Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[O:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(NC(C)C)(C)C>CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[O:7][C:6]3[C:2]([C:25]#[C:24][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:3][S:4][C:5]=3[C:10](=[O:11])[CH:9]=2)[CH2:13][CH2:14]1
Reactant: C#Cc1ccccc1
Reactant: O=c1cc(N2CCOCC2)oc2c(Br)csc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CO
Product: O=c1cc(N2CCOCC2)oc2c(C#Cc3ccccc3)csc12
Temperature: 100 °C
Yield: 45 %

Procedure:
A microwave vial was charged with a magnetic stirring bar, 3-bromo-5-morpholino-7H-thieno[3,2-b]pyran-7-one (103) (50 mg, 158.1 μmol), phenylacetylene (32.0 mg, 316.2 μmol), trans-dichlorobis(triphenylphosphine)palladium (II) (5.6 mg, 7.9 μmol), copper (I) iodide (1.6 mg, 7.9 μmol) and diisopropylamine (1.0 mL). The mixture was magnetically stirred and heated via microwave irradiation to 100° C. for 20 minutes. The mixture was cooled to room temperature, and then concentrated in vacuo resulting in a brown solid. The solid was dissolved in methanol (1.0 mL) and loaded onto Isolute functionalized silica column (PE-AX/SCX-2). The column was washed with methanol and 7N methanolic ammonia. The methanolic ammonia fractions were combined and concentrated in vacuo. The resulting solid was purified using preparative high-pressure liquid chromatography to give 5-morpholino-3-(phenylethynyl)-7H-thieno[3,2-b]pyran-7-one (31) (24.0 mg, 71.1 μmol) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH:9]2[OH:24])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH:9]2[O:24][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CCCC1CN(C(=O)OC(C)(C)C)CC(O)C1c1ccc(Cl)cc1
Reactant: COc1ccc(CCl)cc1
Product: CCCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc(OC)cc2)C1c1ccc(Cl)cc1

Procedure:
In an analogous manner to that described in Example 62(h), by alkylating tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-hydroxy-5-propyl-piperidine-1-carboxylate with 4-methoxybenzyl chloride there was obtained tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-(4-methoxy-benzyloxy)-5-propyl-piperidine-1-carboxylate as a colourless solid, MS: 416 (M-C4H9)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([OH:39])=O)=[N:35][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:37]([C:34]2[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][N:35]=2)=[O:39])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)c1ccc(Cl)cn1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 5-chloro-pyridine-2-carboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 5-chloro-2-pyridinecarboxylic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 577.2 [M]+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:33]([O:37][C:38]([NH:40][C@H:41]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:52][C:49]1[CH:50]=[CH:51][C:46]([CH2:45][C@@H:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])[C:42]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][N:25]=[C:26]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:19]=34)[CH2:13][CH2:14]2)=[O:43])=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: OCC(O)COc1n[nH]c2nccc(N3CCNCC3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccnc3[nH]nc(OCC(O)CO)c23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.0514 mL, 0.295 mmol) was added to 3-(4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)propane-1,2-diol dihydrochloride (0.030 g, 0.0737 mmol, see Example 7), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.022 g, 0.074 mmol) and TBTU (0.0284 g, 0.0885 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and a LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes. Ether (20 mL) was then added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of solvent, the resulting residue was purified by chromatography (ethyl acetate:MeOH, 20:1) to give tert-butyl(2R)-3-(4-chlorophenyl)-1-(4-(3-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (2R)-2-amino-3-(4-chlorophenyl)-1-(4-(3-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.010 g, 25%). MS APCI (+) m/z 475.2 detected.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCSCc1ccccn1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NCCSCc1ccccn1)c1ccccc1

Procedure:
A solution of 2-[(2-aminoethyl)thiomethyl]pyridine (6.0 g.) and benzoyl isothiocyanate (6.0 g.) in chloroform (150 ml.) is heated under reflux for one hour and concentrated to give N-benzoyl-N'-[2-(2-pyridylmethylthio)ethyl]thiourea.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5]([O-:7])=[O:6])([CH3:3])[CH3:2].[K+].[F:16][CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1.O>CN(C)C=O>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5]([O:7][CH:17]([F:16])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(C(=O)[O-])c1ccc(Cl)cc1
Reactant: FC(Br)c1cccc(Oc2ccccc2)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(C(=O)OC(F)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
A mixture of potassium α-isopropyl-4-chlorophenylacetate (0.91 g) and α-fluoro-3-phenoxy benzyl bromide (1.06 g) in dimethylformamide (10 ml) was stirred at ambient temperature over a period of 2 hours. The reaction mixture was poured into water and the aqueous solution was extracted with diethyl ether. The ether extract was washed with aqueous sodium carbonate solution and was then dried over anhydrous sodium sulfate. The ether was removed by distillation under reduced pressure and the residue chromatographed over silica gel to give α-fluoro-3-phenoxybenzyl α-isopropyl-4-chlorophenylacetate (0.62 g; 37%) as a colourless oil. The product was characterised by pmr spectroscopy. Chemical shift δppm (solvent CDCl3): 0.69(3H, d, J=6Hz, CH3); 1.05(3H, d of d, J=6Hz and J=2Hz, CH3); 2.34(1H, m, --CH(CH3)2); 3.29 (1H, d, J=10Hz, CH); 7.22(1H, d of d, J=56Hz and J= 2Hz, CHF) and c. 7.24(13H, m, aromatic protons).
