046 g) and potassium carbonate (0.43 g) under nitrogen and stirred at 80° C. for 4 h. After cooling to room temperature methanol (10 mL) was added and the mixture stirred for 1 h. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (250 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution with 100% ethyl acetate) to afford the subtitle compound (0.55 g) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].B(O)(O)[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.C(O)C.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>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:41]4[C:42]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:38]=[CH:39][CH:40]=4)[CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
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: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4cccc5ccccc45)c3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (433 mg, 0.907 mmol) (see Ex. 3, part F) and 1-naphthyleneboronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3 (aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (52.5 mg) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes). Rf=0.16 in 1:9 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ8.11-8.05 (m, 2H), 7.90-7.82 (m, 3H), 7.56-7.39 (m, 6 H), 6.80-6.72 (m, 4H), 4.22-4.19 (m, 4H), 2.98 (t, 2H), 2.35 (s, 3H) 1.47 (s, 3H), 1.22 (t, 6H); MS (EI) 436.5 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].C1(=O)CCCCC1.[OH:20][C:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[N:23][C:22]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:27][C:25]1[N:24]=[N:23][C:22]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:21]([OH:20])[CH:26]=1
Reactant: Cc1cccc(C2CC2)c1[O-]
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a mixture of 27.4 g (purity: 92.9%; 149 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of cyclohexanone was added 2.5 g (purity: 98.5%; 14.9 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 7 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 120 g of pure water and 100 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 2.48 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 60.2%) and 16 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: C[N:2]1[CH:7]2[CH2:8][C:9]([CH2:11][CH:3]1[CH2:4][CH2:5][CH2:6]2)=O.C[N:13]1C2[CH2:18][C:19]([CH2:21][CH:14]1CC2)=[O:20].[H-].C([Al+]CC(C)C)C(C)C.[O:32]1[C:36]([CH2:37]P(=O)(OCC)OCC)=[CH:35][CH:34]=[N:33]1>>[CH:3]12[NH:2][CH:7]([CH:5](/[CH:6]=[CH:18]/[C:19]3[O:20][N:13]=[CH:14][CH:21]=3)[CH2:4]1)[CH2:8][CH2:9][CH2:11]2.[CH:3]12[NH:2][CH:7]([CH:5](/[CH:6]=[CH:37]\[C:36]3[O:32][N:33]=[CH:34][CH:35]=3)[CH2:4]1)[CH2:8][CH2:9][CH2:11]2
Reactant: CN1C2CCC1CC(=O)C2
Reactant: CN1C2CCCC1CC(=O)C2
Reactant: CCOP(=O)(Cc1ccno1)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: C(=C/C1CC2CCCC1N2)\c1ccno1
Product: C(=C\C1CC2CCCC1N2)\c1ccno1

