Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][NH:22][CH3:23])[C@@H:17]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38].CCN(C(C)C)C(C)C>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][N:22]([CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH3:23])[C@@H:17]2[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:8]=1
Reactant: COC(=O)CCCCl
Reactant: CNC[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CCCN(C)C[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 65 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((methylamino)methyl)cyclopentane from Example 18, Step B in 1 mL of acetonitrile was added 0.019 mL of methyl 4-chlorobutyrate and 0.037 mL of DIPEA. The reaction was heated at 50° C. for 48 hours, then an additional 0.038 mL of methyl 4-chlorobutyrate, 0.074 mL of DIPEA and 3 mg of tetrabutylammonium iodide were added and heating continued at 70° C. for 48 hours. The reaction was evaporated under a stream of nitrogen and the residue purified by prep TLC (10% methanol in ethyl acetate) to give 41 mg of title compound and 17 mg of recovered starting material. Mass spec (ESI): 564 (M+1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:17]([CH2:18][OH:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH2:28][CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[C@@H:10]1[F:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:31](Cl)Cl>C1COCC1>[Si:1]([O:8][C@@H:9]1[C@@H:17]([C@@H:18]([OH:19])[CH3:31])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH2:28][CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[C@@H:10]1[F:30])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)O[C@@H]2S1
Reactant: ClCCl
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]([C@H](C)O)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3aR,5R,6R,7S,7aR)-6-(tert-butyldimethylsilyloxy)-7-fluoro-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate (600 mg, 1.3 mmol) in DCM (30 mL) was added DMP (806 mg, 1.9 mmol) at 0° C. After stirring at room temperature for 2 h, the reaction was quenched with mixed saturated aqueous NaHCO3 (20 mL) and Na2S2O3 (20 mL). The resulting solution was extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude aldehyde. The aldehyde was dissolved in THF (30 mL), treated with MeMgC1 (3 M in THF, 1.1 mL, 3.3 mmol) at 0° C.˜25° C. for 3 h. The reaction was then quenched with H2O (50 mL) and extracted with EtOAc (3×40 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by a silica gel column, eluted with 3%-30% EtOAc in petroleum ether to give tert-butyl (3aR,5R,6R,7S,7aR)-6-(tert-butyldimethylsilyloxy)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate as a yellow oil (355 mg, 57% of 2 steps). (ES, m/z) [M+H]+ 479.0; 1H NMR (300 MHz, CDCl3) δ 6.20-6.14 (m, 1H), 4.95-4.65 (m, 1H), 4.44-4.25 (m, 2H), 4.08-3.79 (m, 4H), 1.51 (s, 9H), 1.25-1.14 (m, 6H), 0.87 (s, 9H), 0.12-0.06 (m, 6H).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH2:20])=[S:19])=[CH:16][C:3]1=2.[CH2:21](I)[CH3:22]>CS(C)=O>[CH2:21]([S:19][C:18](=[NH:20])[NH:17][C:15]1[CH:14]=[CH:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][C:2](=[O:1])[C:3]=2[CH:16]=1)[CH3:22]
Reactant: CCI
Reactant: NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Solvent: CS(C)=O
Product: CCSC(=N)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
To a solution of (11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-2-yl)-thiourea (Example 9, 100 mg, 0.35 mmol) in DMSO was added ethyl iodide (28.2 μL, 0.35 mmol). The mixture was stirred at room temperature for 48 hr. DMSO was removed under vacuum and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate, filtered and the solvent evaporated to give a yellow semi-solid which was chromatographed on silica gel (10% methanol/90% ethyl acetate) to give a yellow solid (109 mg, 55%). H1 NMR (DMSO d6) δ: 8.96 (s, 1H), 7.34 (s, 1H), 7.09-7.03 (m, 2H), 6.99-6.93 (m, 4H), 6.88-6.86 (m, 3H), 3.0-2.95 (q, 1H, J=7), 1.30-1.27 (t, 3H, J=7), MS (ES): MH+ 313.2.
Reaction SMILES: [Mg].[CH:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.[Ru:7](Cl)(Cl)Cl>C(O)C>[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[Ru+2:7]
Reactant: C1=CCC=C1
Reactant: Cl[Ru](Cl)Cl
Agent: [Mg]
Solvent: CCO
Product: [Ru+2]
Product: c1cc[cH-]c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A magnesium slurry was produced by adding 45.62 g of minus 100 (−100) mesh magnesium powder (made by READE) (1.88 moles, 3 equivalents) slowly to a 5 liter vessel containing 1.2L of ethanol (Filmex) at room temperature (25° C.). 323.00 g of 76.8% pure cyclopentadiene (3.75 moles) at a temperature of about −50° C. was added to the magnesium slurry, which was at room temperature, through an addition funnel. To this, a 0.35M solution of RuCl3*1.8H2O in ethanol (Filmex) (0.625 moles in 1.8L of ethanol) was added over a 2.5 hour time period, via addition funnel, between −10° C. and 10° C. The slurry turned sequentially from a grey color to brown to green to blue, and then back to grey/brown as each addition of ruthenium trichloride was made. The mixture was then stirred at a temperature of from 5° C. to 10° C. for 3 hours, and was then stirred out to room temperature overnight. The ethanol was then distilled off under rough pump, and about three to four liters of toluene was added back. The distillation was switched from rough pump to atmospheric pressure and was continued until a pot temperature of 110° C. was reached. The yellow solution was hot filtered (100° C.) through a cake of Celite® that had been washed with hot toluene (100° C.). The filtrate was concentrated by distillation until the yellow solution reached a volume of 650 mL. The yellow product crystallized out of the toluene solution as it cooled to room temperature. The yellow slurry was further cooled in a dry ice/acetone bath, and the light yellow crystalline solids were filtered on to a Buchner funnel, washed with 100 mL of hexane, and pumped dry giving 134.3 g of ruthenocene (93% yield from first crop).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]([NH2:24])=O)[CH:19]=[N:18]2)=[CH:13][CH:12]=1.S(Cl)(Cl)=O.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([C:22]#[N:24])[CH:19]=[N:18]2)=[CH:13][CH:12]=1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(N)=O)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C#N)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxamide obtained in Example 2-(2) (0.466 g) in N,N-dimethylformamide (5.0 mL), thionyl chloride (1.0 mL) was added dropwise under ice cooling and stirred at 0° C. for 30 minutes. The reaction mixture was adjusted to pH 8 by addition of water and saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=1:1), and the resulting crystal was washed with hexane:diisopropyl ether (1:1) to give the titled compound (0.253 g) as a colorless solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:25]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Brc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4ccc(Br)cc4C3)c(F)cc2c1=O
Yield: 35.5 %

