Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([I:19])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([C:13]([O:15]CC)=[O:14])=[C:7]2O.C1COCC1.[Li+].[OH-]>CO.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([I:19])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2
Reactant: CCOC(=O)c1c(O)c2cc(I)cc(F)c2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)c1cnc2c(F)cc(I)cc2c1
Temperature: 40 °C
Yield: 70.6 %

Procedure:
To a solution of ethyl 8-fluoro-4-hydroxy-6-iodoquinolone-3-carboxylate (1.5 g) in 60 mL of 1:1 MeOH:THF is added 16 mL of 1M LiOH. The reaction is maintained at 40° C. overnight. The reaction mixture is cooled to room temperature, then diluted with 40 mL glacial acetic acid. The resulting precipitate is collected, washed with H2O, and dried to yield 0.890 g of 8-fluoro-6-iodoquinoline-3-carboxylic acid as a white solid. This acid (0.25 g) and 1,1'-carbonyldiimidazole (0.146 g) are dissolved in mL anhydrous THF and heated at 65° C. for 3 days. After the reaction mixture is cooled to room temperature, 4-chlorophenylhydrazine (0.161 g) and diisopropylethylamine (0.16 mL) are added. The reaction mixture is heated at 65° C. overnight to solubilize the reactants. The mixture is cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer is extracted with EtOAc (2×). The combined organic layers are washed with brine (1×), dried over Na2SO4, and condensed. The crude product is recrystallized with EtOAc/hexanes to yield 0.13g of the desired product as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:40][CH2:41][N:42]([CH3:44])[CH3:43].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (19 mg, 0.04 mmol) in dry DMF (1 mL) was added sodium hydride (8 mg, 0.18 mmol) at 0° C. under nitrogen. After 1 h at 0° C., 2-chloro-N,N-dimethylethanamine.hydrochloride (18 mg, 0.12 mmol) was added and the resulting mixture was stirred for an additional 5 h at 40° C. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient 0 to 3% MeOH in dichloromethane) to give the title compound (7 mg, 32%). 1H NMR (500 MHz, CDCl3): 7.38 (1H, s), 7.31-7.24 (7H,m), 7.20-7.18 (2H,m), 5.01 (1H, br s), 4.88 (2H, s), 4.08 (2H,t), 2.60 (2H, t), 2.55-2.25 (4H, m), 2.33 (6H, s), 2.09-2.01 (1H, m), 1.85-1.76 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)=[O:4].Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].ClC([O-])=O.[CH:30]([N:33](CC)[CH:34](C)[CH3:35])(C)[CH3:31]>Cl.O1CCOCC1.ClCCl.CO.ClCCl>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18]([N:7]1[CH2:8][CH2:9][CH:5]([C:3](=[O:4])[N:33]([CH2:34][CH3:35])[CH2:30][CH3:31])[CH2:6]1)=[O:19]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)C1CCN(Cc2ccccc2)C1
Agent: Cl
Agent: O=C([O-])Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CCN(CC)C(=O)C1CCN(C(=O)OCC(Cl)(Cl)Cl)C1
Yield: 60 %

