Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].N1C=C(C#C[C:23]2[CH:24]=[C:25]([CH:47]=[CH:48][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])N2C=CN=CC=12.N#N.C(N(CC)C(C)C)(C)C>[Cu]I.CN(C=O)C>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:48]2[CH:47]=[C:25]([CH:24]=[CH:23][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12
Reactant: C#Cc1cnc2ccccn12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Agent: [Cu]I
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Reaction time: 16 h
Yield: 52.7 %

Procedure:
3-Ethynylimidazo[1,2-a]pyridine (37 mg, 0.26 mmol), 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (103.4 mg, 0.2 mmol), (prepared as in Example 2), Pd[(PPh3)4] (11.6 mg, 5 mol %), and CuI (2.9 mg, 7.5 mmol %) was placed in a vial with rubber septum. The mixture underwent 3 cycles of vacuum/filling with N2, and DMF (1.5 ml) and N,N-diisopropylethylamine (53 mL, 0.3 mmol) was added. The mixture was stirred at it for 16 h, and the reaction was quenched with H2O. EtOAc and more water were added for extraction. The combined organic layer was dried (Na2SO4), filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluent: 5% MeOH in methylene chloride, MeOH was pre-saturated with ammonia gas), giving the titled compound as an off-white solid (53%, 56 mg): MS (M+H)+ 532.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]C(OCC)=O)[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.[CH3:24][Mg]Br.[NH4+].[Cl-].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C1COCC1.CCOCC.CCOC(C)=O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:32]([CH3:31])([OH:34])[CH3:24])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:32]([OH:34])([CH3:31])[CH3:24])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: C[Mg]Br
Reactant: CCOC(=O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To a stirred solution, under N2, of ethyl 3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propionate (3.1 g, 9 mmol), in THF (100 ml) was added, dropwise, methylmagnesium bromide (9.0 ml, 27 mmol of a 3M solution in ether). The reaction was stirred at ambient temperature for 16 hours and then a saturated solution NH4Cl was added dropwise, with cooling. The reaction was further diluted with H2, and after extractive workup of the aqueous mixture with EtOAc, 2.8 g of a waxy solid resulted. The solid was dissolved in EtOAc and 3.0 g of fumaric acid was added, and 5.0 g of a fumarate salt was collected, which was contaminated with unreacted fumaric acid. The crude salt was recrystallized from MeOH-Et2O, and then from DMF to afford 1.6 g (45.7%) of the desired compound as a hemifumarate, m.p.=237°-239° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9].Cl[Sn]Cl.Cl[Sn](Cl)(Cl)Cl>>[CH:8](=[O:9])[C:2]1[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:7]
Reactant: Oc1ccccc1
Reactant: C=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: Cl[Sn]Cl
Product: O=Cc1ccccc1O

Procedure:
The reaction in the step (I) is carried out by reacting a phenol derivative, a base and paraformaldehyde in the presence of SnCl2 and/or SnCl4 in an organic solvent at 0-85° C. to the conversion of 30-80%, preferably 50-80% and then to complete the reaction at 95-105° C. to give a salicylaldehyde derivative of the formula (3) in a high yield and in a high selectivity.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.Cl.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)O1
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCC(=O)c1ccc(Br)cc1
Temperature: -10 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
AlCl3 (26.7 g, 0.200 mol) was added in one portion to a stirred mixture of succinic anhydride (10.0 g, 0.100 mol) in bromobenzene (97.0 g) at −10° C. under N2 atmosphere. The reaction temperature was maintained at −10° C. for 1 hour and was then allowed to warm to room temperature. The mixture was stirred at room temperature overnight and poured into ice water. HCl (1M) was added slowly until pH 5. The mixture was extracted with ethyl acetate (150 mL×2). The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was washed with ether to afford 4-(4-bromophenyl)-4-oxobutanoic acid (16.0 g, 62%) as a white solid. 1H NMR (300 MHz, DMSO) δ 12.15 (br s, 1H), 7.90 (d, J=8.7, 2H), 7.73 (d, J=8.7, 2H), 3.22 (t, J=6.0, 2H), 2.55 (t, J=6.0, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:24])([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br.[Br-].[K+].S([O-])([O-])=O.[Na+].[Na+].CBr>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:24])([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P(=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Br
Agent: CBr
Agent: O=S([O-])[O-]
Product: O=P(c1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 74 %

