Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Si]([N:9]1[C@H:12]([CH2:13][C:14](SC)(SC)SC)[C@@H:11]([C@H](O)C)[C:10]1=[O:24])(C(C)(C)C)(C)C.[C:25](=O)(O)[O-:26].[Na+].C[OH:31]>>[C:14]([CH2:13][CH:12]1[NH:9][C:10](=[O:24])[CH2:11]1)([O:26][CH3:25])=[O:31]
Reactant: CSC(C[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Reactant: O=C([O-])O
Reactant: CO
Agent: [Cl-]
Agent: [Na+]
Product: COC(=O)CC1CC(=O)N1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
Mecuric chloride (12.37 g, 45.6 mmol) is added in one portion to a solution of (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-[2,2,2-tri(methylthio)-ethyl]azetidin-2-one (6.0 g, 15.2 mmol) in 250 ml of absolute methanol at 0° C. The resulting mixture (heavy white precipitate) is stirred at 0° C. for 3 min., then quenched by addition of sodium bicarbonate (8.99 g, 107 mmol). This mixture is then filtered and the solid residue is washed with additional methanol. The combined filtrate and washings are concentrated in vacuo and the residue is partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic phase is separated, washed with saturated aqueous ammonium chloride solution, water and brine and dried over magnesium sulfate. Removal of solvents in vacuo gives an oil which is chromatographed on a silica gel column (3:2 cyclohexane:ethyl acetate) to yield (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl)]-4-carbomethoxymethyl azetidin-2-one.
Reaction SMILES: COC(=O)CC1C=CC([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH2:23][C:24]4C=CC=CC=4)[CH2:21][CH2:20]3)=[C:15]([CH3:30])[CH:14]=2)=CC=1.[C:32](=O)([O-])[O-].[K+].[K+]>CO>[C:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([O:22][CH:23]([CH3:24])[CH3:32])[CH2:20][CH2:21]2)=[C:15]([CH3:30])[CH:14]=1)#[CH:11]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OC(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane (Intermediate 80, 250.0 mg, 0.87 mmol) in methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne (180 mg, 98%) was used directly in the next reaction.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1.O>CN(C=O)C>[CH:22]1([CH2:21][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
To a solution of 4-(difluoromethoxy)-3-hydroxybenzaldehyde (18.4 g, 98 mmol) in DMF (200 ml), potassium carbonate (29.7 g, 215 mmol) and KI (16.3 g, 98 mmol) were added followed by (bromomethyl)cyclopropane (14.28 ml, 148 mmol), and the resulting suspension was stirred at RT for 24 hours. The mixture was poured into water (800 ml) and extracted with diethyl ether (3×300 ml); the combined organic layers were dried over Na2SO4 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (22.5 g, 93 mmol, 94.8% yield, MS/ESI+ 243.1 [MH]+). This product was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(C2CCC3(CC2)OCCO3)c1
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCC(c2cccc(F)c2)CC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
The compound (18) (61.9 g), formic acid (120 g) and toluene (120 ml) were put in a reaction vessel under a nitrogen atmosphere, heated under reflux for 3 hours, and cooled slowly to room temperature. Water (300 ml) and toluene (300 ml) were added and mixed thereto. The mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Then the solvent of the solution was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder and dried, giving 47.2 g of 4-(3-fluorophenyl)cyclohexanone (19). The yield based on the compound (18) was 93.7%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:34])[CH2:8][C:9]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C@H:4]([C:35]([N:37]2[CH2:41][CH2:40][CH2:39][C@@H:38]2[C:42]([NH:44][CH2:45][C@H:46]2[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]2)=[O:43])=[O:36])[CH2:3]1.[CH2:52](I)[CH3:53]>>[CH2:52]([N:48]1[CH2:49][CH2:50][CH2:51][C@H:46]([CH2:45][NH:44][C:42]([C@H:38]2[CH2:39][CH2:40][CH2:41][N:37]2[C:35]([C@@H:4]2[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]2[C:7](=[O:34])[CH2:8][C:9]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=2)([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=2)[C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)=[O:36])=[O:43])[CH2:47]1)[CH3:53]
Reactant: CCc1ccc(C(CC(=O)N2C[C@H](O)C[C@H]2C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCNC2)(c2ccc(CC)cc2)c2ccc(CC)cc2)cc1
Reactant: CCI
Product: CCc1ccc(C(CC(=O)N2C[C@H](O)C[C@H]2C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC)C2)(c2ccc(CC)cc2)c2ccc(CC)cc2)cc1

Procedure:
The title compound was prepared by a method similar to Example 77, using (2R)-1-((2S,4R)-4-hydroxy-1-{3,3,3-tris(4-ethylphenyl)propanoyl}pyrrolidin-2-yl)carbonyl-N-{((3S)-3-piperidyl)methyl}pyrrolidine-2-carboxamide and ethyl iodide. The compound was obtained as a white solid.
