Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1([CH3:22])[O:10][C@@H:9]([C@H:11]2[O:15][C@@H:14]3[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:13]3[C@H:12]2[OH:21])[CH2:8][O:7]1.C(N(CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl>[CH3:5][C:6]1([CH3:22])[O:10][C@@H:9]([C@H:11]2[O:15][C@@H:14]3[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:13]3[C:12]2=[O:21])[CH2:8][O:7]1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)C(=O)[C@H]2O1
Temperature: 25 °C
Yield: 112.6 %

Procedure:
To a stirred solution of DMSO (10.65 mL, 150.1 mmol) in CH2Cl2 (300 mL) at -78° C under argon was added trifluoroaeetie arthydride (16.00 mL, 113.3 mmol) dropwise. The resulting white suspension was stirred at -78° C. for 10 min before a solution of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (20.0 g, 76.7 mmol) in CH2Cl2 (200 mL) was slowly added by cannula. The resulting mixture was stirred at -78° C. for 1 h before triethylamine (30.4 mL, 218 mmol) was slowly added and the reaction mixture allowed to warm to room temperature. Saturated aqueous NH4Cl (100 mL) was added and the organic phase was separated and washed with cold 1M aqueous HCl (2×100 mL), H2O (100 mL), saturated aqueous NaHCO3 (100 mL), H2O (100 mL), and saturated aqueous NaCl (100 mL). The organic phase was dried, filtered and concentrated to give the crude ketone (22.3 g) as a pale yellow oil. This material was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[NH2:13][OH:14]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[N:13]/[OH:14])/[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O/N=C1\CCc2cc(Br)ccc21
Yield: 88.5 %

Procedure:
5-bromo-2,3-dihydro-1H-inden-1-one (25 g, 118 mmol) and hydroxylamine hydrochloride (12.35 g, 178 mmol) were heated in Ethanol (150 mL) for 5 hours with stirring. The solvent was evaporated in vacuo and remaining solid partitioned between H2O and EtOAc. The organic layer was separated and washed with brine (2×), dried on Na2SO4 and solvent evaporated in vacuo to afford the title compound as a light brown solid (23.6 g, 87%). MS (ESI): m/z [M+H]+ 227.0
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.O>CN(C=O)C>[I:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cccc2[nH]cnc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(I)cccc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 78.2 %

Procedure:
To a stirring solution of 4-iodo-1H-benzimidazole (1.00 g, 4.1 mmol) in DMF (12 mL) was added sodium hydride (180 mg of a 60% dispersion in mineral oil; 4.5 mmol), and the resulting mixture was stirred at room temperature under nitrogen for 50 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (870 μL, 4.92 mmol) was added dropwise over 5 minutes at room temperature, then the mixture was stirred overnight. Water (50 mL) was added, and the mixture was washed with ethyl acetate (3×25 mL). The combined organic layers were washed with water (2×30 mL), then with saturated sodium chloride solution (30 mL), then dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 0 to 20% ethyl acetate in dichloromethane, affording the product as a white solid (1.20 g, 78%). 1H NMR (400 MHz, CDCl3): δ 8.05 (1H, s), 7.74 (1H, dd, J=0.6, 7.5 Hz), 7.52 (1H, t, J=4.2 Hz), 7.09 (1H, t, J=7.9 Hz), 5.51 (2H, s), 3.50 (2H, t, J=8.2 Hz), 0.90 (2H, dd, J=8.3, 16.4 Hz), −0.05 (9H, s); m/z (ES+) 375 [MH+].
Reaction SMILES: C(N)CC1C=CC=CC=1.C(Cl)(=O)CC.[CH2:15]([CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1)[CH3:16].C1C2C(=CC=CC=2)C=CN=1.[Cl:37][CH:38]([Cl:42])[C:39](Cl)=[O:40]>C1(C)C=CC=CC=1>[Cl:37][CH:38]([Cl:42])[C:39]([N:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]1[CH2:15][CH3:16])=[O:40]
Reactant: CCC1NCCc2ccccc21
Reactant: O=C(Cl)C(Cl)Cl
Agent: CCC(=O)Cl
Agent: NCCc1ccccc1
Solvent: c1ccc2cnccc2c1
Solvent: Cc1ccccc1
Product: CCC1c2ccccc2CCN1C(=O)C(Cl)Cl

Procedure:
By procedures described in Example 1 (Method A), phenethylamine and propionyl chloride were converted to 1-ethyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 2.5 g of this isoquinoline compound in 50 ml toluene. With this mixture stirred, 1.5 ml dichloroacetyl chloride was added dropwise to the mixture. The mixture was refluxed until a clear solution appeared. The mixture was stripped of solvent and subjected to Kugelrohr distillation (150° C. @ 0.25 mm Hg) to provide 2.7 g of product having the elemental analysis reported in Table I.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([S:20][CH2:21][CH3:22])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:28].CCCCCC>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([S:20]([CH2:21][CH3:22])=[O:28])[N:3]=1
Reactant: CCSc1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCS(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1

