Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:31][NH:32][CH:33]([CH3:44])[CH2:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:37]=1[CH3:43]>CN(C)C=O.C(N(CC)CC)C>[CH3:43][C:37]1[C:38]([CH3:42])=[CH:39][CH:40]=[CH:41][C:36]=1[O:35][CH2:34][CH:33]([N:32]([CH3:31])[C:13](=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1)[CH3:44]
Reactant: CS(=O)(=O)Nc1ccc(CC(=O)O)cc1
Reactant: CNC(C)COc1cccc(C)c1C
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(OCC(C)N(C)C(=O)Cc2ccc(NS(C)(=O)=O)cc2)c1C
Temperature: -10 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution containing 0.80 g (3.5 mmol) of 4-methanesulfonamido-phenylacetic acid (Example 32) in 20 ml of N,N-dimethylformamide (DMF) 0.46 ml (0.42 g, 4,2 mmol) of 4-methylmorpholine is added, the mixture is cooled to −10° C. and 0.65 ml (0.70 g, 5 mmol) of isobutyl chloroformate is added. After 10 minutes a solution containing 0.68 g (3.5 mmol) of N-methyl-2-(2,3-dimethylphenoxy)-1-methylethylamine (Example 44) in 3 ml of DMF pre-cooled to −10° C. is added, then the pH value of the mixture is adjusted to 8.5 by adding triethylamine. The reaction mixture is stirred at −10° C. for 1 hour, then at 0° C. for 1 hour. Then, the solvent is evaporated under reduced pressure and the solid residue is alkalinized by adding aqueous ammonia solution and distributed between water and ethyl acetate. The aqueous phase is washed twice with ethyl acetate, the combined organic phase is washed once with water, dried over sodium sulphate and evaporated. Thus, 1.13 g of the title substance are obtained as an amorphous substance, which is suitable to the next step without further purification. Yield: 80%.
Reaction SMILES: C(Cl)Cl.C(Cl)(Cl)Cl.[CH3:8][C@:9]12[CH2:19][CH2:18][C@@H:17]3[CH2:20][C@:14]1([O:15][C:16]3([CH3:22])[CH3:21])[CH:13]=[CH:12][CH2:11][CH2:10]2.ClC1C=CC=C(C(OO)=[O:31])C=1>C1C=CC=CC=1>[CH3:8][C@:9]12[CH2:19][CH2:18][C@@H:17]3[CH2:20][C@@:14]1([O:15][C:16]3([CH3:22])[CH3:21])[C@H:13]1[O:31][CH:12]1[CH2:11][CH2:10]2
Reactant: CC1(C)O[C@@]23C=CCC[C@@]2(C)CC[C@@H]1C3
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)O[C@@]23C[C@H]1CC[C@]2(C)CCC1O[C@@H]13