Reaction SMILES: [OH2:1].[CH:2]1[C:18]2[CH2:17][C@H:16]3[N:19]([CH2:21][CH2:22][C@@:8]45[C@H:15]3[CH:14]=[CH:13][C@H:11]([OH:12])[C@@H:9]4[O:10][C:6]([C:7]=25)=[C:4]([OH:5])[CH:3]=1)[CH3:20].[H-].[K+].[CH2:25](I)[CH3:26].Cl>O1CCCC1.O>[CH2:25]([O:1][O:12][C@H:11]1[CH:13]=[CH:14][C@@H:15]2[C@:8]34[CH2:22][CH2:21][N:19]([CH3:20])[C@@H:16]2[CH2:17][C:18]2[CH:2]=[CH:3][C:4]([OH:5])=[C:6]([O:10][C@@H:9]13)[C:7]4=2)[CH3:26]
Reactant: O
Reactant: CCI
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOO[C@H]1C=C[C@H]2[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Morphine hydrate (1.42 g, 4.68×10-3 mol) in anhydrous tetrahydrofuran (50 ml) was added dropwise over 20 min. to a stirring suspension, under argon and on an ice/water bath, of potassium hydride (1.75 g, 4.36×10-2 mol) in anhydrous tetrahydrofuran (50 ml). The suspension was stirred for 6 h. under argon on an ice/water bath and then the suspension was allowed to warm to room temperature. Ethyl iodide (0.72 ml, 9×10-3 mol) was added and the suspension was stirred under argon at room temperature for 1 h. The suspension was cooled on an ice/water bath and water (10 ml) was added dropwise to the suspension followed by hydrochloric acid (1N, 50 ml). The solvents were removed in vacuo, water (50 ml) was added to the residue and the suspension was filtered. The aqueous filtrate was extracted 2 times with chloroform (40 ml). The aqueous phase was then treated with hydrochlorid acid (6N, 5 ml) to achieve a pH of 7. The aqueous phase was then extracted 10 times with chloroform (400 ml). The combined chloroform phases were dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The title compound was recovered (430 mg) as a pale brown glassy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[OH:12].Cl.C[CH2:15][O:16]CC>[C-]#N.[Zn+2].[C-]#N>[OH:12][C:4]1[C:5]([CH:15]=[O:16])=[CH:6][C:7]2[CH2:8][CH2:9][O:10][C:11]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c(O)ccc2c1OCC2
Reactant: CCOCC
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1c(O)c(C=O)cc2c1OCC2
Reaction time: 2 h

Procedure:
A mixture of 2.49 g. (15 mmole) of 2,3-dihydro-7-methoxy-6-benzofuranol, 5.87 g. (50 mmole) zinc cyanide and 100 ml. of dry ether was saturated with hydrogen chloride for 1 hour at 0°, then for 2 hours at room temperature. The mixture was then allowed to stand overnight at room temperature then concentrated in vacuo and the residue treated with 100 ml. of 0.1N HCl for 1 hour at reflux. After cooling, ether extraction provided the product which was purified by chromatography over silica gel (E. Merck 60), eluting with CHCl3, to yield a colorless solid, m.p. 71°-72°.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16]/[CH:17]=[CH:18]/[CH3:19])([C:11]([O:13]CC)=[O:12])[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:1]([NH:4][C:5]([CH2:16]/[CH:17]=[CH:18]/[CH3:19])([C:11]([OH:13])=[O:12])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C/C=C/CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C=C/CC(NC(C)=O)(C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
39.63 g (146 mmol) of diethyl (E)-2-acetamido-2-(2-butenyl)malonate were dissolved in 200 ml of ethanol and a solution of 19.24 g (481 mmol) of sodium hydroxide in 100 ml of water was added. The mixture was stirred for 2 hours at 60° C., evaporated to dryness under a vacuum and theresidue was partitioned between diethyl ether and water. The aqueous phase was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and the solvent was removed by evaporation under a vacuum to give 26.1 g of (E)-2-acetamido-2-(2-butenyl)malonic acid as a white solid which was used in the next step without further purification. 1 H NMR (250 MHz, MeOD) δ: 1.65 (d, 3 H), 2.0 (s, 3 H), 2.9 (d, 2 H), 5.25 (m, 1 H), 5.5 (m,1 H).