Procedure:
A stirred solution of (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (7.4 g, 23 mmol, Example 102) in dichloromethane (150 mL) at 0° C. was treated portionwise with 74% meta-chloroperoxybenzoic acid (6 g, 26 mmol) over about 30 minutes. The cold reaction mixture was quenched with 25 ml of 10% aqueous sodium thiosulfate solution and the layers separated. The organic layer was washed once with 10% aqueous sodium thiosulfate solution, twice with saturated aqueous sodium carbonate solution, once with brine, dried (Na2SO4) and evaporated. Trituration of the residue with hexane provided a quantitative yield of (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone as a colorless solid, mp 165 dec. Mass Spectrum (LR-ES) (M+H)+: 342.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:17]([OH:20])[CH2:18][OH:19].CCCCCC.C(OCC)(=O)C>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:19][CH2:18][CH2:17][OH:20])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(OCCO)cc1
Temperature: 80 °C

Procedure:
In a 50 mL, 3-neck RBF equipped with a magnetic stirrer, reflux condenser, and thermo pocket were sequentially charged 4-fluoro nitrobenzene (2.00 g), Cs2CO3 (9.21 g) and ethylene glycol (20 mL). The reaction mixture was heated to 80° C. for 30 minutes. The reaction was monitored on TLC using Hexane:Ethyl acetate (7:3) as mobile phase. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into cold water. Solid precipitate was filtered and washed with water. Solid was dried under reduced pressure at 45° C. for 1 hr. 2.70 g of 2-(4-nitrophenoxy)ethanol was obtained as a solid and was taken for the next step without further purification.
Reaction SMILES: CC1[N:3]([C:8]2[CH:12]=[C:11]([I:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[N:9]=2)C(C)=CC=1.[Cl-].O[NH3+].C(N(CC)CC)C>CCCCCC.C(OCC)(=O)C>[F:20][C:16]1[CH:15]=[C:14]([N:10]2[C:11]([I:13])=[CH:12][C:8]([NH2:3])=[N:9]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(C)n1-c1cc(I)n(-c2cccc(F)c2)n1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: Nc1cc(I)n(-c2cccc(F)c2)n1
Temperature: 95 °C
Reaction time: 17 h
Yield: 89.4 %

Procedure:
To a solution of 3-(2,5-dimethylpyrrol-1-yl)-1-(3-fluorophenyl)-5-iodo-1H-pyrazole (4.5 g) in ethanol/water (2/1, 81 ml) were sequentially added hydroxylammonium chloride (16.3 g) and triethylamine (3.3 ml), and the mixture was stirred at 95° C. for 17 hours. This reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the resulting residue was added an 8M aqueous solution of sodium hydroxide, and the mixture was extracted with ethyl acetate. This organic layer was sequentially washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the titled compound (3.2 g).
Reaction SMILES: C(NC1CC2C(=CC=CC=2)C1)(=O)C.ClS(O)(=O)=O.C([NH:22][CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([S:32](=[O:35])(=[O:34])[NH2:33])[CH:29]=2)[CH2:24]1)(=O)C.N>C1COCC1.O>[S:32]([C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH:23]([NH2:22])[CH2:31]2)(=[O:34])(=[O:35])[NH2:33]
Reactant: CC(=O)NC1Cc2ccc(S(N)(=O)=O)cc2C1
Agent: CC(=O)NC1Cc2ccccc2C1
Agent: N
Agent: O=S(=O)(O)Cl
Solvent: O
Solvent: C1CCOC1
Product: NC1Cc2ccc(S(N)(=O)=O)cc2C1
Temperature: 25 °C