Procedure:
142 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 150 mg of 5-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 82 mg of the target compound.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][N:12]=1>C(O)C>[Br-:1].[C:4]([C:3]1[CH2:10][C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][N+:12]=2[CH:2]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cc1ncnc2ccccc12
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)C1=C[n+]2cnc3ccccc3c2C1
Product: [Br-]

Procedure:
A solution of ethyl bromopyruvate (32.76 g, 0.172 m) and 4-methylquinazoline (15.61g, 0.109 m) in dry ethanol (400 ml) was heated at reflux for 16 hours during which time a yellow precipitate formed. The reaction mixture was cooled and the solid filtered and dried to yield crude product. Crystallization from MeOH afforded the product as a yellow solid; m.p. 274°-275° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1.O=P(Cl)(Cl)[Cl:14]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([Cl:14])=[N:4][CH:3]=1
Reactant: CCOc1cc(Br)c[n+]([O-])c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(Br)cnc1Cl
Temperature: 45 °C
Yield: 33.3 %

Procedure:
To a solution of 3-bromo-5-ethoxypyridine 1-oxide (40 g, 183 mmol) in DCM (200 mL) at 0° C. was slowly added POCl3 (159 mL, 1701 mmol) over 30 min. Then the resulting solution was warmed to 45° C. for 15 h. The mixture was concentrated and extracted with DCM (2×200 mL), dried over Na2SO4 and concentrated to give 5-bromo-2-chloro-3-ethoxypyridine (30 g, 60.9 mmol, 33.2% yield): 1H NMR (400 MHz, CD3OD) δ 8.00-7.99 (d, J=2.0 Hz, 1H), 7.65-7.64 (d, J=2.0 Hz, 1H), 4.17-4.12 (m, 2H), 1.44 (t, J=7.0 Hz, 2H); ES-LCMS m/z 235 (M+H).
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][C:5]([C:7]1[S:11][CH:10]=[N:9][CH:8]=1)=[O:6].O>CO>[Br:3][CH2:4][CH:5]([C:7]1[S:11][CH:10]=[N:9][CH:8]=1)[OH:6]
Reactant: O=C(CBr)c1cncs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(CBr)c1cncs1
Reaction time: 0.75 h
Yield: 62.5 %