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][S:2]1(=[O:13])=[O:12].[OH-].[K+].Cl[CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].CN(C)C=O>CO>[O:20]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][CH2:17][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:1][S:2]1(=[O:12])=[O:13]
Reactant: O=C(CCCl)c1ccccc1
Reactant: O=C1NS(=O)(=O)Cc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCN1C(=O)c2ccccc2CS1(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
1H-2,3-Benzothiazin-4(3H)-one 2,2-dioxide (1 g, 5.08 mmol.) was added to a solution of powdery potassium hydroxide (334 mg, 5.08 mmol.) in methanol (4 mL). The mixture was then stirred at room temperature for 15 min. The solution was placed under reduced pressure to distill the solvent off to dryness. To the dried product were added 3-chloropropiophenone (856 mg, 5.08 mmol.) and dimethylformamide (8 mL). The mixture was heated to 120° C. for 6 hours under stirring. The reaction liquid was placed under reduced pressure to distill the solvent off. To the resulting residue was added water, and it was extracted with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried extract solution was placed under reduced pressure to distill the solvent off. The resulting oil was treated by silica gel column chromatography (chloroform) to give the desired compound (1.13 g, yield 68%) as a white solid.
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[CH2:3][C:4](=[O:6])[CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5]
Reactant: COc1ccccc1SCCC(O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccccc1SCCC=CC(C)=O
Yield: 94.6 %

Procedure:
1.00 Gram of 4-hydroxy-6-(2-methoxyphenylthio)-2-hexanone was dissolved in 100 ml of toluene, and 0.02 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 1 hour with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 0.96 g of 6-(2-methoxyphenylthio)-3-hexen-2-one. (trans : cis =6.6 : 1) (purity: 91.9%). The yield was 94.6%.
Reaction SMILES: [CH:1]1([NH:8][CH:9]([P:18](=[O:25])([O:22]CC)[O:19]CC)[P:10](=[O:17])([O:14]CC)[O:11]CC)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.CC(C)=O>Cl>[CH:1]1([NH:8][CH:9]([P:18](=[O:19])([OH:22])[OH:25])[P:10](=[O:11])([OH:14])[OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOP(=O)(OCC)C(NC1CCCCCC1)P(=O)(OCC)OCC
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: O=P(O)(O)C(NC1CCCCCC1)P(=O)(O)O
Yield: 86.9 %

Procedure:
4.0 g of tetraethyl (cycloheptylamino)methylenebis(phosphonate) was dissolved in 40 ml of concentrated hydrochloric acid and heated under reflux for 2.5 hours. After cooling, the reaction solution was concentrated under reduced pressure to eliminate hydrochloric acid. Then, 30 ml of purified water was added to the residue and the mixture was again concentrated under reduced pressure. The oily product thus obtained was solidified by methanol and acetone and subject to the filtration. The residue was washed with acetone to give 2.5 g of (cycloheptylamino)methylenebis(phosphonic acid) as a white solid.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][CH2:17][C@@H:18]1[CH2:20][C@@H:19]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][N:28]=2)[CH2:23][CH2:22]1.[N:37]1([C:41](=[O:51])[CH2:42][C:43]2[CH:48]=[CH:47][C:46](O)=[CH:45][C:44]=2[F:50])[CH2:40][CH2:39][CH2:38]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N:37]1([C:41](=[O:51])[CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:15][CH2:16][CH2:17][C@@H:18]3[CH2:20][C@@H:19]3[CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:34])[CH3:35])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)=[CH:45][C:44]=2[F:50])[CH2:40][CH2:39][CH2:38]1