Procedure:
1.75 g. of N-acetyl-2-indanamine (0.01 mole) was added to 20 g. of chlorosulfonic acid (0.18 mole), stirred at -60° C. and allowed to warm to 25° C. The mixture was stirred until the reaction was complete, poured into cold water and extracted with ethyl acetate. Evaporation gave the crude N-acetyl-5-chlorosulfonyl-2-indanamine which was converted to N-acetyl-5-sulfamyl-2-indanamine with ammonia in THF. The N-acetyl sulfonamide was purified by recrystallization from water, m.p. 237°-239° C. and hydrolyzed in refluxing 10% hydrochloric acid to give 5-sulfamyl-2-indanamine which was recrystallized from methanol-ether, m.p. 261°-264° C.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.CS(O[C@H:29]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[C:30]1=[O:42])(=O)=O>CC#N>[F:1][C@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:29]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[C:30]2=[O:42])[CH2:3]1
Reactant: Oc1ccc([C@H]2CCNC[C@H]2F)cc1
Reactant: Cc1ccc(CN2CC[C@H](OS(C)(=O)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
To a solution of cis-4-(3-fluoropiperidin-4-yl)phenol (60 mg, 0.31 mmol) in 1.0 mL of CH3CN and DIPEA (0.2 mL, 1.2 mmol) at 80° C. was added a solution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (87 mg, 0.3 mmol) in 0.5 mL of CH3CN over 1.5 h. The mixture was then stirred at 80° C. for 16 h. The mixture was allowed to cool to rt and then concentrated. The residue was purified via silica gel chromatography (4 g of silica) eluting with a gradient of 0-100% EtOAc in hexanes to give a mixture of two diastereomers, which were further separated via chiral HPLC under the following conditions: Chiralcel OD column (21×250 mm, 10μ) eluting with an isocratic mixture of 30% B where solvent A=0.1% diethylamine in n-heptane and solvent B=100% ethanol. The absolute stereochemistry of the 2 products has not been assigned and is shown and named for convenience. The first eluting isomer (Example 112, P-1) was (R)-3-((3S,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (33.8 mg, 0.086 mmol, 28% yield). 1H NMR (500 MHz, methanol-d4) δ 7.21-7.07 (m, 6H), 6.78-6.68 (m, 2H), 4.70 (d, J=48.8 Hz, 1H), 4.41 (dd, J=58.0, 14.5 Hz, 2H), 3.61 (t, J=8.8 Hz, 1H), 3.30-3.03 (m, 5H), 2.77-2.60 (m, 1H), 2.51 (t, J=11.1 Hz, 1H), 2.32 (s, 3H), 2.31-2.15 (m, 2H), 2.01 (dq, J=13.2, 8.4 Hz, 1H), 1.69 (dd, J=13.1, 2.6 Hz, 1H), (M+H)+=383.25. HPLC RT under separation conditions=8.87 min. The second eluting isomer (Example 112, P-2) was (R)-3-((3R,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (35.2 mg, 0.084 mmol, 27.3% yield), 1H NMR (500 MHz, methanol-d4) δ 7.19-7.08 (m, 6H), 6.74 (d, J=8.4 Hz, 2H), 4.66 (d, J=47.9 Hz, 1H), 4.41 (dd, J=53.7, 14.8 Hz, 2H), 3.58 (t, J=8.8 Hz, 1H), 3.42 (t, J=10.8 Hz, 1H), 3.30-3.14 (m, 2H), 3.05-2.88 (m, 2H), 2.79-2.51 (m, 2H), 2.33 (s, 3H), 2.31-2.13 (m, 2H), 2.06-1.90 (m, 1H), 1.67 (d, J=10.8 Hz, 1H), (M+H)+=383.25. HPLC RT under separation conditions=11.97 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]2[CH:56]=[C:57]([CH:59]=[CH:60][CH:61]=2)[NH2:58])[CH:50]=1>CN(C=O)C>[N:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]2[CH:56]=[C:57]([NH:58][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=[CH:60][CH:61]=2)[CH:50]=1
Reactant: Nc1cccc(-c2cccnc2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cccnc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 32.5 %

Procedure:
DIEA (0.028 mL, 0.160 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.030 g, 0.146 mmol) and HATU (0.061 g, 0.160 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyridin-3-ylaniline (0.025 g, 0.146 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 32% yield: LCMS (ESI) m/z 359 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH2:2].C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC1(C)C(C)(C)OB[O:49]1.B(O[O-])=O.[Na+]>C1COCC1>[OH:49][CH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1(C)OBOC1(C)C
Reactant: C=Cc1cc(C(=O)OC)c2ccccc2c1
Agent: O=BO[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(CCO)cc2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl 3-ethenyl-1-naphthalenecarboxylate (1 eq.) from the previous step, [Ir(COD)Cl]2 (0.025 eq.) and DPPB (0.05 eq.) were combined in THF (0.12 M). To this solution was then added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 eq.) and the resulting red solution was stirred at RT for 16 h. Finally, sodium perborate (0.1 M aqueous solution, 2 eq.) was added and the now black biphasic solution was vigorously stirred at RT for another 12 h. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed further with 1 N aq. NaOH, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→1:1 (v/v) EtOAc:Hex) afforded the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].CCOC(C)=O>C1COCC1>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=NOCc1cccc(C=O)n1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1nnnc1C(=NOCc1cccc(CO)n1)c1ccccc1
Yield: 49.7 %

