Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]([C:22]#[N:23])[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:23][CH2:22][CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)(CC(C#N)Cc1ccccc1)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)Cc1ccccc1)OCC

Procedure:
A solution of 3.5 g of ethyl 2-benzyl-2-cyanoethyl(diethoxymethyl)phosphinate in 50 ml of ethanol is added to 25 g of an 8% solution of ammonia in ethanol. To this are added 2 ml of Raney Nickel end the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-benzylpropyl(diethoxymethyl)phosphinate as a viscous oil, 31 p=+46.3 ppm (CDCl3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:53]=1[CH:59]([NH2:61])[CH3:60]>C(Cl)(Cl)Cl>[F:51][C:52]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:53]=1[CH:59]([NH:61][C:43]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[C:2]([F:1])[CH:3]=1)=[O:49])[CH3:60]
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Reactant: CC(N)c1ccc(F)cc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4F)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 71.5 %

Procedure:
3-Fluoro-4-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy}-aniline (30 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml) to prepare a solution. A solution of triphosgene (17 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 25 min. Next, a solution of 1-(2,4-difluorophenyl)ethylamine (14 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 5 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (25 mg, yield 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]2[C:10]3[N:11]([CH3:28])[C:12]([CH2:22][C:23]([O:25]CC)=[O:24])=[C:13](C(OCC)=O)[C:14]=3[CH2:15][CH2:16][C:4]=2[CH:3]=1.[OH-:29].[Na+].Cl.[CH2:32]([OH:34])C>>[Cl:1][C:2]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]2[C:10]3[N:11]([CH3:28])[C:12]([CH2:22][C:23]([OH:25])=[O:24])=[C:13]([OH:29])[C:14]=3[C:15](=[C:32]=[O:34])[CH2:16][C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2c(n1C)-c1c(cc(Cl)ccc1=O)CC2
Reactant: CCO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cn1c(CC(=O)O)c(O)c2c1-c1c(cc(Cl)ccc1=O)CC2=C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Ethyl 1,4,5,10-tetrahydro-7-chloro-3-ethoxycarbonyl-1-methyl-10-oxo-benzocyclohepta[1,2-b]-pyrrole-2-acetate (7.87 g, 19.5 mmol) is suspended in ethanol (20 ml) and is heated at reflux. To the resulting mixture is added 2.5 N aqueous sodium hydroxide (20 ml, 50 mmol). The reaction is heated at reflux with stirring for 1 hour after it becomes homogeneous. The solution is cooled and diluted with ice water (150 ml), then acidified to pH 2 with 6 N aqueous HCl. The resulting precipitate is filtered and dried in vacuo to give 5.06 g (75%) of 1,4,5,10-tetrahydro-7-chloro-3-hydroxy-carbonyl-1-methyl-10-oxobenzocyclohepta[1,2-b]pyrrole-2-acetic acid.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][O:8]CCCC)(=[O:5])[OH:4])[CH3:2].[OH-:13].[Na+].C.OO>O.[Pd]>[CH2:1]([P:3]([OH:4])([CH2:6][C:7]([OH:8])=[O:13])=[O:5])[CH3:2]
Reactant: CCCCOCCP(=O)(O)CC
Reactant: [OH-]
Agent: [Pd]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CC(=O)O
Temperature: 70 °C
Yield: 79 %

Procedure:
19.4 g (0.1 mol) of ethyl-2-butoxyethylphosphinic acid (produced as in Example 6) are dissolved in 150 ml of water and adjusted to pH 9 with 2N NaOH solution. Then, 0.25 g of charcoal with 5% Pd and 1% Bi is added, the suspension is heated to 70° C. and 30% strength hydrogen peroxide solution is passed into the suspension at a flow rate of 1 mol equivalent per hour. All the while, the pH of the suspension is maintained at pH=9 by adding 2N NaOH solution. After the reaction is ended, the reaction solution is filtered to remove the catalyst, which is washed, and made acidic with hydrochloric acid and the water is distilled off in vacuo. The residue is taken up in tetrahydrofuran and extracted. The insoluble salts are filtered off to leave 12.0 g (79% of theory) of 2-(ethylhydroxyphosphinyl)acetic acid as a colorless solid material
Reaction SMILES: [C:1]1([N:7]2[C:11](=[S:12])[N:10]([CH2:13]Cl)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].O.C(OCC)(=O)C>CN(C)C=O>[C:1]1([N:7]2[C:11](=[S:12])[N:10]([CH2:13][N:19]3[C:18](=[O:20])[C:17]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]4[C:15]3=[O:25])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=c1n(CCl)nnn1-c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cn1nnn(-c2ccccc2)c1=S

