Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[O:6]
Reactant: CC(C)OC(=O)[C@@H]1CCCN1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)[C@@H]1CCCN1C(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
A mixture of 1.50 g (8.10 mmol; 1.0 eq) of 2-fluoro-3-nitrobenzoic acid and 16 ml of thionyl chloride was refluxed for 3 hours. The excess thionyl chloride was then concentrated and the residue was co-evaporated twice with toluene. The resulting acid chloride was taken up in 25 ml of dichloromethane. 1.27 g (8.10 mmol; 1.0 eq) of isopropyl (S)-pyrrolidine-2-carboxylate were added to this mixture cooled to 0° C. The reaction medium was stirred at 0° C. for 30 minutes and then at ambient temperature for 2 hours. The reaction medium was diluted and washed with a 1 M hydrochloric acid solution (100 ml) and then with a saturated sodium hydrogen carbonate solution (100 ml). The organic phase was dried over MgSO4, filtered and evaporated. 2.12 g of isopropyl (S)-1-(2-fluoro-3-nitrobenzoyl)pyrrolidine-2-carboxylate were obtained. Yield=81%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11][CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Pd]>[C:20]([C:7]1[CH:8]=[C:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(CC=Cc2ccccc2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CCCc2ccccc2)cc(C(C)(C)C)c1O
Yield: 82.8 %

Procedure:
2,6-Di-t-butyl-4-cinnamylphenol (30 g., prepared as described in Example 2) was catalytically hydrogenated at room temperature and pressure in tetrahydrofuran (100 ml.) in the presence of 5% palladium on charcoal. The reaction was allowed to proceed until uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated to an oil. Distillation of the oil gave the desired compound (25 g.) as an oil, b.p. 195°-200° C. at 10.5 mm. Hg. The nmr spectrum in CDCl3 at 100 MHz exhibited absorbances as follows: a singlet (9 protons) at δ 1.40, a singlet (9 protons) at δ 1.43, a multiplet (2 protons) at δ 1.75-2.10, a multiplet (4 protons) at δ 2.43-2.82, a singlet (1 proton) at δ 5.00, a singlet (2 protons) at δ 6.98, and a multiplet (5 protons) at δ 7.08-7.40.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)[CH3:16])=[C:11]([CH2:31][CH2:32][CH3:33])[N:10]3[N:34]=[CH:35][N:36]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+]>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([CH:15]([C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:34]=[CH:35][N:36]=3)[C:11]=2[CH2:31][CH2:32][CH3:33])[CH3:16])=[CH:18][CH:19]=1)#[N:30]
Reactant: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Reaction time: 0.5 h

Procedure:
To a mixture of 4′-{1-[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile (1.24 g), rhodium(I) acetate (0.34 g) and toluene (20 mL) was added dropwise a solution of ethyl diazoacetate (1.38 g) in toluene (10 mL) at 70° C., and the mixture was stirred at the same temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed 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 oil (0.70 g, 48%).
Reaction SMILES: C1COCC1.[C:6](O)(=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].COCCO[AlH2-]OCCOC.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:6]([OH:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Agent: COCCO[AlH2-]OCCOC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCC/C=C\C/C=C\CCCCCCCCO
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A clean, dry 200 L glass reactor fitted with an argon inlet and thermowell was charged with 60 L of THF and 5.73 Kg (20.4 mol) of linoleic acid. The contents of the reactor were cooled below 0° C. using an acetone-dry ice bath. To this cold solution 13.8 L of Vitride (60% wt/vol) in toluene was added slowly maintaining the internal temperature of the reaction mixture below 0° C. (Note: Initial addition of vitride was exothermic and frothing was observed. The frothing ceased after 15 minutes of addition). The addition of vitride took 3 hr and 45 minutes. After completion of the addition, the reaction mixture was stirred at ambient temperature for 2 hr. An aliquot was taken and quenched with sat. Na2SO4 and the thus obtained crude product was analyzed by TLC for the presence of the starting acid. The TLC showed completion of the reaction and the reaction mixture was again cooled below 0° C. in about 45 minutes. A saturated solution of sodium sulfate (prepared by dissolving 1.1 Kg of sodium sulfate in 1.5 L of water) was slowly added to the reaction mixture over 45 min. After completion of the addition, 25 L of ethyl acetate was added over a period of 30 min with stirring. The obtained reaction mixture was filtered through a celite bed over a period of 45 min and the celite bed was washed with an additional 17 L of ethyl acetate to remove all product from the residue. The combined organics were concentrated under reduced pressure. The residue was dissolved in 15 L of ethyl acetate and the organic layer was washed with water (2×7 L) and dried over sodium sulfate (1.1 Kg). After filtration the organic layer was concentrated under reduced pressure and dried under high vacuum to obtain the product linoleyl alcohol as an oil. Crude yield=5.5 Kg (theoretical yield=5.43 Kg). This product was used without further purification in the next step.
Reaction SMILES: [C:1]([CH2:4][C:5]([NH2:7])=[NH:6])(=[O:3])[NH2:2].Br[CH:9]([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>C(O)C>[NH2:6][C:5]1[NH:7][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([CH3:18])[C:4]=1[C:1](=[O:3])[NH2:2]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: N=C(N)CC(N)=O
Solvent: CCO
Product: Cc1c(-c2ccccc2)[nH]c(N)c1C(N)=O
Yield: 4.9 %