Procedure:
Bis(4-methoxyphenyl)phenylphosphine oxide mixture (2359 g, 6.97 mol), hydrobromic acid (48%, 8344 g, 49.5 mol), and potassium bromide (243 g, 2.04 mol) were stirred at 120° C. for 48 h. The flask was fitted with a sodium sulfite scrubber for containment of methyl bromide. The lower aqueous layer was removed and the product layer was worked up to afford bis(4-hydroxyphenyl)phenylphosphine oxide mixture (Composition VI) as a tan powder (1601 g, 74%). m.p. (DSC): 93° C. 31P NMR (d6-DMSO): δ 27.7 (s, 24.7%); 27.5 (s, 47.7%); 27.4 (s, 25.4%); 27.2 (s, 2.2%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)(O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:25].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]=[C:10]([C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 30 °C
Reaction time: 7 h

Procedure:
0.91 g of 1-(4-bromo-3-methylphenyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 1.82 g of toluene and 0.36 g of thionyl chloride were fed, and the mixture was heated to 30° C. 0.56 g of n-tributylamine was slowly added in dropwise. The mixture was heated to 70° C., and stirred for 7 hours. The mixture was cooled to room temperature, and separated by adding iced water. The organic phase was washed with water, and the solvent was distilled off under reduced pressure. 0.86 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O>O1CCCC1>[CH3:2][O:3][CH:4]=[CH:30][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (6.366 g, 18.5 mmol) in dry tetrahydrofuran (50 ml) under argon atmosphere at −78° C. slowly (ca. for 5 minutes) a 2.46 N solution of potassium tert-butoxide in tetrahydrofuran (8.2 ml, 20.2 mmol) was added and the reaction mixture was stirred at this temperature for 1 hour. A solution of methyl 4-formylbenzoate (E8) (2.531 g, 15.4 mmol) in tetrahydrofuran (10 ml) was added to the reaction mixture and the resultant suspension was stirred at −78° C. for 30 minutes. The cooling bath was removed and the reaction was stirred for 30 minutes allowing to warm up to room temperature. The reaction mixture was partitioned between benzene (150 ml) and water (150 ml), and the organic layer was washed successively with water (150 ml), brine (50 ml), and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silicagel (100 g) with toluene-triethylamine (100:0.25) as eluent to give the title compound (2.696 g, 91%) as a mixture of E and Z isomers (ca. 95:5). (E)-(E9): 1H NMR (CDCl3, HMDSO) δ: 3.67 (3H, s); 3.86 (3H, s); 5.81 (1H, d, J=13.5 Hz); 7.14 (1H, d, J=13.5 Hz); 7.25 (2H, d, J=8.5 Hz); 7.89 (2H, d, J=8.5 Hz). A small additional singlet at 3.80 ppm and 2 doublets at 5.23 (d, J=7.6 Hz); 6.22 ppm (d, J=7.6 Hz) in the 1H NMR spectrum of E9 was attributed to minor amounts (ca. 5%) of (Z)-(E9) isomer present in the product.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2].[CH3:18][C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]=1[CH2:30][OH:31]>ClCCl.C(OCC)C>[CH3:18][C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]=1[CH:30]=[O:31]
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1C=O
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a stirred solution of pyridinium chlorochromate (19.4 g, 90.0 mmol) and anhydrous magnesium sulfate (36 g) in dichloromethane (100 mL) was added a solution of (5-methyl-3-phenyl-4-isoxazolyl)methanol (14.0 g, 74.0 mmol) in dichloromethane (50 mL) and the resulting solution stirred under argon for 2 h. The solution was then dissolved in diethylether (100 mL), filtered through silica and concentrated to give a viscous brown oil. Purification by chromatography (silica, heptane:ethyl acetate 9:1 to 3:2) afforded the title compound (10.5 g, 76%) which was obtained as a white solid. MS: m/e=188.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].CO.[OH-].[Li+].Cl>O>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3]([OH:4])=[O:2])=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(C)noc1-c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester (7.5 g, 25 mmol) was suspended in 2:1 methanol:water. Lithium hydroxide (2.1 g, 50 mmol) was added, and the reaction was stirred overnight at room temperature. The mixture was acidified to pH 1 with 1N aqueous HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.Cl>C(O)C.[Fe]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[NH2:10]
Reactant: COc1ccc([N+](=O)[O-])cc1C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1C
Yield: 123 %