Procedure:
A solution of 1-phenyl-4-chloromethyltetrazoline-5-thione (4.53 g) and potassium phthalimide (4.00 g) in 50 ml dimethylformamide was heated at 55° C. for 2 hours. The solution was poured into water. Ethyl acetate extractive workup gave a colorless solid. Recrystallization from ethanol afforded a colorless solid, m.p. 130°-134° C. (2.75 g).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16]C#N)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].O.C(P(CC)CC)C>CC(C)=O>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([SH:16])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(SC#N)cc(C(C)(C)C)c1O
Agent: CCP(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Temperature: 0 °C
Yield: 86.9 %

Procedure:
3,5-bis(1,1-Dimethylethyl)-4-hydroxyphenyl thiocyanate (55 g, 0.209 mole) was dissolved in acetone (200 ml) under an argon atmosphere. Water (7.2 g, 0.42 mole) was added and the reaction cooled to 0° C. Triethylphosphine (24.7 g, 0.209 mole) was added dropwise over a period of 1 hour and the reaction was then allowed to warm to room temperature with stirring. The solution was concentrated, solvents removed, and the resulting oil purified by chromatography on silica. The fractions containing the thiol were combined, the solvents removed to yield a white powder which was recrystallized from methanol/water and dried to yield 43.3 g of the desired product. NMR confirmed the structure of the product.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](N)=[N:4][C:2]1=[O:3].FS(O)(=O)=[O:11].[F].[FH:15]>>[F:15][C:7]1[C:5](=[O:11])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: F
Reactant: O=S(=O)(O)F
Agent: [F]
Product: O=c1[nH]cc(F)c(=O)[nH]1

Procedure:
Into a solution of cytosine (11.1 g) in hydrogen fluoride (50 ml) kept at 5° C., fluorine fluorosulfonate was blown while stirring. The cytosine was completely consumed in 2 hours, and the total amount of fluorine fluorosulfonate was 0.21 mol. The reaction mixture was heated to distill out the hydrogen fluoride, water (100 ml) was added thereto, and the resulting mixture was heated under reflux for 2 hours. An aqueous solution of calcium hydroxide was added thereto to make pH 6, and precipitated materials were eliminated by filtration. The filtrate was cooled, and the separated crystals were collected by filtration to give 5-fluorouracil (9.9 g). Yield, 76.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[C:6]([CH3:12])=[CH:5][CH:4]=1.C(O[C:18](=O)[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](=[O:31])N(OC)C)[CH2:22][CH2:21]1)(C)(C)C.[O:33]=[C:34]1[NH:39][C:38]2[CH:40]=[C:41](C=O)[CH:42]=[CH:43][C:37]=2[S:36][CH2:35]1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:26]([C@H:23]3[CH2:22][CH2:21][C@H:20]([NH:19][CH2:18][C:41]4[CH:42]=[CH:43][C:37]5[S:36][CH2:35][C:34](=[O:33])[NH:39][C:38]=5[CH:40]=4)[CH2:25][CH2:24]3)=[O:31])[S:11][C:7]=2[C:6]([CH3:12])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(C)c2scnc12
Product: COc1ccc(C)c2sc(C(=O)[C@H]3CC[C@H](NCc4ccc5c(c4)NC(=O)CS5)CC3)nc12

