Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6](=O)[CH2:7][N+:8]([O-:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(O)(O)(=O)=O.[NH2:17][OH:18]>C1(C)C=CC=CC=1.C(O)C>[CH:1]1([C:6](=[N:17][OH:18])[CH2:7][N+:8]([O-:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(C[N+](=O)[O-])C1CCCC1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])CC(=NO)C1CCCC1
Yield: 88.7 %

Procedure:
9.90 g (63 mmol) of 1-cyclopentyl-2-nitro-ethanone (example II) and 20.688 g (126 mmol) of hydroxylamine sulfate are heated under reflux, for 4 hours, in 310 ml of a toluene/ethanol mixture (1:1). The solvent is removed in vacuo and the residue is taken up in ethyl acetate; the organic phase is washed 2 times with water and dried over sodium sulfate and the solvent is removed in vacuo. 9.62 g (74%) of pale yellow solid are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.Br[C:11]1[C:12]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[Cl:29])(=[O:21])=[O:20])=[N:13][CH:14]=[C:15]([CH3:17])[N:16]=1>>[Cl:29][C:23]1[C:24]([Cl:28])=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:18][C:12]1[C:11]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:16][C:15]([CH3:17])=[CH:14][N:13]=1)(=[O:20])=[O:21]
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Reactant: Cc1cccc(CO)n1
Product: Cc1cccc(COc2nc(C)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)n1

Procedure:
Prepared by the method of Example 20 using 6-methylpyridine-2-methanol (0.05 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.1 g). Yield 0.023 g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1.C(O)(C(F)(F)F)=O>C(O)(C)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:12]1[C:11]2[CH:10]=[C:9]([NH2:8])[CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: O=Cc1cccs1
Reactant: Nc1ccc2c(c1)Cc1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Nc1ccc2c(c1)C(=Cc1cccs1)c1ccccc1-2

Procedure:
2-Thiophenecarboxaldehyde (80.4 mg, 0.72 mmol) was added to 2-aminofluorene (100 mg, 0.55 mmol) and refluxed in isopropanol for 12 hours with a catalytic amount of TFA. The solvent was evaporated and the product was purified by flash chromatography using anhydrous basic activated alumina gel (AlO2) and 40% ethyl acetate and 60% hexanes. The title compound was obtained as a yellow product. (45.4 mg, 0.165 mmol, 30%). M.p.: 143° C. 1H-NMR (300 MHz, [D] DMSO): δ=8.65 (s, 1H), 7.89 (t, 2H, 3J=10.9 Hz), 7.81 (d, 1H, 3J=6.7 Hz), 7.69 (dd, 1H, 3J=4.8 Hz, 4J=1.4 Hz), 7.57 (d, 1H, 3J=9.76 Hz), 7.50 (s, 1H), 7.37 (t, 1H, 3J=9.88 Hz), 7.32 (t, 2H, 3J=11 Hz), 7.22 (dd, 1H, 3J=4.84 Hz, 4J=1.8 Hz), 3.94 (s, 2H). 13C-NMR (300 MHz, [D] DMSO): δ=152.9, 148.4, 144.2, 143.1, 144.4, 141.0, 129.7, 128.8, 128.2, 128.4, 127.4, 127.1, 126.8, 125.8, 123.6, 120.3, 36.5. C.V. −1.36, −0.96, −0.56, −0.02, 0.62, 1.39 V. In 0.1 M TBAPF6 as supporting electrolyte in degassed anhydrous acetonitrile λmax=352 nm. λem=302 nm. Eg=454 nm, 62.95 Kcal/mol. ΔE=300 nm, 95.26 Kcal/mol.
Reaction SMILES: B(O)(O)[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C1COCC1.Br[C:24]1[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32].[OH-].[Na+]>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>[Br:30][C:28]1[CH:27]=[CH:26][C:25]([N+:31]([O-:33])=[O:32])=[C:24]([C:2]2[C:15]3[C:10]([C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[CH:3]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:29]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Br)cc1-c1cc2ccccc2c2ccccc12
Yield: 61.6 %