Procedure:
To a solution of 3-methyl-4-methoxynitrobenzene(7.59 g, 45 mmol) in ethanol was added iron powder (35 g), water(5 mL) and concentrated hydrochloric acid (0.4 mL). The mixture was refluxed for 1 hour and then filtered while hot. The filtrate was concentrated to dryness. The residue was dissolved in chloroform. The chloroform solution was dried with sodium sulfated and evaporated to give 3-methyl-4-methoxyaniline (7.59 g). To a solution of this compound (6.17 g, 45 mmol) in acetic acid (55 mL) were added dropwise acetic anhydride (4,4 mL, 46 mmol) at room temperature with stirring and then bromine(2,4 mL, 46 mmol) at 50° C. with stirring. The reaction mixture was stirred at the same temperature for 2 hours and poured into ice-water. The resulting precipitate was filtered off, washed with water and dissolved in ethyl acetate. This solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness to give 2-bromo-4-methoxy-5-methylacetanilide as a crude product. Crystallization from diethyl ether gave pure product (8.27 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O.CCCCCC>C1C=CC=CC=1>[Br:33][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: OCCc1ccc2ccccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: BrCCc1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
To a solution of 25 g (145 mmole) of 2-(2-naphthyl)ethanol and 67.9 g (259 mmole) of triphenylphosphine in 200 ml of benzene was added in portions 46.1 g (259 mmole) of N-bromosuccinimide. A temperature of 45°-50° was maintained by cooling the reaction mixture as needed in an ice bath. After the mixture was poured into 750 ml of hexane and filtered, the filtrate was diluted with an additional 400 ml of hexane and allowed to stand overnight. The solution was concentrated to dryness and the resultant solid was purified by chromatography on silica gel. The title compound (30.5 g), m.p. 55°-57°, was homogeneous by thin-layer chromatography (5%, 10%, and 15% by volume ethyl acetate-hexane on silica gel plates), and was used in subsequent reactions without further purification.
Reaction SMILES: [Mg].C1COCC1.[C:7]([O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH:18](Br)[CH2:19][CH2:20]Br)(=[O:9])[CH3:8].Cl>C1(C)C=CC=CC=1.O>[C:7]([O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH:18]1[CH2:20][CH2:19]1)(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1c(C)cccc1C(Br)CCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)Oc1c(C)cccc1C1CC1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A 300 ml four-necked round-bottomed flask was equipped with a magnetic stirrer bar, a thermometer, a reflux condenser and a drying tube. Magnesium (1.50 g, 61.7 mmol), toluene (15 ml) and anhydrous THF (15 ml) were added to the flask under a nitrogen atmosphere. The mixture was heated in an oil bath of 75° C. for 15 minutes (temperature of the mixture was 62-64° C.). Subsequently, the mixture was heated in an oil bath of 75° C. and a solution of 2-(1,3-dibromopropyl)-6-methylphenyl acetate (17.9 g, purity: 67%, 34.3 mmol) in toluene (60 ml) was added thereto over 30 minutes. The temperature of the mixture was raised to 89° C. After the mixture was stirred in an oil bath of 75° C. for 5.5 hours, the mixture was cooled and 6M hydrochloric acid (20.5 ml, 123 mmol) was added dropwise thereto over 15 minutes such that the temperature of the reaction mixture did not exceed 45° C. After the mixture was stirred at room temperature for 1 hour, it was diluted with water (20 ml) and it was stirred for 10 minutes. The solution was separated and the organic layer was successively washed with a saturated aqueous NaHCO3 solution (50 ml) and water (50 ml) and concentrated to obtain 11.1 g (purity: 45.2%, 26.4 mmol) of 2-cyclopropyl-6-methylphenyl acetate as a brown gum.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5]1.[C-:29]#[N:30].[Na+]>CS(C)=O.O.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][C@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:7][C@@H:6]([C:29]#[N:30])[CH2:5]1
Reactant: COC[C@H]1C[C@H](S(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC[C@@H]1C[C@H](C#N)CN1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
trans-5-Methoxymethyl-3-tosyl-Cbz-pyrrolidine (3.55 g, 8.8 mmol) was dissolved in DMSO (8.8 mL). Finely ground NaCN(0.65 g, 13.2 mmol) was added, and the resulting reaction mixture was stirred 4 h at 80° C. The solution was cooled to room temperature, diluted with H2O (9 mL) and brine (9 mL), and extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with hexanes/ethyl acetate (2/1, v/v) to afford 2.09 g (87% yield) of the desired product as an oil.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([NH2:18])[CH2:16][NH2:17]>O>[C:2]1([C:1]2[NH:18][CH2:15][CH2:16][NH:17][C:10](=[O:12])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NCCN
Solvent: O
Product: O=C1C=C(c2ccccc2)NCCN1

Procedure:
A solution of 192 g. (1 mol) of ethyl benzoylacetate in mixed xylenes (total volume 400 ml.) was added dropwise over a 1 hour period to a solution of 60 g. (67 ml.; 1 mol) of ethylenediamine in 1 l. of mixed xylenes refluxing under nitrogen. The reaction mixture was then refluxed for an additional hour after which the water was azeotroped off. The solvent was then distilled off over a 2 hour period and the resulting reaction product was allowed to stand at room temperature. The crystalline material formed was isolated by filtration, washed several times with chloroform and dried to obtain the crystalline product (59 g.). m.p. 207°-210° C. Lit. Ried et al., Chem. Ber. 87, 1811-1814 (1954), m.p. 209°-210° C.; Hofmann et al., J. Org. Chem. 27, 3565-3568 (1962), m.p. 206°-209° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1OS(C(F)(F)F)(=O)=O)[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2].[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][CH2:25][CH2:26][C:27]#[CH:28]>C(NCC)C.[Pd](Cl)Cl.[Cu]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[C:28]#[C:27][CH2:26][CH2:25][CH2:24][C:23]([O:30][CH3:31])=[O:29])[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: C#CCCCC(=O)OC
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(C)=O)c1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)CCCC#Cc1ccc(C(=O)OC)cc1NC(C)=O
Temperature: 20 °C
Reaction time: 14 h
Yield: 86.5 %