Procedure:
Using 4-methoxy-7-methyl-benzothiazole (5 mmol; J. Org. Chem. (1984), 49, 997), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (0.3 mmol) according to the same protocol as that described for example 1, steps 1.a to 1.c, the title compound was obtained as a yellowish solid (20 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[C:7]([CH2:13]O)[CH:6]=1)[CH:2]=[CH2:3].CCN(CC)CC.C[S:23](Cl)(=O)=O.[S-2].[Na+].[Na+]>C(Cl)Cl.O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]2[CH2:11][S:23][CH2:13][C:7]=2[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(CO)c(CO)c1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOc1ccc2c(c1)CSC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
Crude diol from stage (i) (3.5 g, 18 mmol) was dissolved in DCM (60 mL) and treated with Et3N (10 mL, 72 mmol) and the solution was cooled to 0° C. Methanesulfonyl chloride (4.2 mL, 54 mmol) was added dropwise and the solution was stirred for 1 h being allowed to reach room temperature. The reaction was then quenched by the addition of water followed by 2M HCl (50 mL). The DCM layer was separated and the aqueous layer was re-extracted with DCM (50 mL). The combined organic fractions were washed with water (50 mL), dried (MgSO4) and concentrated to a volume of ca. 30 mL. Benzyltriethylammonium chloride (1 g) was added followed by a solution of sodium sulfide (5 g, 91 mmol) in water (50 mL). The mixture was stirred rapidly under a nitrogen atmosphere for 15 h. The organic layer was separated and the aqueous layer was re-extracted with DCM (50 mL). The combined organic layers were dried (MgSO4) and evaporated to a yellow oil. Flash chromatography afforded two fractions; the first was pure product and the second product contaminated with dimeric material. Trituration of the second fraction caused crystallisation of the dimeric material which was removed by filtration. The filtrate was combined with the first chromatography fraction to afford the desired product (800 mg, 23%); δH (CDCl3, 400 MHz) 4.16 (2H, s), 4.19 (2H, s), 4.48 (2H, m), 5.26 (1H, d), 5.37 (1H, d), 5.95-6.06 (1H, m), 6.74 (2H, m), 7.09 (1H, d).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1F>CS(C)=O.C(OCC)C>[Cl:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1[O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(OC2CCCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cylcohexanol (2.9 g) in dimethylsulfoxide (20 mL) is added slowly to a flask containing potassium hydride (0.90 g, pre-washed three times with hexanes) under an atmosphere of argon and the solution is stirred for about 1 hour at room temperature. A solution of 3-chloro-4-fluoro-nitrobenzene (1 g) in dimethylsulfoxide (10 mL) is added and the resulting dark red colored solution is then heated for three hours to approximately 100 degrees. The reaction mixture is then cooled, diluted with diethyl ether (300 mL), and washed successively with saturated aqueous ammonium chloride, three times with water, then with saturated aqueous sodium chloride. The organic layer is then dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, and the resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an orange solid.
Reaction SMILES: [F:1][C:2]1([F:17])[C:7]([F:9])([F:8])[C:6]([F:11])([F:10])[C:5]([F:13])([F:12])[C:4]([F:15])([F:14])[C:3]1=[O:16].[Cl:18][C:19]([Cl:24])([Cl:23])C(O)=O>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]1([F:17])[C:7]([F:9])([F:8])[C:6]([F:10])([F:11])[C:5]([F:12])([F:13])[C:4]([F:14])([F:15])[C:3]1([C:19]([Cl:24])([Cl:23])[Cl:18])[OH:16]
Reactant: O=C1C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Reactant: O=C(O)C(Cl)(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: OC1(C(Cl)(Cl)Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F
Temperature: -10 °C
Reaction time: 17 h

Procedure:
A solution of 30 g of perfluorocyclohexanone and 31.7 g of trichloroacetic acid was stirred in a pre-dried reaction vessel containing 113 mL of hexamethylphosphoramide. This mixture was cooled to −10° C. in a dry ice/acetone bath. Slight gas evolution was noted before and during the ketone addition. The stirred milky white reaction mixture was maintained at about 0° C. for an hour and then allowed to warm to 23° C. and stirring was continued 17 hours. The clear yellow solution was quenched with 150 mL of 10% HCl and then transferred to a separatory funnel with 400 mL of ethyl ether. This organic phase was washed with 4×500 mL of dilute HCl and then 300 mL of saturated NaCl solution. The solvent was removed by evaporation. The residue (33.7 g) contained 40.8% product by GC, confirmed by fluorine NMR. This carbinol can be converted to the corresponding acrylate by methods previously described (cf. Example 24).
Reaction SMILES: [N+:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][N:4]1[CH2:5][CH2:6][N:7]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9]1
Reactant: O=C(c1ccccc1)N1CCN([N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NN1CCN(C(=O)c2ccccc2)CC1
Reaction time: 1.5 h
Yield: 92.7 %