Procedure:
A 2 L round bottom flask was charged with phenanthracene-9-boronic acid (76.61 g, 345 mmol), THF (700 mL), and H2O (350 mL), and the mixture was dissolved. To the resultant mixture, 2,4-dibromo-1-nitrobenzene (146 g, 518 mmol), NaOH (42 g, 1035 mmol), and Pd(PPh3)4 (20 g, 17.3 mmol) were sequentially added, followed by reaction at 80° C. for 24 hours. After the reaction was completed, the resultant product was extracted with methylene chloride, water, and brine, and the organic layer was dried with MgSO4. The obtained organic layer was purified by silica gel column (methylene chloride:hexane=1:3) so as to give 80.4 g of a product (62%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][CH:60]([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH2:61][CH:60]([F:63])[F:59])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Reactant: OCC(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (111.0 mg, 0.287 mmol) in tetrahydrofuran (2.8 mL) was added 1,1′-(azodicarbonyl)dipiperidine (144.8 mg, 0.574 mmol) and tributylphosphine (143.0 μL, 0.574 mmol). After 10 min, to the mixture was added 2,2-difluoroethanol (209.1 μL, 2.870 mmol). The reaction mixture was stirred at 60° C. for 4 hrs. To the mixture was added 1,1′-(azodicarbonyl)dipiperidine (144.8 mg, 0.574 mmol) and tributylphosphine (143.0 μL, 0.574 mmol). After 30 min, to the mixture was added 2,2-difluoroethanol (209.1 μL, 2.870 mmol). The reaction mixture was stirred at 60° C. for 1.5 hrs. The mixture was concentrated. To the residue was added diethyl ether and the precipitate was removed by filtration. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the mixture contained the title compound. The residue was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless solid (50.0 mg, 0.111 mmol, 39%).
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[Br:11]N1C(=O)CCC1=O>C1COCC1>[NH2:1][C:2]1[S:6][C:5]([Br:11])=[N:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ncsc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)c1nc(Br)sc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of methyl 5-amino-1,3-thiazole-4-carboxylate (J & W PharmLab, 10.0 g, 63.2 mmol) in THF (100 mL), N-bromosuccinimide (12.0 g, 67.4 mmol) was added portion-wise. After stirring at room temperature for 1 h, the mixture reaction was filtered to give a first crop of product as a pink solid (9.8 g). The filtrate was concentrated under reduced pressure. The resulting residue was triturated with EtOAc (15 mL) and filtered to give a second crop of product as a pink solid (5.0 g, total yield: 99%). LCMS calc. for C5H6BrN2O2S (M+H)+: m/z=236.9. found 237.0.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1.P(Cl)(OCC)(OCC)=O>C(OCC)(=O)C>[C:6]1(=[O:7])[N:2]([O:1][C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=2)=[O:23])[C:3](=[O:8])[CH2:4][CH2:5]1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C1CCC(=O)N1O
Agent: CCOP(=O)(Cl)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Temperature: 25 °C

Procedure:
Analogous example 3 2,76 g (0.024 mol) of N-hydroxysuccinimide and 5.06 g (0,050 mol) of triethylamine were initially introduced into 5 ml of ethyl acetate and stirred at room temperature. 2.72 g (0.020 mol) of solid 4-toluic acid were added to this suspension in the course of 5 min. and then a solution of 3.47 g (0,020 mol) of diethyl chlorophosphate was added dropwise in the course of 20 min., the reaction mixture warming to about 35° C. The mixture was stirred at room temperature for 3 hours until the reaction was complete. The further proceeding was performed analogous example 3. 2.8 g of crude 4-toluic acid succinimidyl ester were isolated.
Reaction SMILES: O=[C:2]1[CH2:37][C@@H:36]2[C@:23]([CH3:40])([CH2:24][CH2:25][C@H:26]3[C@H:35]2[CH2:34][CH:33]=[C:32]2[C@:27]3([CH3:39])[CH2:28][CH2:29][C@H:30]([OH:38])[CH2:31]2)[C@H:3]1[C@H:4]([CH3:22])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:21])[CH2:9][N:10]1C(=O)C2=CC=CC=C2C1=O.O.NN.[OH-].[K+].C(O)COCCOCCO>O>[NH2:10][CH2:9][C@@H:8]([CH2:7][CH2:6][CH2:5][C@H:4]([C@@H:3]1[C@:23]2([CH3:40])[C@H:36]([C@H:35]3[C@H:26]([CH2:25][CH2:24]2)[C@:27]2([CH3:39])[C:32]([CH2:31][C@H:30]([CH2:29][CH2:28]2)[OH:38])=[CH:33][CH2:34]3)[CH2:37][CH2:2]1)[CH3:22])[CH3:21]
Reactant: C[C@H](CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CN1C(=O)c2ccccc2C1=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: C[C@@H](CN)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 150 °C
Yield: 64.1 %