Procedure:
The synthesis of arylethenyl-substituted 8-azabicyclo[3.2.1]octanes and arylethynyl-substituted 8-azabicyclo[3.2.1]octanes are accomplished in a manner similar to that described for arylethenyl-substituted 7-azabicyclo[2.2.1]heptanes and arylethynyl-substituted 7-azabicyclo[2.2.1]heptanes. Treatment of pseudopelletierine (N-methyl-9-azabicyclo[3.3.1]nonan-3-one) as described earlier for tropinone (Daly et al. Eur. J. Pharmacol. 321:189-194 (1997)) will generate ethyl 8-aza-6-(ethoxycarbonyl)bicyclo[3.2.1]octane-8-carboxylate. Pseudopelletierine is made according to Howell et al., Org. Syn. Coll. Vol IV: 816-819 (1963). Reduction of ethyl 8-aza-6-(ethoxycarbonyl)bicyclo[3.2.1]octane-8-carboxylate with diisobutylaluminum hydride and subsequent reaction of the 6-formyl derivative with diethyl (5-isoxazolylmethyl)phosphonate and n-butylithium will provide mixture of ethyl (E)- and (Z)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole-8-carboxylate. Separation of the isomers followed by deprotection will provide (E)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole and (Z)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole. The other methods described previously for the preparation of five-membered heterocycle analogues of ethenyl-substituted 7-azabicyclo[2.2.1]heptanes may be applied similarly.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>O1CCCC1>[Br:1][C:2]1[S:3][C:4]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 2-bromo-4-methylthiazole-5-carboxylic acid (10.00 g, 45.00 mmol) and 4-methylmorpholine (6.5 mL, 59.0 mmol) in tetrahydrofuran (150 mL) was added isobutyl chloroformate (6.5 mL, 49.6 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hour and 3-(aminomethyl)pyridine (5.2 mL, 51.4 mmol) was added. The reaction mixture was stirred at ambient temperature for 17 hours, and then concentrated in vacuo. The residue was purified by column chromatography to afford 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide in 52% yield (7.3 g): 1H NMR (300 MHz, CDCl3) δ 8.39-8.80 (m, 2H), 7.80-7.72 (m, 1H), 7.40-7.35 (m, 1H), 6.47 (br s, 1H), 4.60 (d, J=6.0 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 312.1 (M+1), 314.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:24](OC)(=[O:29])[C:25]([O:27][CH3:28])=[O:26].Cl>C1COCC1>[CH3:28][O:27][C:25](=[O:26])[C:24]([OH:29])=[CH:9][C:8](=[O:10])[N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:13][CH:12]=1)[CH3:11]
Reactant: CC(=O)N(C)Cc1ccc(F)cc1
Reactant: COC(=O)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
N-(4-Fluoro-benzyl)-N-methyl-acetamide (3.6 grams, 20 mmol) was dissolved in 20 mL of THF and cooled to −78° C. To this was added 40 mL of 1M LiHMDS (in THF) and the resulting solution stirred for 30 min. Next dimethyl oxalate (3.5 grams, 30 mmol) dissolved in 8 mL of THF is added and the reaction stirred for 2 h at −78° C., then warmed to 0° C. and stirred an additional 30 min. To this was added 1N HCl and the mixture then extracted with EtOAc. The organic layer was washed with saturated NaCl, dried over Na2SO4, filtered and the solvent removed. The crude product was purified by column chromatography (4×4 cm SiO2, 80:20 Hex/EtOAc) to yield 4.3 grams solid (80% yield). HRMS (M+H) calcd for C13H15NO4F: 268.0985; found: 268.0983. Anal calcd for C13H14NO4F: C, 58.42; H, 5.28; N, 5.24. found: C, 58.48; H, 5.21; N, 5.26. 1H NMR and 13C NMR show a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl3) δ: 3.00 (s), 3.86 (s), 3.89 (s), 4.55 (s), 6.29 (s), 6.31 (s), 7.00–7.24 (overlapping m, 4). 13C NMR δ; 33.43, 34.79, 49.97, 52.63, 52.97, 93.27, 93.55, 115.63, 115.80, 115.95, 116.13, 128.36, 128.42, 129.71, 129.78, 131.32, 132.03, 159.70, 161.40, 163.25, 163.35, 170.93, 171.16.
Reaction SMILES: [Cl-].[Li+].O.[CH2:4]([C:11]([CH2:22][CH2:23][CH2:24][C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])(C(OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]>CS(C)=O>[F:36][C:25]([F:37])([C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:29])([F:31])[F:30])[CH2:24][CH2:23][CH2:22][CH:11]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reaction time: 12 h
Yield: 44.5 %

Procedure:
Lithium chloride (985 mg, 23.24 mmol) and water (0.21 ml, 11.62 mmol) were added to a solution of diethyl 2-(6-heptenyl)-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)malonate (6.0 g, 11.62 mmol) in dimethyl sulfoxide (40 ml) followed by stirring for 12 hours at a temperature of 160° C. to 180° C. After the reaction was completed, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/40→1/30) to give ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate (2.3 g, Yield 44%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N:10]2CCCC2)=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.Cl.N[NH:20][C:21]([NH2:23])=[O:22]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[N:10]/[NH:20][C:21]([NH2:23])=[O:22])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: NNC(N)=O
Reactant: O=[N+]([O-])c1cc(F)ccc1/C=C/N1CCCC1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)N/N=C/Cc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-[(E)-2-(4-fluoro-2-nitrophenyl)ethenyl]pyrrolidine (77.25 g, 0.327 mol) in warm MeOH (500 mL) was added a solution of semicarbazide HCl (38.3 g, 0.343 mol) in warm water (200 mL). The reaction mixture was stirred at room temperature for 1 h and was then cooled in ice and filtered. The solid was washed with cold 1:1 MeOH/water (2×30 mL) and dried to give 71 g (90% over two steps) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[C:9]#[N:10].[CH2:12](N)[CH2:13][NH2:14]>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:9]1[NH:14][CH2:13][CH2:12][N:10]=1)[CH3:11]
Reactant: NCCN
Reactant: CC(C#N)c1ccccc1I
Product: CC(C1=NCCN1)c1ccccc1I

Procedure:
rac-2-[1-(2-Iodo-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2-iodo-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): white solid; MS (EI): 301.0 ((M+H)+.).