Procedure:
Sodium borohydride (38 mg, 1.0 mmol) was added in one portion to a solution of 207 mg (1.0 mmol) of the product from Example 3 in 2 mL of methanol at 0° C. After stirring for 0.75 h, water was added and the mixture extracted three times with diethyl ether. The combined organic phase was washed with brine, dried(MgSO4) and the solvent removed in vacuo. Flash chromatography (silica gel, 30-40% ethyl acetate-hexanes) afforded 130 mg (62%) of the title compound as a colorless oil: 1H NMR (400 MHz, CDCl3) δ8.78 (s, 1H), 7.83 (s, 1H), 5.28-5.24 (m, 1H), 3.70 (dd, 1H, J=10.6, 3.9 Hz), 3.61 (dd, 1H, J=10.6, 7.9 Hz), 2.95 (d, 1H, J=4.3 Hz).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:15]([N:8]1[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccccc1
Temperature: 0 °C
Yield: 48.2 %

Procedure:
In 150 ml of dimethylformamide, there were stirred 206.5 g of 2-phenyl-4-chloro-5-formylimidazole, 133 g of benzyl chloride and 103.5 g of anhydrous potassium carbonate at 110°-120° C. for an hour. The reaction mixture was poured in ice-water and the resulting precipitate was recovered by filtration and recrystallized from acetonitrile twice. By the above procedure was obtained 143 g of 1-benzyl-2-phenyl-4-chloro-5-formylimidazole as colorless needles, m.p. 117°-118° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:3]=1.C(O[BH-](O[C:31](=O)[CH3:32])OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].Cl[CH2:41][CH2:42]Cl>>[NH:3]1[C:41]2[C:42](=[CH:5][CH:4]=[CH:9][C:31]=2[CH2:32][N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:16][CH2:17]2)[CH:1]=[CH:2]1
Reactant: ClCCCl
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc2c(OCCN3CCNCC3)cccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc2c(OCCN3CCN(Cc4cccc5cc[nH]c45)CC3)cccc2n1
Temperature: 20 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
A mixture of 2-methyl-5-(2-piperazin-1-ylethoxy)quinoline (0.04 g, 0.15 mmol) and indole-7-carboxyaldehyde (0.023 g, 0.15 mmol) in 1,2-dichloroethane (2.5 mL) was treated with sodium triacetoxyborohydride (50 mg, 0.24 mmol) and stirred at 20° C. under an atmosphere of argon for 24 h. The mixture was then treated with saturated aqueous NaHCO3 (20 mL) and the organic layer separated and purified directly by chromatography on silica (ethyl acetate to 10% methanol/ethyl acetate), to afford the title compound (0.042 g, 71%) as a solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:17]=[C:18]([P:22](Cl)(Cl)=[O:23])[CH:19]=[CH:20][CH:21]=1>>[CH3:15][C:16]1[CH:17]=[C:18]([P:22]2(=[O:23])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc(P(=O)(Cl)Cl)c1
Reactant: c1ccc(CNc2ccccc2)cc1
Product: Cc1cccc(P2(=O)c3ccccc3CN2c2ccccc2)c1
Yield: 26 %

Procedure:
The procedure of Example 38 was employed utilizing N-benzylaniline and 3-methylphenyl phosphonic dichloride to yield 1-(3-methylphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.5 g, 26% yield) as a white solid having a melting point of 155°-156° C., and the following analysis:
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24]>CC(O)=O>[Br-:13].[CH3:9][N:8]1[CH2:10][CH2:11][CH2:12][C@H:7]1[C:5]1[CH:6]=[N+:1]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14])[CH:2]=[CH:3][CH:4]=1
Reactant: CN1CCC[C@H]1c1cccnc1
Reactant: C=CCCCCCCCCCBr
Solvent: CC(=O)O
Product: C=CCCCCCCCCC[n+]1cccc([C@@H]2CCCN2C)c1
Product: [Br-]
Yield: 64.7 %