Procedure:
A mixture of (25R)-16-oxo-26-phthalimidocholesterol (5) (0.70 g, 1.32 mmoles), hydrazine monohydrate (5 ml, 102.8 mmoles), potassium hydroxide (2.85 g, 50.8 mmoles) and triethylene glycol (20 ml) was heated to 150° C. for 30 minutes, then heated to 200° C. over 2 hours during which time water vapor distilled out of the mixture. The reaction mixture was maintained at this temperature for about 16 hours, under nitrogen, until the reaction was complete as determined by thin layer chromatography. Thereafter, the reaction mixture was cooled, poured into water, and extracted with chloroform. The extract was washed with water, dried over sodium sulfate, and evaporated under reduced pressure. Chromatography of the residue on silica gel eluted with CHCl3 gave 0.34 g (66%) of (25R)-26-aminocholesterol. The product was recrystallized from methylene chloride-ether and was found to have a melting point of 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=3)[N:11]([CH2:21][CH:22]([OH:25])[CH2:23][CH3:24])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:26]([NH2:28])[CH3:27]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:28][CH2:26][CH3:27])[CH:15]=3)[N:11]([CH2:21][C@@H:22]([OH:25])[CH2:23][CH3:24])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN
Reactant: CCC(O)Cn1nc(Nc2cccc(Cl)c2)nc1-c1ccnc(Cl)c1
Solvent: CO
Product: CCNc1cc(-c2nc(Nc3cccc(Cl)c3)nn2C[C@@H](O)CC)ccn1
Temperature: 160 °C
Reaction time: 16 h

Procedure:
Intermediate 1-[3-(3-chloro-phenylamino)-5-(2-chloro-pyridin-4-yl)-[1,2,4]triazol-1-yl]-butan-2-ol (prepared according to description 4) (1.15 g; 3.04 mmol) was dissolved in CH3OH (20 ml) and then ethylamine (3 g) was added. The reaction mixture was stirred for 16 hours at 160° C. under pressure (until the reaction had proceeded to completion). The solvent was then evaporated in vacuo. The residue was purified by reversed-phase high-performance liquid chromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). A gradient with 2 mobile phases was applied (phase A: a 0.25% NH4HCO3 solution in water; phase B: CH3CN). The desired fractions were collected, worked-up and finally the residue was crystallized from diisopropyl ether. Yield: 0.1595 g of compound E2 (S-enantiomer).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:15].C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>CN(C)C=O>[NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6]([Cl:25])=[O:7])=[CH:4][C:3]=1[Cl:15]
Reactant: O=S(Cl)Cl
Reactant: CON=Cc1cc(C(=O)O)cc(Cl)c1N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CON=Cc1cc(C(=O)Cl)cc(Cl)c1N
Temperature: 70 °C

Procedure:
In a 5-liter three-necked round-bottomed flask was placed 180 g of the previously prepared 4-amino-3-chloro-5-methoxyiminomethylbenzoic acid, 2 l of toluene, 3 mL of dimethylformamide and 104 g (64 mL) of thionyl chloride. The resulting mixture was heated at 70° C. for 2 hours, filtered while hot and the solvent removed using a rotary evaporator yielding 178.1 g of the expected 4-amino-3-chloro-5-methoxyiminomethylbenzoyl chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][CH2:9][C:10](OCC)=O)[CH:2]=1.[Cl:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]2[N:24]=[N:25][C:26]([NH:29][NH2:30])=[CH:27][CH:28]=2)[CH:19]=[CH:20][CH:21]=1>CS(C)=O.Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][CH2:9][C:10]2[N:25]3[N:24]=[C:23]([NH:22][C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=4)[CH:28]=[CH:27][C:26]3=[N:29][N:30]=2)[CH:2]=1
Reactant: NNc1ccc(Nc2cccc(Cl)c2)nn1
Reactant: CCOC(=O)COCc1cccnc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Product: Clc1cccc(Nc2ccc3nnc(COCc4cccnc4)n3n2)c1

