Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][NH2:23].[BH4-].[Na+]>CO>[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][NH:23][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2)cn1
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2cnc(C(N)=O)cn2)cc1
Reaction time: 8 h
Yield: 31.2 %

Procedure:
Place 5-(4-formylphenoxy)pyrazine-2-carboxamide (0.150 g, 0.617 mmol), 3-methylbutylamine (0.0537 g, 0.617 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.1 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with 2.0 M NH3 in methanol, ethyl acetate and hexanes to give the title compound (0.0606 g, 31.2%): MS ES+ 315.1 (M+H)+, base peak 228.0 (M−C5H12N)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=8.5 min., 96.4% purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])[C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)(OC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:18]=[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])[C:12]([C:13]3[O:14][C:23]([CH3:24])=[N:16][N:15]=3)=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: CC(C)Nc1cc(Nc2ccc(F)cc2)ncc1C(=O)NN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(C)(OC)OC
Product: Cc1nnc(-c2cnc(Nc3ccc(F)cc3)cc2NC(C)C)o1

Procedure:
A solution of 6-((4-fluorophenyl)amino)-4-(isopropylamino)nicotinohydrazide (91) (100 mg) and PTSA (10 mg) in trimethyl orthoacetate (5 mL) was heated at 100° C., overnight. The reaction mixture was concentrated, diluted with EtOAc. The organic layer was washed with sat. NaHCO3 solution, water and brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by prep. HPLC to afford N2-(4-fluorophenyl)-N4-isopropyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine (Example 149).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)=O.Cl.[H][H]>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1
Reactant: CN(C)CCC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)CCCc1ccc(N)cc1
Reaction time: 6 h

Procedure:
A solution of 3-dimethylamino-1-(4-nitrophenyl)propan-1-one (hydrochloride, 0.25 g) in glacial acetic acid (10 ml) was adjusted to pH 1 with concentrated hydrochloric acid and, under nitrogen, palladium(II) hydroxide (20% on carbon, 0.1 g) was added. The nitrogen atmosphere was replaced by hydrogen, and the suspension was shaken for 6 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous phase was adjusted to pH>12 with sodium hydroxide solution and extracted with ethyl acetate. The combined organic phases were dried and concentrated. The product with the molecular weight of 178.28 (C11H18N2); MS (ESI): 179 ([M+H]+), was obtained in this way.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:14]([CH3:15])=[C:13]([O:16][C:17]([CH:19]2CC2)=[O:18])[C:12]2[C:7](=[CH:8][C:9]([F:23])=[C:10]([F:22])[CH:11]=2)[N:6]=1)[CH3:4].C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC=C(F)C=2F)N=1)C.O>O1CCCC1>[CH2:3]([C:5]1[C:14]([CH3:15])=[C:13]([O:16][C:17](=[O:18])[CH3:19])[C:12]2[C:7](=[CH:8][C:9]([F:23])=[C:10]([F:22])[CH:11]=2)[N:6]=1)[CH3:4]
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2cc(F)c(F)cc2c(OC(C)=O)c1C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
2-Ethyl-3-methyl-4-cyclopropanecarbonyloxy-6,7-difluoroquinoline (5.5 g) prepared as described in Example 1 was dissolved in 50 ml of methanol. A solution of 2.5 g of sodium hydroxide in 50 ml of water was added to this solution, and the mixture was stirred at 50° C. for 3 hr. The reaction solution was allowed to stand for cooling and was then poured into 50 ml of water. The mixture was neutralized with 1N hydrochloric acid, and the precipitate was then collected by filtration to give 5.1 g of 2-ethyl-3-methyl-4-hydroxy-6,7-difluoroquinoline. In 20 ml of tetrahydrofuran was suspended 96 mg of 60% sodium hydride. Separately, 446 mg of the 2-ethyl-3-methyl-4-hydroxy-6,7-difluoroquinoline (starting material 1) was suspended in 10 ml of tetrahydrofuran, and this suspension of starting material 1 was added dropwise to the above suspension under ice cooling. The mixture was stirred for 1 hr, and 188.4 mg of acetyl chloride (starting material 2) was then added thereto. The mixture was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 168.6 mg of 2-ethyl-3-methyl-4-acetyloxy-6,7-difluoroquinoline (compound 3). 1H-NMR data are shown in Table 3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:32][CH3:33])=[CH:4][C:5]([C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:12]([C:28]([F:31])([F:30])[F:29])[CH:11]=2)=[N:6][C:7]=1[C:8]#[N:9].Cl.[N:35]([O-])=O.[Na+]>O1CCOCC1.O>[C:8]([C:7]1[C:2]2[N:1]=[N:35][N:32]([CH3:33])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[C:12]([C:28]([F:29])([F:30])[F:31])[CH:11]=2)[N:6]=1)#[N:9]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCCN(C)C(=O)OC(C)(C)C)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(CCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoro-methyl)phenoxy)ethyl(methyl)carbamate (7.43 mmol, 3.46 g) was dissolved in 1M Hydrochloric Acid (14.87 mmol, 14.87 ml) and Dioxane (5 ml). Sodium nitrite (10.41 mmol, 0.718 g) in Water (5.00 ml) was added to the reaction mixture and it was stirred at room temperature for 1 hr. The acetonitrile was removed and the reaction taken up in dioxane/water. The reaction mixture was filtered and the solid washed with water to afford tert-butyl 2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl(methyl)carbamate. (2.82 g)
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:3]1([C:1]#[N:2])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccccn2)CCNCC1
Reaction time: 0.67 h
Yield: 100 %