Procedure:
A mixture of methyl 3-acetamido-4-trifluoromethanesulfonyloxybenzoate (1.43 g), methyl 5-hexynoate (582 mg), palladium(II) chloride (14.9 mg), triphenylphosphine (43.8 mg) and copper(I) chloride (32 mg) in diethylamine (18 ml) was stirred at 20° C. for 14 hours. The solvent was evaporated in vacuo an the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (1:2) to give methyl 3-acetamido-4-(5-methoxycarbonyl-1-pentynyl)benzoate (1.15 g) as colorless crystals.
Reaction SMILES: [Li]CCCC.[O:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.O([Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])S(C(F)(F)F)(=O)=O>C(OCC)C>[CH:20]([Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[C:7]1[O:6][CH:10]=[CH:9][N:8]=1)([CH3:22])[CH3:21]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: c1cocn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)[Si](c1ncco1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
n-BuLi (1.6M in hexanes, 76 mL, 190 mmol) was added dropwise over 30 minutes to a stirred solution of oxazole (12.0 g, 174 mmol) in diethyl ether (400 mL) at −78° C. under argon. The solution was allowed to stir for 60 minutes at −78° C. and then triisopropylsilyl triflate (46.3 mL, 172 mmol) was added dropwise over 30 minutes. The reaction mixture was slowly warmed up to room temperature and stirred overnight. The mixture was concentrated in vacuo and the residue was taken up in hexanes and filtered through a pad of silica gel eluting with 8:1 hexanes/ethyl acetate. Concentration gave the title compound (36.0 g, 93%) as a colourless oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH3:8][O:9][CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:8][O:9][CH2:10][CH2:11][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7]
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccsc1Br
Product: COCCc1sccc1C

Procedure:
This compound was prepared analogous to Example 61, starting with 2-bromo-3-methylthiophene (1.5 g, 8.5 mmol) and toluene-4-sulfonic acid 2-methoxy-ethyl ester (2.9 g, 12.7 mmol, 1.5 equiv.) The crude product was purified on silica gel with eluent n-heptane and tert.butylmethyl ether. The title compound was obtained as a light yellow oil, 490 mg. GC-MS (EI): M=156
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.[CH3:19][C:20](Cl)=[O:21].Cl>C(Cl)Cl.CN(C1C=CC=CN=1)C>[C:20]([O:12][CH2:11][CH:10]=[CH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:21])[CH3:19]
Reactant: CC(=O)Cl
Reactant: OCC=Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC=Cc1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Yield: 96.8 %

Procedure:
Treat a solution of the product of step 2 (13.2 g, 65 mmol) in CH2Cl2 (250 mL) at 0° C. with pyridine (7.89 mL, 97.5 mmol, 1.5 eq) and dimethylaminopyridine (397 mg, 3.25 0.05 eq), followed by CH3COCl (6.48 mL, 74.75 mmol, 1.1 5 eq). Allow the mixture to warm to 23° C., pour into 1M HCl (100 mL) and wash the resulting organic layer again with 1M HCl (100 mL), followed by water (5×100 mL; pH=6.5-7). Dry the organic layer (Na2SO4) and concentrate to obtain 15.4 g (62.9 mmol, 97%) of 3-(3,4-dichlorophenyl)-2-propene-1-ol acetate as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][C@:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:3]1[CH2:4][CH2:5][C@H:6]2[O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1.[C:39](O)(=[O:41])[CH3:40].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:39]([NH:1][C@@H:2]1[CH2:8][C@:7]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:3]1[CH2:4][CH2:5][C@H:6]2[O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)(=[O:41])[CH3:40]
Reactant: N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
(1R*,2R*,5S*,6R*)-6-Amino-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 108; 475 mg, 0.89 mmol), glacial acetic acid (0.076 ml, 1.34 mmol), triethylamine (0.14 ml, 0.98 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (257 mg, 1.34 mmol) and 4-dimethylaminopyridine (2 crystals) were combined in dichloromethane (4 ml) and stirred overnight at room temperature. The reaction mixture was washed with water and extracted with dichloromethane (×3). The organics were dried (MgSO4), and concentrated in vacuo to give the title compound as a yellow oil (384 mg, 75%).