Procedure:
(Step 4-ii) Ethyl 2-((pyridin-3-yl)methoxy)acetate (65 mg, 0.33 mmol) and N-(3-chlorophenyl)-6-hydrazinylpyridazin-3-amine (60 mg, 0.25 mmol) were combined in a 16×100 mm test tube and placed into a 160° C. oil bath for 15 min. The residue was dissolved in 1 mL DMSO and purified by reversed-phase HPLC. Fractions containing pure product were concentrated in vacuo to yield a solid, dissolved in HCl/methanol, and concentrated in vacuo to give the yellow solid product, 3-(((pyridin-3-yl)methoxy)methyl)-N-(3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine, as an HCl salt (22 mg, 0.055 mmol, 22% yield). 1H-NMR (500 MHz, DMSO-d6) 10.25 (s, 1H), 8.80 (s, 1H), 8.77 (d, J=5.2 Hz, 1H), 8.40 (d, J=8.1 Hz, 1H), 8.16 (d, J=9.9 Hz, 1H), 8.07 (t, J=2.0 Hz, 1H), 7.90 (dd, J=5.6, 7.9 Hz, 1H), 7.61 (dd, J=2.0, 8.2 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.20 (d, J=9.9 Hz, 1H), 7.08-7.06 (m, 1H), 5.11 (s, 2H), 4.89 (s, 2H); MH+367.3.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc(O)c1
Reactant: NCc1ccccc1
Product: Oc1cccc(NCc2ccccc2)c1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
Resorcinol (22 g) and 21.4 g of benzylamine were heated under an air condenser in a nitrogen atmosphere at 175°-185° C. for 5.5 hr. Then the air condenser was removed, and the temperature raised to 200°-203° where it was held for 1.5 hr. The red, viscous mass was cooled and boiled with 250 ml of 3:2 benzene-cyclohexane to form a solution. The solution was cooled several days at 5° C. to allow for the separation of oily material. The supernatant was decanted and evaporated to leave 12.0 g (30%) of pale-orange, viscous liquid 3-benzylaminophenol which was used without further purification.
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[C:24]1([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:31][CH:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[O:30])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:22])([F:21])[F:23])[O:18][N:17]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Yield: 86 %

Procedure:
As described for Example 18, 6-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-nicotinic acid methyl ester (100 mg, 0.24 mmol), was converted, using 4-aminotetrahydropyran instead of cyclopropanemethylamine, to the title compound (110 mg, 86%) which was obtained as a white solid. MS: m/e=484.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[CH3:12]C(C)=O.C([O-])([O-])=O.[K+].[K+].CI>O>[CH:1]1([C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]1
Reactant: O=C(O)C1CCC=CCCC1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)C1CCC=CCCC1
Reaction time: 8 h