Procedure:
tert-Butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate (5.45 g, 19 mmol) was dissolved in TFA/CH2Cl2 (1:1, 50 mL) at 0° C. After stirring 40 min, the reaction mixture was concentrated under reduced pressure. The residue was diluted with 2 N NaOH in saturated aqueous NaCl (1:1, 80 mL) and extracted with EtOAc (5×200 mL). The combined extracts were washed with saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure to afford 4-pyridin-2-ylpiperidine-4-carbonitrile (3.55 g, 19 mmol) which was used immediately in subsequent reactions. A solution of 4-pyridin-2-ylpiperidine-4-carbonitrile (3.55 g, 19 mmol) in CH2Cl2 (50 mL) at 0° C. was treated with i-Pr2NEt (10 mL) and n-PrSO2Cl (2.24 mL, 21 mmol). After stirring for 1 h at 0° C., the reaction mixture was treated with 2 N NaOH and stirred vigorously for an additional 1 h, before being extracted with EtOAc (4×200 mL). The combined organic extracts were washed with saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure to afford 1-(propylsulfonyl)-4-pyridin-2-ylpiperidine-4-carbonitrile. This material was used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])[CH:5]=[CH:4][N:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:20])[C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c2ccc(Nc3ccnc(Cl)n3)cc2nn1C
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1c2ccc(N(C)c3ccnc(Cl)n3)cc2nn1C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (2.21 g; 8 mmol, 1 equiv) was dissolved in DMF (11 ml) and cesium carbonate (7.9 g; 24.2 mmol, 3 equiv) was added. The reaction mixture was stirred for 30 min under nitrogen. Iodomethane (0.8 ml, 13 mmol, 1.6 equiv) was added and the reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured in ice cold water and stirred for 30 minutes. The resulting precipitate was collected by filtration to yield the desired compound (0.84 g, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].[F:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:20]#[C:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: C#Cc1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#Cc2cccc(F)c2)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (406 mg, 580 μmol, 0.05 equiv.) was dissolved in 25 ml DMF. (2.5 g, 11.6 mmol) 5-Bromo-pyridine-2-carboxylic acid methyl ester and 3-fluorophenylacetylene (2.22 g, 18.5 mmol, 1.6 equiv.) were added at room temperature. Triethylamine (3.5 g, 4.84 ml, 34.7 mmol, 3 equiv.), triphenylphosphine (91 mg, 347 μmol equiv.) and copper(I)iodide (66 mg, 347 μmol, 0.03 equiv.) were added and the mixture was stirred for 20 hours at 80° C. The reaction mixture was cooled and evaporated to dryness with Isolute® sorbent. The crude product was purified by flash chromatography on silica gel (70 g) eluting with an ethyl acetate:heptane gradient 0:100 to 80:20. The desired 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid methyl ester (1.95 g, 66% yield) was obtained as a light yellow solid, MS: m/e=256.3 (M+H+).
Reaction SMILES: [NH3:1].[CH3:2][P:3]([CH3:10])([CH:5]([OH:9])[C:6]([OH:8])=[O:7])=[O:4]>O>[CH3:2][P:3]([CH3:10])([CH:5]([OH:9])[C:6]([O-:8])=[O:7])=[O:4].[NH4+:1]
Reactant: N
Reactant: CP(C)(=O)C(O)C(=O)O
Solvent: O
Product: CP(C)(=O)C(O)C(=O)[O-]
Product: [NH4+]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g of 25% strength aqueous ammonia solution are added dropwise to a solution of 15.2 g (0.1 mol) of 2-(dimethylphosphinoyl)-2-hydroxy-acetic acid in 10 ml of water. The temperature thereby rises to 38°. The mixture is stirred at 25° C. for one hour and concentrated on a rotary evaporator. The residue is first dehydrated azeotropically with toluene and then boiled up with acetonitrile. 14.3 g (84.6%) of the salt of melting point 183°-186° remain.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[O:5][CH:6]=1.[C:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([OH:15])=[O:14]>>[F:9][C:8]([F:11])([F:10])[C:7]([C:4]1[O:5][CH:6]=[C:2]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])[CH:3]=1)=[O:12]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=C(c1cc(Br)co1)C(F)(F)F
Product: O=C(O)c1cccc(-c2coc(C(=O)C(F)(F)F)c2)c1
Yield: 26 %