Procedure:
To a stirred solution of (S)-nicotine (0.14 g, 0.86 mmol) in AcOH (4 ml) was added 11-bromo-undec-1-ene (0.50 g, 2.1 mmol). The mixture was heated at reflux for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 0.22 g (67%) of (S)-3-(1-methyl-pyrrolidin-2-yl)-1-undec-10-enyl-pyridinium bromide (NUNB-10e) as a brown oil. 1H NMR (300 Mz, CDCl3) δ 9.61 (1H, d, J=5.7 Hz), 9.22 (1H, s), 8.40 (1H, d, J=8.1 Hz), 8.08 (1H, dd, J=8.1, 6.0 Hz), 5.77 (1H, m), 4.85–5.10 (4H, m), 3.54 (1H, t, J=8.1 Hz), 3.24 (1H, m), 2.43 (2H, m), 2.23 (3H, s), 1.80–2.15 (6H, m), 1.63 (1H, m), 1.10–1.44 (12H, m); 13C NMR (75 MHz, CDCl3) δ 146.43, 144.21, 143.65, 143.09, 139.05, 128.44, 114.16, 66.97, 62.02, 56.82, 40.62, 35.99, 33.88, 32.24, 29.44×2, 29.18×2, 28.98, 29.26, 23.33.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[S:26][CH:27]=[N:28][N:29]=1>>[S:26]1[CH:27]=[N:28][N:29]=[C:25]1[NH:24][C:1]([C:4]12[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]1)[CH2:6][CH2:5]2)=[O:3]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1nncs1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nncs3)(CC1)CC2
Yield: 33.3 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-1,3,4-thiadiazole (34.4 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(1,3,4-thiadiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (20.9 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9](C2C=CC(F)=CC=2)=[N:8][NH:7][N:6]=1)=[O:4].[H-].[Na+].O.[CH2:20]1COCC1>>[CH3:1][O:2][C:3]([C:5]1[NH:6][NH:7][N:8]([CH3:20])[CH:9]=1)=[O:4]
Reactant: C1CCOC1
Reactant: COC(=O)c1n[nH]nc1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C1=CN(C)NN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
5-(4-Fluoro-phenyl)-2H-[1,2,3]triazole-4-carboxylic acid methyl ester (2.21 g, 10 mmol) in THF (10 ml) was added drop-wise to an ice-cooled slurry of sodium hydride (0.42 g, 60% dispersion in mineral oil, 10 mmol) in TEF (45 ml), under argon. After stirring at room temperature for 1 h, the reaction mixture was heated at 80° C. for 16 h. Water was added to the cooled mixture and the product was extracted with diethyl ether (2×). The combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 10-50% ethyl acetate-pentane) afforded 5-4-Fluoro-phenyl)-1-methyl-2H-[1,2,3]triazole4-carboxylic acid methyl ester (763 mg, 33%) and the title compound (943 mg, 40%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2].[CH3:13][C:14](=[N:18]O)[C:15](=O)[CH3:16].[ClH:20].C(OCC)(=O)C>>[Cl:20][CH2:13][C:14]1[N:18]=[C:1]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[O:2][C:15]=1[CH3:16]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: Cl
Reactant: CC(=O)C(C)=NO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nc(CCl)c(C)o2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 55 %

Procedure:
A mixture of methyl 3-formylbenzoate (11.10 g), 2,3-butanedione-2-oxime (6.84 g) and 4N hydrogenchloride-ethyl acetate solution (100 mL) was stirred at room temperature for 4 days. The reaction mixture was concentrated, and the obtained crystals were washed with diethyl ether. Tetrahydrofuran (150 mL) was added to the crystals and thionyl chloride (12.06 g) was further added. The mixture was heated under reflux for 3 hrs. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzoate as colorless crystals (9.88 g, 55%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 119-120° C.
Reaction SMILES: N#N.C[Si](C)(C)[O:5][C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]=1.[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CC(=O)OCC>C(#N)C>[F:22][CH:11]1[C:6](=[O:5])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: N#N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (5.00 g, 18.40 mmol) in dry acetonitrile (25 mL) was added Selectfluor® (7.55 g, 20.3 mmol) at rt. The reaction mixture was stirred at rt for 2 h then poured into EA and successively washed with aq. 1% NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (hexanes/EA, 4:1) to afford the title compound as a pale yellow solid. LC-MS-conditions 08: tR=0.55 min; [M-CH3+H]+=203.23; TLC: rf (hexanes/EA, 4:1)=0.17.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH2:9]([OH:11])[CH3:10]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][O:11][CH:9]1[CH2:3][CH2:4][O:6][CH2:7][CH2:10]1)[CH3:8]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCO
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COC1CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of tetrahydro-4H-pyran-4-one (1.0 g, 10.0 mmol) in cold (0° C.) THF is added 1.0M lithium aluminum hydride in THF (5 mL, 5.0 mmol). The reaction mixture is stirred at 0° C. for 15 min. followed by the sequential addition of water (0.190 mL), 5M sodium hydroxide (0.190 mL), and water (0.190 mL) and Et2O. The mixture is filtered, and the filtrate is evaporated to give tetrahydro-4H-pyran-4-ol, which is dissolved in dichloromethane (30 mL). To the solution is added rhodium (II) acetate dimer (44 mg) followed by ethyl diazoacetate (1.25 g, 11.0 mmol). The reaction mixture is stirred at RT for 40 min. The reaction mixture is diluted with ethanol, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 1.67 g of the product 409. 1H NMR (CDCl3) δ 4.21 (q, 2H), 4.11 (s, 2H), 3.95 (dt, 2H), 3.59 (m, 1H), 3.42 (dt, 2H), 1.91 (m, 2H), 1.62 (m, 2H), 1.28 (t, 3H); MS: m/z 189 (M++1).