Procedure:
A solution of 1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (109.6 mg, 0.5 mmol) in 2N hydrochloric acid (3 mL) and dioxane (1 mL) was heated to 80-90° C. for 1 h. The solvent was evaporated under vacuum and the residue redissolved in dioxane/methanol/toluene and evaporated under vacuum. The residue was then heated under reflux in chloroform containing an excess of thionyl chloride for 1 h and then the solvent was evaporated under vacuum. The residue was dissolved in anhydrous dichloromethane (5 mL) and diethylamine (300 μL) was added. After 20 minutes the solvent was evaporated and the residue dissolved in dichloromethane, washed with dilute sodium hydroxide, dried over anhydrous sodium sulfate and evaporated under vacuum. This material was dissolved in anhydrous acetonitrile (2 mL) and 2,2,2-trichloroethyl chloroformate (1.1 eq, 76 μL) was added at room temperature. After 1.5 h a further aliquot of the chloroformate (0.52 eq., 36 μL) was added. After 30 minutes thin layer chromatography (5% methanol-dichloromethane) indicated that the reaction was still incomplete so a further aliquot of the chloroformate (0.52 eq., 36 μL) and N,N-diisopropylethylamine (0.2 eq., 20 μL) was added. After 1 h the reaction was diluted with dichloromethane, washed with dilute sodium hydroxide, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel eluting with 40:1 dichloromethane-methanol to give 3-diethylcarbamoyl-pyrrolidine-1-carboxylic acid 2,2,2-trichloro-ethyl ester (102.2 mg, 60%)
Reaction SMILES: [O:1]=[C:2]1[O:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:5]=2[C:4]2[CH:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:3]1=2.[CH2:22]([N:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][Cl:28])[CH3:23]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(O)(C)C>[ClH:28].[ClH:28].[CH2:22]([N:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][O:13][C:12]([C:9]1[CH:10]=[CH:11][C:5]2[C:4]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH2:27][CH2:26][CH2:25][N:24]([CH2:29][CH3:30])[CH2:22][CH3:23])=[O:20])=[CH:18][C:3]=3[C:2](=[O:1])[O:7][C:6]=2[CH:8]=1)=[O:14])[CH3:23]
Reactant: O=C(O)c1ccc2c(c1)oc(=O)c1cc(C(=O)O)ccc12
Reactant: CCN(CC)CCCCl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CC(C)O
Product: CCN(CC)CCCOC(=O)c1ccc2c(c1)oc(=O)c1cc(C(=O)OCCCN(CC)CC)ccc12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 11.0 g (0.04 mole) of 6-oxo-6H-dibenzo [b,d]pyran-3,8-dicarboxylic acid, 18.0 g (0.12 mole) of γ-diethylaminopropyl chloride and 400 ml of isopropyl alcohol are stirred and heated to its reflux temperature. A catalytic amount of benzyltrimethylammonium chloride, 0.3 ml of a 60% aqueous solution, is added and the reaction mixture heated to reflux for an additional 24 hours. On cooling, the reaction mixture is filtered, and the residue washed with isopropyl alcohol. This product is dissolved in boiling ethanol, treated with charcoal, filtered and cooled to room temperature. After standing for 1 hour, the gelatinous precipitate which appears is filtered and the filtrate cooled to -20° C. The product which forms is filtered, washed with ethanol and again recrystallized from ethanol to yield the desired bis[3-(diethylamino) propyl]6-oxo-6H-dibenzo[b,d]pyran-3,8-dicarboxylate dihydrochloride as a tan-colored solid, soluble in water and having a m.p. of 250°-1° C. (dec.) (placed in m.p. bath previously heated at 240° C.), λmax 294, and E1cm1% 464.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]3[NH:15][CH:16]=[CH:17][C:9]=23)[C:5]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[N:4]1)[CH3:2].[CH3:25][NH:26][CH3:27].[O:28]1[CH2:32]CCC1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]3[NH:15][CH:16]=[CH:17][C:9]=23)[C:5]([C:18]2[CH:24]=[CH:23][C:21]([NH:22][C:32](=[O:28])[N:26]([CH3:27])[CH3:25])=[CH:20][CH:19]=2)=[N:4]1)[CH3:2]
Reactant: C1CCOC1
Reactant: CCn1cc(-c2c(F)cnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: CNC
Product: CCn1cc(-c2c(F)cnc3[nH]ccc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described in Example 5a with 4-[1-ethyl-4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and 2M dimethylamine in tetrahydrofuran afforded the title compound. ESMS [M+H]+: 393.4
Reaction SMILES: C([N:8]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[C@H:9]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:14][C@H:12]1[CH2:13][NH:8][C@H:9]([C:19]([OH:21])=[O:20])[C@@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](O)CN[C@@H]1C(=O)O

Procedure:
A mixture of 2-benzyl 3-methyl(2S,3S,5R)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (1.00 g, 0.00261 mol) in 10 mL of methanol was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, for 3 h. After filtered off the catalyst, the filtration was concentrated to dry in vacuo and used directly in next step. MS (ESI): (M+H)+=204.0.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:6]([OH:7])[C:5]=1[OH:14])([O-:3])=[O:2].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([O:7][C:6]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:14])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1cc(O)c(O)c([N+](=O)[O-])c1
Product: O=C(Oc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O)c1ccccc1
Reaction time: 4 h