Reaction SMILES: [S:1]1[C:5]2[C:6]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[O:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.S(Cl)([Cl:18])(=O)=O.CO>C(O)(=O)C.C(OC)(C)(C)C>[ClH:18].[Cl:18][C:2]1[S:1][C:5]2[C:6]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[O:7][CH2:8][CH2:9][C:4]=2[CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1cc2c(s1)C1(CCNCC1)OCC2
Solvent: CO
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: Cl
Product: Clc1cc2c(s1)C1(CCNCC1)OCC2
Temperature: 15 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
A solution of 4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] (50 g, 238.88 mmol) in a mixture of acetic acid (400 mL) and methyl t-butyl ether (40 mL) is cooled to 15° C. Then, a solution of sulfuryl chloride (21.20 mL, 262.77 mmol) in acetic acid (100 mL) is added dropwise in 40 min at that temperature (internal temperature=15° C.-22° C.) and the mixture is stirred at room temperature for 20 hr. Then, a solution of sulfuryl chloride (11.56 mL, 143.33 mmol) in acetic acid (50 mL) is added dropwise at room temperature. The reaction mixture is stirred at room temperature for 30 min. and then it is added dropwise (30 min) over methyl t-butyl ether (1 L) cooling with ice/water bath with stirring. A white suspension is formed and the solid is filtered. To obtain a second crop of material, the filtrate is concentrated (refilling with methyl t-butyl ether via rotavap). Resulting solid is suspended in methyl t-butyl ether (300 mL), suspension is stirred at reflux (bath: 100° C.) and methanol (30 mL) is added till a cloudy suspension is formed. Then, the suspension is cooled to room temperature overnight. The suspension is further cooled in a ice/water bath and filtered. Solid is washed with methyl t-butyl ether (50 mL) and combined with first crop to give the title compound in a 60% yield. MS (m/z): 244 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]=[CH2:30])[C:10](=O)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:23])[O:21][CH3:22])=[CH:15][C:14]=1[N+:24]([O-:26])=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-].C(O[C:35](=[O:43])[CH2:36][N+]1C=CC=CC=1)C.C([O-])(=O)C.[NH4+:48]>CCO>[C:1]([O:5][C:6]([NH:8][CH:9]([C:10]1[NH:48][C:35](=[O:43])[CH:36]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:23])[O:21][CH3:22])=[CH:15][C:14]=2[N+:24]([O-:26])=[O:25])[CH:11]=1)[CH2:28][CH:29]=[CH2:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)/C=C/c1ccc(NC(=O)OC)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C[n+]1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: CCO
Product: C=CCC(NC(=O)OC(C)(C)C)c1cc(-c2ccc(NC(=O)OC)cc2[N+](=O)[O-])cc(=O)[nH]1
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
To a solution of 5F (3.0 g, 7.15 mmol) and 1-(2-ethoxy-2-oxoethyl)pyridinium bromide (1.189 g, 7.15 mmol) in EtOH (130 mL), was added ammonium acetate (11.03 g, 143 mmol) portion wise. After 15 min, the mixture was stirred at 75° C. The reaction mixture was then concentrated and dissolved in EtOAc. The organic layer was then washed with 1.0 N HCl, H2O, saturated sodium bicarbonate solution and finally by brine. The organic phase was dried over sodium sulfate, filtered and concentrated to yield a residue which was purified by normal phase chromatography to isolate 5G (2.2 g, 67%) as a brown solid. MS (ESI) m/z: 459.3 (M+H)+. The racemate was subjected to chiral separation using chiral AD-H 21×250 mm, eluting with a mixture of 35% (50/50 EtOH, i-PrOH and 0.1% DEA) and 65% CO2 with a flow rate of 70 mL/min and 150 bar at 40° C. to give enantiomer 5G1 (peak 1) and enantiomer 5G2 (peak 2).