Procedure:
A 50 mL, 3-neck round bottom flask was charged with cyclooct-4-ene carboxylic acid (0.517 g, 3.35 mmol, prepared as described below in Example 35) and 30 mL reagent-grade acetone and vigorously stirred for several minutes. K2CO3 (1.15 g, 8.32 mmol) was then added, followed by an excess of methyl iodide (4 mL). A reflux condenser (water temperature 5° C.) was then fitted to the flask and the reaction was gently refluxed overnight. The mixture was filtered, the filtrate was concentrated using a rotary evaporator, and the residue was purified by flash chromatography on silica (1:9 ethyl acetate:hexanes mobile phase) to give methyl cyclooct-4-ene carboxylate as a single isomer (0.560 g, 99%). A copolymer of methyl cyclooct-4-ene carboxylate and cyclooctene, prepared similarly to polymer 15 at room temperature, would have the following features: The end groups R2 and R3 would be H or CH3. For this polymer, e and f would be derived from methyl cyclooct-4-ene carboxylate and would equal 3 and 4, respectively; d would derive from cyclooctene and would equal 8. The run lengths would therefore be: rHH=(3+3)+8z; rHT=(3+4)+8z; and rTT=(4+4)+8z; therefore rtotal=(6+8z), (7+8z), (8+8z).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][N:8]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CNCC1c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
A stirred solution of 4-(4-nitro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (7.5 g, Reference Example 4) in methylene chloride (100 ml), at 23° C., was treated dropwise with triethylamine (5.8 ml). After stirring for 15 minutes the mixture was treated dropwise with a solution of benzoyl chloride [prepared in a separate vessel by treating a stirred solution of benzoic acid (5 g) in methylene chloride (15 ml), at 23° C., with oxalyl chloride (5 ml) and after stirring for 2 hours evaporating the reaction mixture] in methylene chloride (3.5 ml). The resulting dark brown mixture was stirred for 1.5 hours at 23° C. then filtered. The filtrate was successively washed with water (100 ml), then twice with hydrochloric acid (100 ml, 1N), then with brine (100 ml), then water (100 ml), then dried over magnesium sulphate and then evaporated (40° C. and 2.7 kPa) affording the title compound (10 g) as a viscous oil. 1H-NMR [400 MHz, (CD3)2SO at 383° K.] δ 1.13 (t, J=7 Hz, 3H); 3.49 (m, 1H); 3.65 (m, 1H); 3.75 to 3.90 (m, 2H); 3.90 to 4.20 (m, 2H); 4.09 (m, 2H);7.40 to 7.65 (m, 5H); 7.66 (d, J=8.5 Hz, 2H); 8.19 (d, J=8.5 Hz, 2H). MS [DCI (reactant gas, ammonia)]: 369[M+H]+, 386[M+NH4]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]1[CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1(C)OC(=O)CC(=O)[O:18]1.C(Cl)Cl.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:13]1([C@H:9]2[C:10](=[O:12])[CH2:16][C:17](=[O:18])[N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:15][CH2:14]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)CC(=O)[C@@H]1C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(tert-Butoxycarbonylamino)-2-cyclopropylacetic acid (13) (5.47 g, 25.4 mmol), Meldrum's acid (14) (4.02 g, 27.9 mmol), and DMAP (4.34 g, 35.56 mmol) were added to CH2Cl2 (100 mL) under nitrogen at 0° C. After 30 minutes EDAC (6.81 g, 35.56 mmol) was added. The reaction was stirred 16 hr at rt and poured into EtOAc (300 mL), washed with brine (200 ml), 5% citric acid (300 mL), and again brine (200 mL). The organic phase was then refluxed for 1 hr. The mixture was evaporated to give (S)-tert-butyl 2-cyclopropyl-3,5-dioxopyrrolidine-1-carboxylate (15) a yellow oil (4.0 g, 69%) that was taken into the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]3[C:24](=[O:27])[NH:25][CH2:26][CH:20]3[CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:32]([N:25]1[C:24](=[O:27])[CH:21]2[CH:20]([CH2:19][N:18]([C:16]([C:8]3[N:7]([CH2:6][C:5]4[CH:28]=[CH:29][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[CH:13][CH:14]=4)=[O:17])[CH2:23][CH2:22]2)[CH2:26]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1NCC2CN(C(=O)c3cc4ccccc4n3Cc3ccc(Cl)cc3)CCC12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCC2C(=O)N(Cc3ccccc3)CC2C1
Reaction time: 1 h

Procedure:
5-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)octahydro-1H-pyrrolo[3,4-c]pyridin-1-one (64 mg, 0.245 mmol) was dissolved in anhydrous DMF (5 mL). NaH (60% oil suspension, 29 mg, 0.735 mmol) was added at rt under nitrogen and stirred for 1 h. Benzylbromide (0.035 mL, 0.294 mmol) was added and stirring continued for 18 h under the same conditions. After this time, the solution was diluted with ethyl acetate and washed with 10% aq. sodium carbonate (2×), dried with magnesium sulfate, and concentrated in vacuo. Purification was done via silica gel flash chromatography (25 g silica, 80% EtOAc/hexanes.) The residue was dissolved in DCM, and rapid solvent removal afforded the title compound as a white powder. (Yield: 56 mg, 0.112 mmol, 72%) 1H NMR (400 MHz, CDCl3) 7.69, 7.33-6.99, 5.47, 4.56, 4.38, 4.11, 3.39-3.36, 2.94-2.82, 2.53-2.47, 1.75, 1.39