Procedure:
A mixture containing 2.0 g of 3,5-dinitrocatechol in 5 ml of benzoylchloride was cooked for 4 hours in 100° C. When cooled petroleum ether (b.p. 40° C.) was added and the product was filtered and washed with petroleum ether. The raw product was crystallized from ethanol. Yield 2.5 g (82%), m.p. 150°-152° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH3:21][O:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:27]3[CH:26]=[CH:25][C:24]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[C:23]([O:22][CH3:21])[CH:28]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
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: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nn(-c3ccc([N+](=O)[O-])cc3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 26 h
Yield: 63 %

Procedure:
A suspension of 4-amino-1-[4-nitrophenyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (0.500 g, 1.31 mmol) in dimethylformamide (8 mL) was treated with tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.915 g, 2.62 mmol), tetrakis(triphenylphosphine)palladium (0.091 g, 0.06 mmol), and a solution of sodium carbonate (0.333 g, 3.14 mmol) in water (4 mL). The reaction mixture stirred at 85° C. for 26 h under a nitrogen atmosphere. Water was added to the reaction mixture. The precipitate was filtered and washed with water. The solid was triturated with diethyl ether to give 0.431 g, (63%) of tert-butyl N-(4-{4-amino-1-[4-nitrophenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate. 1H NMR (DMSO-d6, 400 MHz) δ 8.6862-8.6634 (d, 2H, J=9.12 Hz), 8.4897-8.4423 (m, 3H), 8.1117 (s, 1H), 8.0074-7.9872 (d, 1H, J=8.08 Hz), 7.3743-7.3293 (m, 2H), 3.9189 (s, 3H), 1.4959 (s, 9H); LCMS (Perkin Elmer, Pecosphere C18 column, 3 um particle size, 33×4.6 mm; 100% 50 mM ammonium Acetate in Water to 100% Acetonitrile over 5 min, 3.0 to 3.5 mil/min) tR=4.38 min M+ 478.1.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6](Br)[CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:45][N:46]([CH3:78])[C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][CH:56]=1)[C:53](=[O:57])[N:52]([C:58]1[CH:68]=[CH:67][CH:66]=[C:65](B3OC(C)(C)C(C)(C)O3)[C:59]=1[CH2:60][O:61][C:62](=[O:64])[CH3:63])[CH2:51][CH2:50]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OC(=O)C)C.O.C(O)CCC>[NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([C:65]2[CH:66]=[CH:67][CH:68]=[C:58]([N:52]3[CH2:51][CH2:50][C:49]4[C:54](=[CH:55][CH:56]=[C:47]([N:46]([CH3:78])[CH3:45])[CH:48]=4)[C:53]3=[O:57])[C:59]=2[CH2:60][O:61][C:62](=[O:64])[CH3:63])[CH:7]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Reactant: Cn1cc(Br)cc(N)c1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCO
Product: CC(=O)OCc1c(-c2cc(N)c(=O)n(C)c2)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Temperature: 105 °C
Yield: 50.6 %