Procedure:
To a solution (20 ml) of carbamoylacetamidine (5.1 g) in ethanol was added a solution of 2-bromopropiophenone (4.0 g) in ethanol dropwise thereto under ice-cooling with stirring and the mixture was then stirred at room temperature overnight. The insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The obtained product was washed with benzene, purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 50% ethyl acetate/n-hexane), and recrystallized from ethyl acetate/diethyl ether to provide the title compound as colorless crystals (0.2 g). m.p. 195-197° C.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:22][C@H:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26]>>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([NH:22][C@H:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:14])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 69.1 %

Procedure:
By using 7.37 g of Boc-Ser(Bzl)-OH and 5.00 g of H-Leu-OEt, and the same procedure as in Reference Example 15 was repeated to obtain 7.53 g (yield: 69.1%) of the above-mentioned objective product.
Reaction SMILES: CS([C:5]1[N:10]=[C:9](/[CH:11]=[C:12]2/[C:13](=[O:26])[N:14](CCC3C=CC=CN=3)[C:15](=[O:17])[S:16]/2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C(OC(=O)[NH:33][CH2:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(C)(C)C>>[NH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:7]2[N:6]=[CH:5][N:10]=[C:9](/[CH:11]=[C:12]3/[C:13](=[O:26])[NH:14][C:15](=[O:17])[S:16]/3)[CH:8]=2)[CH2:37][CH2:36]1
Reactant: CS(=O)(=O)c1nccc(/C=C2\SC(=O)N(CCc3ccccn3)C2=O)n1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Product: NCC1CCN(c2cc(/C=C3\SC(=O)NC3=O)ncn2)CC1

Procedure:
(Z)-5-((6-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure, (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)-3-(2-(pyridin-2-yl)ethyl)thiazolidine-2,4-dione, and tert-butyl(piperidin-4-ylmethyl)carbamate followed by the general de-protection procedure (16 mg, 30.6 mg theoretical, 52.3%). LC-MS m/z 425.5 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][NH2:20]>C1(C)C=CC=CC=1>[CH3:18][N:19]1[N:20]=[C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]1=[O:12]
Reactant: O=C(O)c1ccccc1C(=O)c1ccncc1
Reactant: CNN
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccncc2)c2ccccc2c1=O
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a suspension of 2-(isonicotinoyl)benzoic acid (10.0 g, 44.1 mmol) in toluene (50 mL) was added methyl hydrazine (2.59 mL, 48.6 mmol). The mixture was heated to reflux while collecting water in a Dean-Stark trap for 6 hours. Additional methylhydrazine (2.59 mL) was added and the mixture was heated to reflux for another 5 hours. The reaction mixture was cooled to room temperature and the product was collected by filtration. The product was recrystallized from hot methanol to afford 8.5 g (81%) of 2-methyl-4-(4-pyridyl)-1-(2H)-phthalazinone, m.p. 173°-174 ° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:9]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:5]([NH:8][S:35]([CH3:34])(=[O:37])=[O:36])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)c(Cl)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)c(Cl)cn1
Reaction time: 96 h
Yield: 38 %