Reactant: O=C(Cc1ccc(O)cc1F)N1CCC1
Reactant: CC(C)(O)c1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(O)c1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
DIAD (95 μL, 0.491 mmol) was slowly added to a solution of 2-(2-{4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidin-1-yl}pyrimidin-5-yl)propan-2-ol (100 mg, 0.327 mmol), 1-(azetidin-1-yl)-2-(2-fluoro-4-hydroxyphenyl)ethanone (72 mg, 0.344 mmol), and triphenylphosphine (129 mg, 0.491 mmol) in DCM (1.6 mL). The mixture was stirred at rt for 3 hrs. The mixture was diluted with DCM (8 mL) and washed with 2 N NaOH solution (5 mL×1). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC using 2×2000 micron silica preparative TLC plates (uv 254 active) which were developed using 100% EtOAc. The desired band (Rf=0.5 @ 100% EtOAc) was collected and extracted to give the title compound. 1H NMR (500 MHz, CD3CN) δ 8.41 (s, 2H), 7.17 (t, 1H), 6.72 (t, 2H), 4.68 (t, 2H), 4.19 (t, 2H), 4.06 (m, 2H), 3.91 (t, 211), 3.36 (s, 2H), 2.83 (t, 2H), 2.22 (m, 2H), 2.07 (m, 1H), 1.83 (m, 2H), 1.57 (m, 1H), 1.48 (s, 6H), 1.35-1.10 (m, 3H), 0.91 (m, 1H), 0.60 (m, 2H), −0.05 (m, 111). LC/MS (m/z): 497 (M+H)+, GPR119 Human EC50: 7.5 nM.
Reaction SMILES: C([O:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][C@H:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([CH:20]=[O:21])[CH:18]=[CH:19][C:12]=3[O:11]2)=[CH:7][CH:6]=1)(=O)C>CO.O1CCCC1.[OH-].[Na+]>[CH:20]([C:17]1[CH:18]=[CH:19][C:12]2[O:11][C@@H:10]([CH2:9][C:8]3[CH:22]=[CH:23][C:5]([OH:4])=[CH:6][CH:7]=3)[CH2:15][CH2:14][C:13]=2[CH:16]=1)=[O:21]
Reactant: CC(=O)Oc1ccc(C[C@H]2CCc3cc(C=O)ccc3O2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=Cc1ccc2c(c1)CC[C@H](Cc1ccc(O)cc1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
(R)-(-)-2-(4-Acetoxybenzyl)-3,4-dihydro-6- formyl-2H-benzopyran (15.7 g, 51 mmol) was dissolved in a mixture of methanol (200 ml), tetrahydrofuran (200 ml) and 2M NaOH (200 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, diluted with water (100 ml) and acidified with 10% HCl (250 ml). The aqueous solution was extracted with ethyl acetate (2×500 ml) and the combined organics were washed with water (250 ml), brine (250 ml), and dried (MgSO4). The solvent was removed in vacuo and the residue was crystallized from hexanes/ethyl acetate (3:1) to afford 10.1 g of the title compound, m.p. 134°-135° C.; [α]D -155.2° (c 1.0, MeOH);
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([Si](C)(C)C)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:19]I>O1CCCC1.F[B-](F)(F)F.[Ag+]>[I:19][C:10]1[N:9]=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: II
Reactant: CCCc1c([Si](C)(C)C)nnn1-c1ccccc1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CCCc1c(I)nnn1-c1ccccc1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
1-Phenyl-5-propyl-4-trimethylsilanyl-1H-[1,2,3]-triazole (260 mg) prepared in the above 1) was dissolved in 5.0 ml of tetrahydrofuran, 389 mg of silver tetrafluoroborate and 507 mg of iodine were added thereto and the mixture was stirred at room temperature for one night. The reaction solution was filtered through Celite, a saturated aqueous solution of sodium thiosulfate was added to the filtrate and the solvent was evaporated in vacuo. Water was added to the residue, the mixture was extracted with ethyl acetate and the ethyl acetate layer washed with a saturated saline solution and dried over sodium sulfate. After the solvent was evaporated in vacuo, the residue was separated and purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to give 180 mg of the title compound as a white solid.