Procedure:
To a stirred solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridine-2-carbaldehyde (0.4 g, 1.24 mmol, 1 eq.) in 100 ml of dry THF, was added sodium triacetoxyborohydride (0.276 mmol, 1.3 mmol, 1.05 eq.) in one portion. The reaction was stirred for 20 hrs, before the addition of 1M aqueous NaOH (100 ml). The mixture was stirred for 15 mins before extraction with EtOAc. The organic phase was dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel to give {6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}methanol (0.2 g, 47% yield) as a colourless gum.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:10])[CH2:2]2.[Br:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30]>C(#N)C>[Br-:27].[F:26][C:22]1[CH:21]=[C:20]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[O:11][C:9]([CH:3]2[CH:4]3[CH2:5][CH2:6][N+:1]([CH2:28][C:29](=[O:30])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([CH2:8][CH2:7]3)[CH2:2]2)=[O:10])[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OC(c1cccc(F)c1)c1cccc(F)c1)C1CN2CCC1CC2
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)C(C(=O)OC(c1cccc(F)c1)c1cccc(F)c1)C2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (95 mg, 0.27 mmol, prepared as in example 4) and 2-bromo-1-phenylethanone (58.2 mg, 0.29 mmol) were dissolved in acetonitrile (5 ml) and stirred at room temperature overnight. The solvent was evaporated, and the resulting residue was purified by flash chromatography (DCM/MeOH=95/5 to 9/1) to obtain 3-((bis(3-fluorophenyl)methoxy)carbonyl)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (110 mg, racemic mixture).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].Cl.[C:16]([C:18]1[CH:35]=[CH:34][C:21]([O:22][CH2:23][CH:24]([NH:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH2:29])[CH3:25])=[CH:20][CH:19]=1)#[N:17].O>C(Cl)Cl>[C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH:24]([NH:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:31])[CH3:32])[NH:29][C:9]([O:11][C:12]([CH3:14])=[CH2:13])=[O:10])[CH3:25])=[CH:34][CH:35]=1)#[N:17]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: C=C(C)OC(=O)N[C@H](C(=O)NC(C)COc1ccc(C#N)cc1)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 22.2 %

Procedure:
0.6 g of N-methylmorpholine, and subsequently 0.4 g of isopropyl chloroformate were added to a solution containing 0.9 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]L-valinamide hydrochloride dissolved in 50 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the dichloromethane layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.23 g of the desired product in the form of colorless grains (yield: 13% ).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH:6]=1.[CH3:15][N+:16]([CH3:18])=[CH2:17].[I-]>CN(C=O)C>[CH3:15][N:16]([CH2:18][C:6]1[N:5]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH:4]=[N:3][C:2]=1[CH3:1])[CH3:17]
Reactant: Cc1cn(-c2ccccc2C#N)cn1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccccc2C#N)c1CN(C)C
Yield: 57 %

Procedure:
As described for example 84b, 2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 5 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 96:4) afforded the title compound as a light yellow oil (yield: 57%). MS: m/e=241.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:25]4[CH:26]=[C:21]([C:18](=[O:20])[CH3:19])[CH:22]=[CH:23][CH:24]=4)=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1
Yield: 95.2 %

Procedure:
This compound was prepared according to a process similar to that described in stage 6.3, by reacting 5 g (16.26 mmol) of 6-bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridine, prepared according to the protocol described in stage 6.1, with 3.46 g (21.13 mmol) of 3-acetylphenylboronic acid, in the presence of a 2M aqueous solution of sodium carbonate (90 ml) and of 0.94 g (0.81 mmol) of tetrakis(triphenylphosphine)palladium in 180 ml of a mixture of acetonitrile and toluene (v/v). 5.37 g of expected product are obtained
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1C[CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C([Li])CCC.CCCCCC.[C:35]1([CH2:41][CH:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH:42]([OH:43])[CH2:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:3]=3)[N:7]([CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:6]=2)=[CH:18][CH:19]=1
Reactant: O=CCc1ccccc1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(Cc1ccccc1)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C1CCCO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
To a solution of 5-bromo-3-(4-fluorophenyl)-1-(tetrahydropyran-2-yl)-1H-indazole (0.50 g, 1.0 mmol) in dried tetrahydrofuran (15 mL) under nitrogen at −78° C. was added dropwise a 1.6 M solution of butyl lithium in hexane (1.1 mL, 1.7 mmol). After stirring for 20 minutes, to the reaction mixture was added phenylacetaldehyde (0.228 g, 1.9 mmol). The reaction mixture was stirred additional 1 hour at −78° C. and the temperature was gradually raised to room temperature. It was quenched with water and extracted with dichloromethane. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide the title compound (0.246 g, 44% yield): 1H NMR (CDCl3) δ 7.86 (m, 2H), 7.80 (d, 1H), 7.09-7.47 (m, 9H), 6.98 (dd, 1H), 5.70 (dd, 1H), 5.07 (t, 1H), 4.08 (m, 1H), 3.65 (m, 1H), 3.06 (d, 1H), 2.67 (m, 2H), 2.11 (m, 2H), 1.75 (m, 3H); ES-MS (m/z) 417 [M+1]+.