Procedure:
A mixture of 11.75 g (0.05 mole) of p-nitrobenzoylpiperazine in 150 ml of absolute methanol and 0.2 g of 10% palladium on carbon is hydrogenated on a Parr apparatus during which the calculated amount of hydrogen is taken up over a 1.5 hour period. The reaction is left to stand overnight at room temperature. The reaction mixture is filtered from the catalyst and the filtrate concentrated in vacuo giving a near white crystalline residue. This residue is re-crystallized from 1-propanol at the boiling point giving 9.51 g of near-white crystals of melting point 194.5°-195.5° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[N:14]1[C:18]2=[N:19][CH:20]=[N:21][C:22](O)=[C:17]2[CH:16]=[N:15]1>>[Cl:3][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([C:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=3[CH3:6])[N:15]=[CH:16][C:17]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C)c(-n2ncc3c(O)ncnc32)c1
Product: Cc1ccc(C)c(-n2ncc3c(Cl)ncnc32)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Phosphorus oxychloride (7.76 mL, 83.24 mmol) was added to 1-(2,5-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (1 g, 4.16 mmol). The resulting solution was stirred at 100° C. for 2 hours. LCMS showed reaction was complete. The reaction mixture was evaporated. Ice/water and then EtOAc were added. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organics were washed with water, dried (MgSO4) and concentrated to give crude product (1.077 g, 100%) which was used without purification. 1H NMR (400 MHz, DMSO) δ 2.00 (3H, s), 2.35 (3H, s), 7.26-7.37 (3H, m), 8.72 (1H, s), 8.86 (1H, s); m/z (ES+) (M+H)+=259; HPLC tR=2.48 min.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[OH:13].CN(C)C=O>C1C=CC=CC=1>[CH3:20][N:17]1[CH2:18][CH2:19][CH:14]([CH:12]2[C:8]3=[CH:9][CH:10]=[CH:11][N:7]3[CH2:6][C:5]3[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=3[O:13]2)[CH2:15][CH2:16]1
Reactant: CN1CCC(C(O)c2cccn2Cc2ccccc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CN1CCC(C2Oc3ccccc3Cn3cccc32)CC1

Procedure:
To a suspension of sodium hydride (2.0 g, 50% in oil, treated with hexanes, 0.04 mole) in 50 ml benzene was added a suspension of [1-(2-fluorobenzyl)-2-pyrryl]-[(1-methyl)piperidin-4-yl]methanol (10.0 g, 0.033 mole) in 100 ml benzene, followed by 50 ml dimethylformamide.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[Mg].[Cl-:15].[Cd+2:16].[Cl-]>O1CCCC1>[Cl-:15].[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([Cd+:16])[CH:11]=[CH:10]2
Reactant: [Cd+2]
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc2cc([Cd+])ccc2c1

Procedure:
A solution is formed by dissolving 24 grams of 2-bromo-6-methoxynaphthalene prepared as in Example 7 above in 300 mL of tetrahydrofuran. The resulting solution is slowly added to 2.5 grams of magnesium turnings in 100 mL of tetrahydrofuran at reflux temperature. After the addition is complete, 20 grams of cadmium chloride is added, and the resultant mixture is refluxed for 10 minutes to yield a solution of 6-methoxy-2-naphthylcadmium chloride in tetrahydrofuran. A solution of 18 grams of ethyl 2-bromopropionate in 20 mL of tetrahydrofuran is then added to the cooled reaction mixture. After 24 hours at 20° C., the product is hydrolyzed by adding 200 mL of 5 weight percent methanolic sodium hydroxide followed by heating to reflux for 1 hour. The reaction mixture is then diluted with excess 1N sulfuric acid and extracted with ether. The ether phase is separated, evaporated to dryness and the residue is recrystallized from acetone-hexane to yield 2-(6-methoxy-2-naphthyl)propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH3:12]I.[CH2:14](I)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:12])([CH2:14][CH3:15])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: COc1cccc(CC#N)c1
Reactant: CCI
Product: CCC(C)(C#N)c1cccc(OC)c1
Yield: 8 %