Procedure:
3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (392 mg, 1.93 mmol) was placed into 13 ml n-butanol. To this mixture under argon was added: Pddba2 (55.2 mg, 0.096 mmol), XPhos (91.2 mg, 0.191 mmol), acetic acid 2-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (900 mg, 1.93 mmol), potassium phosphate (814 mg, 3.84 mmol) and 4 ml water. The mixture was heated under argon in a sealed flask for 45 minutes at 100-110° C. After cooling, the mixture was diluted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromathography using 5% methanol in dichloromethylene to afford 450 mg of Acetic acid 2-(5-amino-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (49% yield).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])[C:8]([Cl:22])=[N:7][C:6]=2[NH:5][C:3]1=[O:4].[C:23]1(OB(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])[C:8]([Cl:22])=[N:7][C:6]=2[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]1=[O:4]
Reactant: Cn1c(=O)[nH]c2nc(Cl)n(Cc3ccccc3C#N)c2c1=O
Reactant: OB(O)Oc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2C#N)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 829 mg of 1-methyl-7-(2-cyano-benzyl)-8-chloro-xanthine, 640 mg of phenylboric acid, 509 mg of anhydrous copper acetate and 0.43 ml of pyridine in 20 ml methylene chloride is stirred for four days at ambient temperature in the presence of 100 mg of 4 Å molecular sieves. Then another 320 mg of phenylboric acid are added and the reaction mixture is stirred for another day at ambient temperature. For working up the mixture is filtered through talc and washed with ethyl acetate. The filtrate is evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate (7:3 to 1:1) as eluant.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[H-].[Na+].[N:12]([C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:26])=[CH2:25])[CH:19]=1)([CH3:17])[CH3:16])=[C:13]=[O:14]>C1COCC1>[CH2:25]=[C:24]([C:20]1[CH:19]=[C:18]([C:15]([NH:12][C:13](=[O:14])[O:9][C@@H:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)([CH3:17])[CH3:16])[CH:23]=[CH:22][CH:21]=1)[CH3:26]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)c1cccc(C(C)(C)NC(=O)O[C@H]2CN3CCC2CC3)c1
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
To a solution of (R)-quinuclidin-3-ol (194 mg, 1.52 mmol) in THF (5 mL) at room temperature was added NaH [60%, oil] (64 mg, 1.6 mmol). The reaction mixture was stirred for 15 min and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (302 uL, 1.53 mmol) was added dropwise. The reaction was stirred for a period of 30 min and quenched with brine. The solution was extracted with EtOAc and the organic layer was dried over Na2SO4 and concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding carbamate (475 mg, 95%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.31 (br s, 3H), 5.33 (s, 1H), 5.17 (s, 1H), 5.08 (s, 1H), 4.77-4.61 (m, 1H), 3.33-2.27 (m, 5H), 2.14 (s, 3H), 2.25-0.75 (m, 6H), 1.68 (br s, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 154.7, 147.2, 143.7, 141.6, 128.5, 124.2, 122.1, 112.8, 70.9, 55.7, 55.5, 47.5, 46.6, 32.2, 31.5, 29.9, 29.6, 25.5, 24.6, 22.9, 22.2, 19.6 ppm. Purity: 100% UPLCMS (210 nm); retention time 0.84 min; (M+1) 329.2. Anal. Calcd. for C20H28N2O2.0.06 (CHCl3): C, 71.59; H, 8.40; N, 8.58. Found: C, 71.51; H, 9.05; N, 8.60.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:16][CH2:17][O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[N:7]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: COc1ccc2c(OCCBr)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.5 %

Procedure:
A mixture of 6-chloropyridazin-3(2 H)-one (3000 mg, 22983 μmol), K2CO3 (5000 mg, 36178 μmol), and 4-(2-bromoethoxy)-7-methoxyquinoline (6110 mg, 21656 μmol) in DMF (25 mL) was stirred at room temperature for 1.5 h. H2O (50 mL) was added and the mixture was extracted with CH2Cl2 (3×50 mL). The organic layer was washed with H2O (50 mL), dried over Na2SO4, and concentrated to an orange oil. The oil was diluted with ether (40 mL) and the mixture was concentrated to slurry. Hexane (20 mL) was added and the mixture was agitated at 60° C. for 50 min and cooled to room temperature. The mixture was filtered, washed with ether to give a light tan solid (3.2 g). The filtrate was concentrated and partitioned between H2O (20 mL) and EtOAc (50 mL). The organic layer was washed with H2O and concentrated. The residue was triturated with acetone-hexane (1:2) to give a second crop of product (1.5 g). MS (ESI pos. ion) calc'd for C16H14ClN3O3: 331.1; found 332.1 (MH+). 1H NMR (400 MHz, Chloroform-d) δ ppm 3.93 (s, 3 H) 4.55 (t, J=5.28 Hz, 2 H) 4.67 (t, J=5.38 Hz, 2 H) 6.64 (s, 1 H) 6.94 (d, J=9.59 Hz, 1 H) 7.14 (dd, J=9.10, 2.45 Hz, 1 H) 7.18 (d, J=9.78 Hz, 1 H) 7.34 (d, J=2.54 Hz, 1 H) 8.05 (d, J=9.19 Hz, 1 H) 8.65 (d, J=5.28 Hz, 1 H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:10][CH:11]=[C:12]([CH3:14])[CH3:13])C.[C:15]1(C)C=CC=C[CH:16]=1>[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>[CH2:15]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH3:16]
Reactant: Oc1ccccc1
Reactant: Cc1ccccc1
Reactant: CCOC=C(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCOc1ccccc1OCC(C)C
Reaction time: 15 h
Yield: 67.8 %