Procedure:
To a methylene chloride solution (10.0 ml) of [5-chloro-4-[(2,5-difluorophenyl)-(4-fluorophenylsulfonyl)methyl]pyridin-2-yl]amine (114 mg, 0.276 mmol) was added pyridine (440 μl, 5.5 mmol). To the resulting mixture was added methanesulfonyl chloride (addition of 77 μl once a day for 3 days, 230 μl in total, 3.0 mmol). The resulting mixture was stirred for 4 days in total. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1), followed by crystallization in ether to give the title compound (51 mg, 38%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][N:25]([C:28]3[CH:29]=[CH:30][C:31]4[C:32]5[CH2:42][NH:41][CH2:40][CH2:39][CH2:38][C:33]=5[N:34]([CH3:37])[C:35]=4[CH:36]=3)[C:24](=[O:43])[CH:23]=2)=[N:18][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([N:41]1[CH2:40][CH2:39][CH2:38][C:33]2[N:34]([CH3:37])[C:35]3[CH:36]=[C:28]([N:25]4[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:17]5[CH:16]=[CH:15][C:14]([F:13])=[CH:19][N:18]=5)=[CH:23][C:24]4=[O:43])[CH:29]=[CH:30][C:31]=3[C:32]=2[CH2:42]1)(=[O:10])[CH3:9]
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc31)CNCCC2
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCc2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
Triethylamine (48 μL, 0.34 mmol), DMAP (4.0 mg, 0.034 mmol) and acetyl chloride (18 μL, 0.26 mmol) were added to a solution of 4-((5-fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (78 mg, 0.17 mmol) in CH2Cl2 (10 mL), and the resulting solution was stirred at ambient temperature for 3 h under N2. The resulting solution was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 50:50 over 20 column volumes and held for 1 column volume, then increased to 0:100 over 10 column volumes and held for 12 column volumes) gave the title compound (55 mg, 70%) as an off-white solid: mp 78-83° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=3.0 Hz, 1H), 7.83 (ddd, J=8.5, 8.5, 3.0 Hz, 1H), 7.66-7.49 (m, 3H), 7.39 (dd, J=21.0, 2.0 Hz, 1H), 6.93 (ddd, J=22.5, 8.0, 1.5 Hz, 1H), 6.11 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (dd, J=5.0, 3.0 Hz, 1H), 5.21 (s, 2H), 4.69-4.68 (m, 2H), 3.78-3.75 (m, 2H), 3.67-3.65 (m, 3H), 3.03-2.96 (m, 2H), 2.09-1.90 (m, 5H); ESI MS m/z 461 [M+H]+; HPLC (Method A) 98.7% (AUC), tR=16.0 min.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:31][CH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:25][CH2:26]1
Reactant: OCC1CCNCC1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(CO)CC3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and piperidin-4-ylmethanol (35 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 20-50% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (55 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 8 H) 1.65-1.95 (m, 3 H) 2.96-3.15 (m, 2 H) 3.34 (d, J=6.06 Hz, 2 H) 4.39-4.56 (m, 2 H) 6.35 (d, J=2.02 Hz, 1 H) 7.38 (s, 1 H) 7.60 (d, J=8.59 Hz, 2 H) 8.00 (d, J=8.59 Hz, 2 H) 8.08 (d, J=2.27 Hz, 1 H) 10.87 (s, 1 H). ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl-].[Cl-].[Ca+2].[N-:37]=[N+:38]=[N-:39].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.[Cl-].[Na+].O>[N:37]([C@@H:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C@H:10]1[F:15])=[N+:38]=[N-:39].[C:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](F)C1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](F)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 0.60 g (2.74 mmol) of cis-1-Boc-3-fluoro-4-hydroxypiperidine 3 in 15 mL DCM was added 0.42 g (4.11 mmol) of triethylamine and 37 mg (0.3 mmol) of 4-(N,N-dimethylamino)pyridine (DMAP) at rt. Then a solution of 0.57 g (3.01 mmol) of p-toluenesulfonyl chloride in 2 mL of DCM was added under a dry atmosphere (CaCl2-tube) at rt. After stirring for 15 h at rt, the solution was poured in brine (20 mL) and extracted with DCM (3×25 mL). After drying over MgSO4, filtration and evaporation of the solvent, the crude mixture was used as such in the next step without further purification. The obtained tosylate was dissolved in 5 mL of dry DMSO and 0.36 g (5.48 mmol) of NaN3 was added. The mixture was stirred under N2-atmosphere at 90° C. for 15 h. After cooling, the mixture was poured in brine (10 mL) and extracted with EtOAc. The combined extract were washed with brine, dried over MgSO4, filtered and evaporated in vacuo. trans-4-Azido-1-Boc-3-fluoropiperidine 4 was obtained as a colorless oil in 92% yield from 4-hydroxypiperidine 3 and was sufficiently pure for further use. 1H NMR (CDCl3): δ 1.43 (9H, s); 1.44-1.64 (1H, m); 1.97 (1H, ddd, J=4.3 Hz, 8.4 Hz, 18.0 Hz); 2.99 (1H, ddd, J=3.3 Hz, 10.5 Hz, 13.8 Hz); 3.00-3.15 (2H, m); 3.57-3.68 (1H, m); 3.79 (1H, dt, J=13.8 Hz, J=4.4 Hz); 4.00-4.19 (1H, m); 4.33 (tdd, J=47.9 Hz, J=8.3 Hz, J=4.4 Hz). 19F NMR (CDCl3): δ −188.1 (1F, d(br), J=47.4 Hz). 13C NMR (CDCl3): δ 28.3 (4×), 41.2 (br), 45.5 (br), 61.4 (d, J=20.7 Hz), 80.6, 88.9 (d, J=182.3 Hz), 154.4. IR (ATR, cm−1): ν=2099, 1693, 1417, 1236, 1161, 1141. MS (ES+) m/z (%): 227 (M+H+, 100).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:19][NH2:20])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc(C(=O)NCc2ccccc2)cn1
Yield: 78 %