Reaction SMILES: CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C(N(CC)C1C=CC=CC=1)C.B.[Cl:34][C:35]1[CH:36]=[C:37]([C:42](=[O:45])[CH2:43][CH3:44])[CH:38]=[CH:39][C:40]=1[Cl:41].Cl>CO.CC(OC)(C)C>[Cl:34][C:35]1[CH:36]=[C:37]([C@@H:42]([OH:45])[CH2:43][CH3:44])[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: CCC(=O)c1ccc(Cl)c(Cl)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: CO
Solvent: CCN(CC)c1ccccc1
Solvent: COC(C)(C)C
Product: CC[C@H](O)c1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A 250 mL round-bottom flask was charged with MTBE (35 mL), a solution of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (2.51 mL, 2.51 mmol) and borane diethylaniline (4.45 mL, 25.1 mmol) at RT then heated to 40° C. A MTBE (20 mL) solution of 156 (6.00 g, 25.1 mmol) was added dropwise and the reaction was stirred at 40° C. for 3 h. The reaction was cooled to RT and MeOH (5 mL) was then added slowly, followed by 1M HCl and the reaction was stirred for 18 h. The water was removed and the remaining organic phase dried (Na2SO4), filtered and concentrated to get a light gray oil. The crude product was purified by SiO2 chromatography (SNAP 100) eluting with EtOAc/hexane (1:3) to afford 3.45 g (66%) of (S)-1-(3,4-dichlorophenyl)propan-1-ol (158) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][C:3]=1[S:25]([CH3:28])(=[O:27])=[O:26].[CH3:29][NH2:30].C1COCC1.[BH4-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:23][NH:30][CH3:29])[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][C:3]=1[S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: CN
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1-c1ccc(F)c(S(C)(=O)=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1ccc(OCC(=O)OC(C)(C)C)c(-c2ccc(F)c(S(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Intermediate 29 (270 mg, 0.66 mmol, 1 eq) was stirred with methylamine (1.5 mL of a 0.88 M THF solution, 1.32 mmol, 2 eq.) in MeOH for 2 h. Sodium borohydride (50 mg, 0.66 mmol, 1 eq.) was added, and the resulting mixture was stirred at room temperature for an additional 2 h. Water (3 mL) was added and the MeOH was removed in vacuo. The resulting solution was extracted with EtOAc, dried (Na2SO4), and concentrated in vacuo to give 260 mg (93%) of t-butyl 2-(2-(4-fluoro-3-(methylsulfonyl)phenyl)-4-((methylamino)methyl)phenoxy)acetate (30) as oil.
Reaction SMILES: Cl.[CH:2]1([O:7][C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:16][CH2:17][NH2:18])[CH2:6][CH2:5][CH2:4][CH2:3]1.C([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])C.Cl.[C:27](O)(=[O:34])[C:28]1C=CN=C[CH:29]=1>[Cl-]>[CH:2]1([O:7][C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:16][CH2:17][NH:18][C:27](=[O:34])[CH2:28][C:29]2[CH:23]=[CH:22][N:21]=[CH:24][CH:25]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccncc1
Reactant: CCN(CC)CC
Reactant: COc1cccc(CCN)c1OC1CCCC1
Agent: Cl
Agent: [Cl-]
Product: COc1cccc(CCNC(=O)Cc2ccncc2)c1OC1CCCC1
Yield: 108.9 %

Procedure:
Operating analogously to example 46 using 2-(2-cyclopentyloxy-3-methoxy-phenyl)-ethylamine hydrochloride (1 g, 3.68 mmoles), obtained as described in example 3, in methliene chloride (20 ml), triethylamine (1.69 ml, 1.23 g, 12.14 mmoles) and isonicotinic acid hydrochloride (0.72 g, 4.05 mmoles), 1.42 g of the title product were obtained (yield: 99.9%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][N:10]=1.CS(Cl)(=O)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CN(C)C=O>[Cl:8][C:9]1[CH:14]=[C:13]([CH2:15][O:16][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:12]=[CH:11][N:10]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: Oc1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1ccc(OCc2ccnc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