Procedure:
In 5.00 g of toluene were dissolved 1.00 g of phenol, 2.12 g of 1-ethoxy-2-methylpropene and 27 mg of a p-toluenesulfonic acid pyridinium salt, and a reaction was allowed at room temperature for 15 hours. After distilling toluene out from the reaction mixture under a reduced pressure, the concentrated residue was purified on a silica gel chromatography to give 1.40 g of 1-ethoxy-2-methylpropoxybenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: FC(F)(F)c1ccc(Br)nc1
Product: C[C@@H](c1ccc(-c2ccc(C(F)(F)F)cn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-5-(trifluoromethyl)pyridine following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.86, m/z=503 (M+1); 1H NMR (CDCl3) 8.87 (s, 1H), 7.93 (dd, 1H), 7.72 (t, 3H), 7.18 (m, 2H), 6.98 (m, 4H), 5.67 (m, 1H), 3.52 (t, 1H), 2.89 (m, 1H), 1.49 (d, 3H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[CH3:8])(=[O:3])[CH3:2]>O1CCCC1.O>[C:1]([NH:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1)[CH3:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)CCNC(C)=O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCCC(C)c1ccc(C(=O)O)cc1
Temperature: 45 °C
Reaction time: 12 h
Yield: 99.2 %

Procedure:
Methyl 4-(4-acetamidobutan-2-yl)benzoate (0.23 g, 0.9 mmol) was dissolved in a mixture of in tetrahydrofuran (10 mL) and water (50 mL), then stirred at 45° C. for 12 hours, after the completion of the reaction, the organic phase was removed under reduced pressure, to the residue was added 1 N hydrochloride to adjust the pH 3-4, then the mixture was extracted with ethyl acetate (10 mL×3), collected the organic phase and dried over Sodium sulfate anhydrous, removed the solvent to afford 4-(4-acetamidobutan-2-yl)benzoic acid (0.21 g, 100%) as a pale yellow oil and directly used in next step. LRMS (M+H+) m/z: calcd for 235.28. found 235.
Reaction SMILES: N(CC[O:6]CCOCCOCCN)=[N+]=[N-].[CH:16]1([N:22]=[C:23]=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)CC[C@H](NC(C1C=CC(NCC2N=C3C(N=C(NC3=O)N)=NC=2)=CC=1)=O)C(O)=O>CS(C)=O.N1C=CC=CC=1>[C:23]([NH:22][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:6]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-(2-(2-Azidoethoxy)ethoxy)ethoxy)ethanamine (0.3 ml, 1.2, equiv.) (commercially available or prepared as described by Schwabacher et al., J. Org. Chem. 1998, 63: 1727) and dicyclohexylcarbodiimide (DCC) (650 mg, 2.5 equiv.) were added to a solution of folic acid dehydrate (600 mg, 1.26 mmol) in DMSO (20 ml) and pyridine (10 ml). The reaction mixture was stirred overnight, in darkness, at ambient temperature, giving rise to the formation of a precipitate of dicyclohexylurea (DCU). After removal of the precipitate, filtrate was poured into a solution of anhydrous ether (400 ml) cooled to 0° C. The yellow precipitate thus obtained was recovered by filtration, then washed with Et2O to remove traces of DMSO. An HPLC analysis of the precipitate (Method 1) showed that the two isomers 6a and 6b were obtained in a ratio of 7/3. The solid (812 mg) was dissolved in a solution (8 ml) 8:2:0.3:0.3 H2O/ACN/DMSO/Et3N, and purified by reverse phase preparative HPLC (Method 2). The fraction containing the inseparable isomers 6a and 6b was concentrated under reduced pressure. The residue was then dissolved in methanol under reflux and poured into a solution of Et2O cooled to 0° C. The precipitate was recovered by filtration and washed with Et2O to yield a yellow powder (240 mg, 30%).