Procedure:
This compound was synthesized from 1-(4-bromofuran-2-yl)-2,2,2-trifluoroethanone and 3-carboxyphenylboronic acid as described in example 88 step 3 (150 mg, yield 26%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.99 (s, 1H), 8.44 (s, 1H), 8.31 (m, 1H), 8.07-8.04 (m, 1H), 7.93-7.90 (m, 1H), 7.60-7.55 (t, J=7.7 Hz, 1H). MS (ESI) m/z: Calculated for C13H7F3O4: 284.03. found: 282.9 (M−H)−.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[N:19][C:18]=1[O:24]C)=O)(C)(C)C.C[Si](Cl)(C)C.O>C(#N)C>[Cl:23][C:21]1[CH:22]=[C:17]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:18](=[O:24])[NH:19][N:20]=1
Reactant: COc1nnc(Cl)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: O
Product: O=c1[nH]nc(Cl)cc1-c1cc2ccccc2[nH]1

Procedure:
2 g of 2-(6-chloro-3-methoxy-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester is treated for 16 h at 85° C. with 2.76 g of KI and 1.8 g of trimethylsilylchloride in 200 ml acetonitrile. On completion of the reaction the reaction solution is poured into water and the precipitated product is isolated by filtration. Yield: 1.33 g. LC-MS (ES+) 246 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH2:23](NN)[CH3:24]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: CCNN
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reaction time: 16 h

Procedure:
Compound 18 was synthesised following similar procedures outlined in Example 22 (Compound 9), using ethyl hydrazine instead of hydrazine hydrate in Step 3. As a slightly modified procedure, Step 3 was performed at 90° C. for 16 h in a sealed tube. Subsequently, the reaction mixture was partitioned between CH2Cl2 and water. The organic phase was separated using a phase separating cartridge and concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, 5% ethyl acetate/isohexane) yielding Compound 18 as a solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([O:13][C@@H:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:28][CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>CCOC(C)=O.C(#N)C>[Cl-:28].[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([O:13][C@@H:14]2[CH:19]3[CH2:20][CH2:21][N+:16]([CH2:29][C:30](=[O:31])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([CH2:17][CH2:18]3)[CH2:15]2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(C(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)CC1
Reactant: O=C(CCl)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(C(C(=O)O[C@H]2C[N+]3(CC(=O)c4ccccc4)CCC2CC3)c2ccccc2)CC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.4 %

Procedure:
(R)-Quinuclidin-3-yl 2-(4-acetylpiperazin-1-yl)-2-phenylacetate (210 mg, 0.56 mmol) was dissolved in a mixture EtOAc (3.8 ml) and acetonitrile (1.8 ml). 2-Chloro-1-phenylethanone (96 mg, 0.62 mmol) was added and the reaction was stirred at room temperature for 16 hours. The solvent was evaporated and the crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (3R)-3-(2-(4-acetylpiperazin-1-yl)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (178 mg, 59.9% yield) as an off-white spongy solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[C:13]([NH2:22])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[O:23]=[C:24]1[NH:28][C@@H:27]([C:29](O)=[O:30])[CH2:26][NH:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH2:1]([C:5]1[CH:6]=[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[C:13]([NH:22][C:29]([C@H:27]3[CH2:26][NH:25][C:24](=[O:23])[NH:28]3)=[O:30])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cccc(-c2cc(N)nn2-c2ccccc2)c1
Reactant: O=C1NC[C@H](C(=O)O)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cccc(-c2cc(NC(=O)[C@H]3CNC(=O)N3)nn2-c2ccccc2)c1
Reaction time: 2 h
Yield: 21.7 %