Triethylamine (1.2 mL, 8.4 mmols) was added to a mixture of (2-chloro-4-pyridinyl)methanol (1.0 g, 7.0 mmols), methanesulfonyl chloride (0.6 mL, 7.7 mmols) and ethyl acetate (20 mL) under cooling with ice, and stirred at room temperature for 2 hours. Filtering the reaction liquid, the filtrate was concentrated. To the resulting residue, 4-fluorophenol (0.94 g, 8.4 mmols), potassium carbonate (1.93 g, 14.0 mmols) and N,N-dimethylformamide (20 mL) were added and s at 80° C. for 20 hours. Cooling the reaction liquid to room temperature, ethyl acetate was added thereto, followed by washing with saturated aqueous sodium hydrogencarbonate solution and saturated brine and drying over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil, FLASH 40+M, chloroform) to provide the title compound (845 mg, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[C:10]2[O:13][CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1.C1N=C[N:22](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:17]([NH2:22])=[O:19])=[C:10]2[O:13][CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2ccc(C(=O)O)c(OC(C)C)c2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2ccc(C(N)=O)c(OC(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68 %

Procedure:
To a room temperature solution of 7-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxylic acid (141 mg, 0.54 mmol) in 10 mL of THF is added N,N-carbonyldiimidazole (105 mg, 0.65 mmol). The solution is heated at reflux for 1 hour and cooled slightly. Aqueous NH4OH (2.5 mL) is added and the reaction mixture is stirred at room temperature for 40 minutes then partitioned between 1:1 hexane:ethyl acetate and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is recrystallized from hexane and ethyl acetate to provide 7-methoxy-1-(1 methylethoxy)-2-naphthalenecarboxamide in 68% yield; mp 172°-174° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[CH2:10](O)[CH2:11][CH:12]=[CH2:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH2:13][CH2:12][CH:11]=[CH2:10])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1
Reactant: Oc1ccc(Br)nc1Br
Reactant: C=CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCOc1ccc(Br)nc1Br

Procedure:
To a stirred mixture of 2,6-dibromopyridin-3-ol (47.3 g, 0.188 mol) and but-3-en-1-ol (13.8 g, 0.191 mol) in anhydrous THF (200 ml) at 0° C. was added PPh3 (59.4 g, 0.226 mol), followed by diethyl azodicarboxylate (41.77 g, 0.207 mol). The mixture was heated at reflux for 1 h and then concentrated in vacuo to give a dark brown oil. The oil was dissolved in EtOAc, washed with saturated NaHCO3 solution and brine, dried with Na2SO4, and concentrated in vacuo. Petroleum (300 ml) was added to the crude product mixture. The white solid was removed by filtration, and the filtrate was purified by silica gel chromatography (petroleum/EtOAc, 30/1) to afford the title compound as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)C1C=CC=CC=1>C(O)C>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]1=[O:23]
Reactant: O=c1cc(OCc2ccccc2)ccn1Cc1cccc(F)c1
Solvent: CCO
Product: O=c1cc(O)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a Fischer-Porter bottle, added a solution of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.5 g, 14.56 mmol) in absolute ethanol (20 mL). Flushed the solution with nitrogen then added palladium catalyst (1.05 g, 10% Pd/C). Sealed bottle and evacuated system. The system was purged with hydrogen gas (2×15 psi) to check for leaks. The reaction was charged with hydrogen (35 psi) and stirred at room temperature for 45 minutes. The system was evacuated and flushed with nitrogen. The reaction was filtered and the catalyst was carefully washed with fresh ethanol. The filtrate was concentrated under reduced pressure 1H-NMR (CD3OD, 400 MHz) δ7.54 (d, 1H, J=7.6 Hz), 7.32 (m, 1H), 7.06 (d, 1H, J=7.6 Hz), 6.99 (m, 2H), 6.05 (dd, 1H, J=2.4 Hz, 2.8 Hz), 5.83 (d, 1H, J=2.4 Hz), 5.09 (s, 2H); ES-HRMS m/z 220.0774 (M+H calculated for C12H11NO2F requires 220.0787).