Procedure:
The procedures described in the portion of Example 1 which is concerned with the preparation of starting materials were repeated except that 3-methoxyphenylacetonitrile was alkylated in turn with methyl iodide and ethyl iodide. The 2-(3-methoxyphenyl)-2-methylbutyronitrile so obtained was treated with boron tribromide to give the required starting material in an overall yield of 8% as a gum.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([O:26][CH3:27])([O:24][CH3:25])[C:16](=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].Cl[CH2:29][O:30][CH3:31].[Cl-].[NH4+]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:27][O:26][C:15]([O:24][CH3:25])([O:14][CH3:13])[C:16](=[O:23])[CH2:17][CH:18]([CH2:29][O:30][CH3:31])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CCC(=O)C(OC)(OC)OC
Reactant: COCCl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCC(CC(=O)C(OC)(OC)OC)C(=O)OC
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To 2.85 ml of diisopropylamine dissolved in 30 ml of anhydrous tetrahydrofuran was added 12.5 ml of 1.5M n-butyl lithium (hexane solution) at -78° C. under nitrogen atmosphere. The mixture was stirred for 15 minutes. To the solution was added 3.45 g of dimethyl 2-oxoglutarate dimethyl acetal in 15 ml of anhydrous tetrahydrofuran, taking 10 minutes. The mixture was stirred for 15 minutes. To the mixture was added a solution of 1.32 ml of chloromethyl methylether and 1.36 ml of hexamethylphosphoramide in anhydrous tetrahydrofuran, taking 10 minutes. The temperature of the reaction mixture was raised up to -20° C. taking 30 minutes, followed by stirring at the same temperature for 3 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The extract solution was washed with water and dried (MgSO4). The solvent was evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexaneethyl acetate (2:1) to give 2.28 g of dimethyl 4-methoxymethyl-2-oxoglutarate dimethyl acetal as a pale yellow oily product.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[F:10][C:11]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:12]=1[CH2:13][N:14]1[C:19]([CH3:20])=[C:18]([C:21](OCC)=[O:22])[C:17](=[O:26])[C:16]([Br:27])=[C:15]1[CH3:28].CO>C1COCC1.C(Cl)Cl>[F:10][C:11]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:12]=1[CH2:13][N:14]1[C:19]([CH3:20])=[C:18]([CH:21]=[O:22])[C:17](=[O:26])[C:16]([Br:27])=[C:15]1[CH3:28]
Reactant: CCOC(=O)c1c(C)n(Cc2c(F)cccc2F)c(C)c(Br)c1=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1c(Br)c(=O)c(C=O)c(C)n1Cc1c(F)cccc1F
Reaction time: 1 h
Yield: 64.3 %

Procedure:
DIBAL (5.3 mmol, 5.3 mL of a 1.0 M solution in hexanes) was added dropwise via syringe to a stirred solution of 1-(2,6-difluorobenzyl)-2,6-dimethyl-3-bromo-5-ethoxycarbonyl-4-pyridone (1.40 g, 3.5 mmol) in THF/DCM (60 mL/20 mL), at −78° C. under N2. A suspension was formed at the end of the addition. After 1 hour, an additional aliquot of DIBAL (3.0 mmol, 3.0 mL of a 1.0 M solution in hexanes) was added. The reaction was deemed complete after 1 hour at −78° C. MeOH (5 mL) was carefully added to quench any unreacted DIBAL and the mixture was partitioned between EtOAc and 1 M HCl. The organic layer was separated and washed with brine, dried over anhydrous MgSO4 and filtered. Upon removal of the solvents in vacuum, the crude solid residue was triturated with Et2O. The product was obtained as a beige solid (0.80 g, 2.25 mmol, 64%). 1H NMR (CDCl3, 300 MHz): 10.55 (s, 1H), 7.40-7.33 (m, 1H), 7.00-6.93 (m, 2H), 5.38 (s, 2H), 2.78 (s, 3H), 2.69 (s, 3H); LRMS m/z 356.0 (M+−1), 358.0 (M++1).