Reaction SMILES: [Li]CCCC.CCCCCC.[C:12]([C:14]1([OH:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1)#[CH:13].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:27][CH:26]=1>C1COCC1>[OH:32][C:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[C:13]#[C:12][C:14]1([OH:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: COc1ccc(C(=O)c2cccs2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)(C#CC2(O)CN3CCC2CC3)c2cccs2)cc1
Reaction time: 0.5 h

Procedure:
A 1.6 N solution of BuLi in hexane (1.12 ml, 1.79 mmol) was added dropwise to a solution of 3-ethynyl-1-azabicyclo[2.2.2]octan-3-ol 47 (123 mg, 0.81 mmol) in THF (5 ml) at room temperature. After stirring for 30 minutes, (4-methoxyphenyl)(2-thienyl)methanone (231 mg, 1.06 mmol, commercial) in THF (1 ml) was added slowly. After 2 hours, the reaction was quenched by addition of saturated aqueous NH4Cl solution and diluted with AcOEt. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The yellowish oil was purified by chromatography on silica gel (CH2Cl2/MeOH 85/15) and 3-[3-hydroxy-3-(4-methoxyphenyl)-3-(2-thienyl)-1-propynyl]quinuclidin-3-ol 152 was obtained as a white solid (41 mg, 14%, mixture of diastereomers).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]([F:53])([F:52])[C:32]([NH:34][C@H:35]1[C:41](=O)[CH2:40][CH2:39][N:38]([C:43]2[N:44]([CH3:51])[N:45]=[CH:46][C:47]=2[N+:48]([O-:50])=[O:49])[CH2:37][CH2:36]1)=[O:33]>C(OCC)C.C1COCC1>[F:30][C:31]([F:53])([F:52])[C:32]([NH:34][C@H:35]1[C:41](=[CH:2][O:3][CH3:4])[CH2:40][CH2:39][N:38]([C:43]2[N:44]([CH3:51])[N:45]=[CH:46][C:47]=2[N+:48]([O-:50])=[O:49])[CH2:37][CH2:36]1)=[O:33]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(=O)[C@H](NC(=O)C(F)(F)F)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC=C1CCN(c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)C(F)(F)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (5.59 g, 15.8 mmol) (dried on vacuum overnight before use) was suspended in ethyl ether (65 mL). The suspension was cooled to −15° C. Potassium tert-butoxide (1.0 mol/L) in THF (12.6 mL, 12.6 mmol) was added slowly and the bright orange suspension was stirred at −25° C. to −10° C. for 1 h while the color persisted. 2,2,2-Trifluoro-N-[(4R)-1-(2-methyl-4-nitro-pyrazol-3-yl)-5-oxo-azepan-4-yl]acetamide (1.38 g, 3.95 mmol) was dissolved in THF (12 mL) and added to the ylide at −15° C. The mixture was slowly allowed to warm to room temperature and stirred overnight then quenched with saturated ammonium chloride, and extracted with EA 3×. The combined organic layers were concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to give 2,2,2-trifluoro-N-[(4R)-5-(methoxymethylene)-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]2[N+:10]([O-])=[CH:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N:10]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CNc2cc([N+](=O)[O-])cc[n+]2[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: COc1ccc(CNc2cc([N+](=O)[O-])ccn2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
To a 2 L 3 neck round bottom flask fitted with a mechanical stirrer, was added N-(4-methoxybenzyl)-4-nitropyridin-2-amine 1-oxide (38.72 g, 0.14 mol) and chloroform (580 mL). The reaction mixture was cooled to 0° C. and phosphorus trichloride (36.8 mL, 0.42 mol) was added dropwise. The reaction mixture was allowed to warm to rt and stir overnight. The reaction mixture was filtered and the resulting solid was slurried with hexanes and filtered (repeated several times) to afford N-(4-methoxybenzyl)-4-nitropyridin-2-amine (39.34 g, 102%) as a yellow solid. LCMS: (FA) ES+ 260.3.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]=[CH2:6].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]>C1COCC1.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]([OH:20])([CH2:6][CH2:5][CH:4]=[CH2:3])[C:16]([F:19])([F:17])[F:18]
Reactant: C=CCCBr
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a 300 mL oven dried 3 necked, round bottomed flask with a stirring bar, argon inlet, addition funnel and a reflux condenser was added magnesium (turnings, 3.03 g, 125 mmol) and dry THF (75 mL). To this well stirred mixture was added 4-bromo-1-butene (12.0 mL, 118.21 mmol) at such a rate as to maintain a gentle reflux. When the addition was complete, the mixture was aged 30 min then cooled to 0° C. in an ice bath. To this well stirred solution was added a solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (5.00 g, 22.36 mmol) in THF (35 mL), dropwise over 30 min. The cooling bath was allowed to expire and the mixture was stirred 20 h at ambient temperature. The reaction was diluted with EtOAc and 10% aqueous citric acid. This mixture was stirred for 4 h. The layers were separated and the organic phase was washed with aqueous NaHCO3 and brine. Drying (MgSO4), filtration, removal of the solvent in vacuo, and chromatography on 300 g of silica gel using 15% EtOAc in hexane as eluantas eluant gave 4.80 g of (+/-) 2-(2-amino-5-chlorophenyl)-1,1,1-trifluoro-5-hexen-2-ol as a yellow solid.