Procedure:
Combined N-benzyl-6-chloronicotinamide (13 g, 52.8 mmol) and ethanol (60 mL) then added hydrazine hydrate (85%, 30 mL) drop wise at room temperature. After the addition, the solution was heated to reflux overnight. The reaction mixture was then concentrated to remove ethanol and a solid was obtained. The solid was collected by filtration, washed with EtOAc (3×20 mL), and dried under reduced pressure to give the title compound (10 g, 78%) as an off-yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH:5]=[C:6]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=[O:18].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH:5]=[C:6]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=[O:18]
Reactant: COc1ccccc1C=C1N=C(C)N(c2ccccc2)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1=NC(=Cc2ccccc2O)C(=O)N1c1ccccc1
Temperature: -40 °C
Yield: 99.9 %

Procedure:
3,5-Dihydro-5-(2′-methoxybenzylidene)-2-methyl-3-phenylimidazol-4-one (1.85 g) was dissolved in dichloromethane (30 ml) and boron tribromide (2 ml) was added dropwise while stirring the mixture at −40° C. Thereafter, the mixture was stirred under ice-cooling for 1 hr, poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3,5-dihydro-5-(2′-hydroxybenzylidene)-2-methyl-3-phenylimidazol-4-one (1.76 g) as red crystals. The crystals and (S)-glycidyl nosylate (1.63 g) were dissolved in dimethylformamide (20 ml) and potassium carbonate (1.74 g) was added. The mixture was heated at 50° C. for 2 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily product (2.13 g). This oily product and 4-(naphthalen-2-yl)piperidine were dissolved in methanol (20 ml) and refluxed under heating for 2 hr. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.45 g) as an oil.
Reaction SMILES: CN(CC1N=C(OCCCN)C=CC=1)C.NC1C(OC)=NS(=O)N=1.[NH2:25][C:26]1[C:30]([NH:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][N:43]3[CH2:48]CCC[CH2:44]3)[N:37]=2)=[N:29][S:28](=O)[N:27]=1>>[NH2:25][C:26]1[C:30]([NH:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][N:43]([CH3:44])[CH3:48])[N:37]=2)=[N:29][S:28][N:27]=1
Reactant: NC1=NS(=O)N=C1NCCCOc1cccc(CN2CCCCC2)n1
Agent: CN(C)Cc1cccc(OCCCN)n1
Agent: COC1=NS(=O)N=C1N
Product: CN(C)Cc1cccc(OCCCNc2nsnc2N)n1

Procedure:
When a methanolic solution of 3-(6-dimethylaminomethyl-2-pyridyloxy)propylamine [prepared according to published U.K. patent application No. 2,098,988] is reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide according to the general procedure described in U.K. patent application No. 2,067,987 and the resulting 3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole 1-oxide is successively reacted by the general procedure described in Example 1, Step A, and then by either Example 1, Step B, or Example 10, the title compound is thereby produced.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)CCC.[CH2:20]([O:22][C:23](=[O:47])[C@H:24]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42](Br)[CH:41]=2)[CH:34]=1)[NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH3:21].C(OCC)(=O)C>O1CCOCC1>[CH2:20]([O:22][C:23](=[O:47])[C@H:24]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=3)[CH:45]=2)[CH:34]=1)[NH:25][C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])[CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: CCOC(=O)[C@H](Cc1cccc(Oc2cccc(Br)c2)c1)NC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](Cc1cccc(Oc2cccc(-c3ccncc3)c2)c1)NC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 65.6 %

Procedure:
A solution of 4-(tributylstannyl)pyridine (288 mg, 0.782 mmol) in degassed 1,4-dioxane (1 ml) and tetrakis(triphenyl-phosphine)palladium (46 mg, 0.04 mmol) were added in turn to a solution of 3-(3-bromophenoxy)-N-trifluoroacetyl-L-phenylalanine ethyl ester (360 mg, 0.782 mmol) in degassed 1,4-dioxane (6 ml) at room temperature and the mixture was stirred under heating for 8 hrs. After the mixture was cooled to room temperature, ethyl acetate was added thereto and the mixture was washed with saturated sodium fluoride solution, water and brine in turn and then dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1) to give N-trifluoroacetyl-3-[3-(4-pyridyl)phenoxy]-L-phenylalanine ethyl ester (235 mg, 66%) as colorless resinous substance.