Procedure:
To a solution of 5-(3-butylphenyl)-1-phenyl-1H-pyrazol-3-ylamine (40 mg) in N,N-dimethylformamide (0.4 ml) were sequentially added (R)-2-oxoimidazolidine-4-carboxylic acid (21 mg) prepared by the same procedures as Preparation 20, HATU (63 mg), diisopropylethylamine (29 μL) at room temperature, and the mixture was stirred for 2 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: n-hexane/acetone=1/5). To the resulting solid was added diisopropyl ether, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (12 mg).
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[O:11][C:9](=[O:10])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19](NC)=[CH:18][CH:17]=1.[CH2:24]([N:26](CC)CC)C>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:24][NH:26][C:12](=[O:14])[CH2:13][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([OH:11])=[O:10])=[CH:22][CH:23]=1
Reactant: O=C1CC(c2ccccc2)CC(=O)O1
Reactant: CNc1ccc(Cl)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CC(CC(=O)NCc1ccc(Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
3-Phenylglutaric anhydride (2.0 g) in CH2Cl2 (25 mL) at 0° C. was treated sequentially with 4-chloro-N-methylaniline (1.86 g), triethylamine (1.33 g) and N,N-dimethylaminopyridine (trace). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was washed with 1N HCl (2×50 mL) and water (100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (2.7 g).
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13](Cl)[N:14]=[CH:15][C:16]([C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:11]2[C:10]([CH3:25])=[CH:9]1)=O)(C)(C)C.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29].CO>C(OCC)C>[C:19]([NH:18][C:17]([C:16]1[C:11]2[C:10]([CH3:25])=[CH:9][NH:8][C:12]=2[C:13]([NH:29][C:28]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:27]=2[F:26])=[N:14][CH:15]=1)=[O:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: Nc1ccc(F)cc1F
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)NC(C)(C)C)c12
Solvent: CCOCC
Solvent: CO
Product: Cc1c[nH]c2c(Nc3ccc(F)cc3F)ncc(C(=O)NC(C)(C)C)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 4-tert-butylcarbamoyl-7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (68 mg) and using 2,4-difluoroaniline (38 ul) instead of 3-bromoaniline. Isolated by trituration with methanol rather than trituration with diethyl ether to give the title compound (28 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.[N:9]([Si](C)(C)C)=[N+:10]=[N-:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[N:9]([CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1)=[N+:10]=[N-:11]
Reactant: Cc1nc(CCl)cs1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(CN=[N+]=[N-])cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
Dissolve 4-(chloromethyl)-2-methyl-thiazole (350 mg, 2.37 mmol) and azidotrimethylsilane (315 μL, 2.37 mmol) in anhydrous THF (1 mL) under nitrogen. Add a 1M solution of tetrabutylammonium fluoride (3.6 mL, 3.56 mmol) in THF and stir at ambient temperature overnight. Pour the reaction mixture into water (10 mL), extract with ethyl ether (3×2 mL), wash the organic extracts with brine, thy over MgSO4, filter, and evaporate. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (165 mg, 45%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.[C-:26]#[N:27].[Na+].C(=O)(O)[O-].[K+].O>CS(C)=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:26]#[N:27]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCC#N
Yield: 97.6 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester (5.00 g, 14.0 mmol), sodium cyanide (852 mg, 16.8 mmol), and potassium bicarbonate (1.70 g, 16.8 mmol) were combined and vigorously stirred in DMSO (50 mL) at 50° C. for 2 h, then overnight at 25° C. The mixture was then poured into H2O (50 mL) and extracted with Et2O (2×50ML). The organic layer were combined then washed with H2O (50 mL), sat. NaCl (50 mL), dried over NaCl. The solvent was removed in vacuo to provide 2.90 g (98%) of product as a white powder: 1H NMR (400 MHz, CDCl3) δ 7.93 (m, 2 H), 7.39 (m, 3 H), 2.81 (t, 2 H), 2.71 (t, 2 H), 2.35 (s, 3 H); MS (EI) 213.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.O>ClCCl>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3](=[O:11])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(CCl)Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)CN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a solution of 1-chloro-3-phenyl-propan-2-one (10 g, 59 mmol) in dichloromethane (100 ml) was added benzylpiperazine (12.3 ml, 71 mmol) and triethylamine (8.2 ml, 59 mmol). The yellow solution was stirred overnight at ambient temperature and water was added (50 ml). The organic phase was decanted, washed with brine (50 ml), dried (sodium sulphate) and evaporated. The residue was purified by column chromatography on silica using petroleum ether (60-80) ethyl acetate to afford a yellow oil (2.4 g, 13%). 1H NMR (250 MHz, CDCl3) δ 2.30-2.64 (8H, m), 3.19 (2H, s), 3.51 (2H, s), 3.74 (2H, s), 7.17-7.38 (10H, m).