Procedure:
In Scheme III, compound of formula (5) is reduced by metallic hydride complex, preferably LiAlH4, to form compound of formula (Ic-1) in organic solvent such as diethylether, tetrahydrofuran, 1,2-dimethoxyethane, or any other solvent that does not interfere with the reaction at room temperature. Oxidation of compound of formula (Ic-1) by CrO3/pyridine, pyridinum chlorochromate (PCC) or Jones reagent, preferably PCC, produces compound of formula (Ic-2) and the reaction is generally conducted in organic solvent such as methylene chloride, chloroform, benzene or any other solvent that does not interfere with the reaction at room temperature or heated. (1S,6S,9R)6,10,10-trimethyl-11-oxatricyclo[7.2.1.01,6]dodec-2-ene (formula 8) is oxidized by organic peracid, preferably meta-chloroperbenzoic acid, to form (1S,2S,6R,9R)6,10,10-trimethyl-2,3-epoxy-11-oxatricyclo[7.2.1.01,6]dodecane (formula 9) and the reaction is conducted in organic solvent such as diethylether, methylene chloride, chloroform, benzene or any other solvent that does not interfere with the reaction at room temperature or cooled. The thus produced compound (9) is reduced by metallic hydride complex, preferably LiAlH4 to form (1S,3S,6R,9R)6,10,10-trimethyl-11-oxatricyclo[7.2.1.01,6]dodecan-3-one (formula 10) and the reaction is conducted in organic solvent such as diethylether, tetrahydrofuran, 1,2-dimethoxyethane or any other solvent that does not interfere with the reaction at room temperature or cooled with ice bath. Compound of formula (10) is oxidized by CrO3/pyridine, PCC, or Jones reagent, preferably PCC to form (1S,6R,9R)6,10,10-trimethyl-11-oxatricyclo[7.2.1.01,6]dodecan-3-one (formula 11 ) and the reaction is conducted in organic solvent such as methylene chloride, chloroform, benzene or any other solvent that does not interfere with the reaction at room temperature or heated. Compound (11) is reacted with organometallic reagent such as Grignard reagent or organolithium reagent to form compound of formula (Ic-3) and the reaction is conducted in organic solvent such as diethylether, tetrahydrofuran or any other solvent that does not interfere with the reaction at room temperature or cooled with ice bath. Compound of formula (10) react with phosphorous trihalide in the presence of triphenylphosphine to form (1S,3R,6R,9R)6,10,10-trimethyl-3-halo-11-oxatricyclo[7.2.1.01,6]dodecane and the reaction is conducted in anhydrous diethylether and cooled with ice bath or ice-salt mixture.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[OH-].[K+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:15]1([S:21]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
After a suspension of 5-nitroindole (25) (1.00 g, 6.17 mmol), tetrabutylammonium bisulfate (0.32 g, 0.93 mmol) and KOH (0.69 g, 12.33 mmol) in CH2Cl2 (20 mL) was stirred for 30 min, benzenesulfonyl chloride (1.18 ml, 9.25 mmol) was added and stirred at room temperature overnight. The reaction was quenched with water extracted with CH2Cl2 (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a yellow residue, which was purified by silica gel chromatography (EtOAc:n-hexane=1:4) to afford 26 (1.72 g). 1H NMR (500 MHz, CD3OD): δ 6.81 (d, J=3.6 Hz, 1H), 7.48-7.51 (m, 2H), 7.58-7.61 (m, 1H), 7.73 (d, J=3.69 Hz, 1H), 7.90 (d, J=7.64 Hz, 2H), 8.09 (d, J=9.0 Hz, 1H), 8.21 (dd, J=9.0, 2.0 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1.Cl.[C:12]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][N:19]([CH3:20])[CH2:18][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:21])=[N:4][CH:5]=1)#[N:8]
Reactant: N#Cc1ccc(CBr)nc1
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cn1
Temperature: 60 °C
Yield: 117.6 %

Procedure:
A mixture of 6-bromomethylnicotinonitrile (Advanced Chemical Intermediates, 1.39 g; 7.06 mmol), sarcosine tert-butyl ester hydrochloride (1.54 g; 8.47 mmol) and K2CO3 (2.34 g; 17.0 mmol) in MeCN (25 mL) heated at 60° C. for 18 hours. The solvent was evaporated in vacuo. The residue was dissolved in a mixture of DCM and water and then poured through a hydrophobic frit. The filtrate was evaporated to afford the title product (2.17 g, quantitative). 1H NMR (CDCl3, 400 MHz) δ 8.82 (1 H, d, J=2 Hz), 7.95-7.92 (1 H, dd, J=8.4, 2 Hz), 7.73 (1 H, d, J=8 Hz), 3.91 (2 H, s), 3.28 (2 H, s), 2.41 (3 H, s), 1.48 (9 H, s).
Reaction SMILES: [OH:1][CH:2]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][N:4]([CH2:14][CH:15]([OH:24])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[K+]>C(O)CC>[CH2:33]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][N:4]([CH2:14][CH:15]([OH:24])[CH2:16][O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:3][CH:2]([OH:1])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:12][CH:11]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(CCN(CC(O)COc2ccccc2)CC(O)COc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: OC(COc1ccccc1)CN(CCc1ccc(OCc2ccccc2)cc1)CC(O)COc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 1.0 g of p-[2-[bis[(RS)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenol, 0.27 ml of benzyl bromide and 257 mg of potassium hydroxide in 30 ml of n-propanol was heated to 120° for 18 hours. The reaction mixture was poured on to ice-water and extracted with ethyl acetate. The crude product obtained after evaporation of the solvent was chromatographed on silica gel. The fractions which were uniform according to thin-layer chromatography were recrystallized from acetone-hexane and yielded pure 1,1'-[[p-(benzyloxy)phenethyl]imino]bis[(RS)-3-phenoxy-2-propanol], m.p. 106°-110°, ε219 =30020.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].C[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C>[C:10]1(=[C:2]2[CH2:3][CH2:4][CH2:5][C:1]2=[O:6])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C1CCCC1
Reactant: CCCCCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CCCC1=C1CCCC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 52 %

Procedure:
To a stirring solution of cyclopentanone (336.5 g, 4.0 moles) in absolute ethanol (500 mL) at room temperature was added KOH (5.6 g, 0.1 mole) in one portion. The reaction was stirred at room temperature for 65 hours. The reaction was determined to be completed by TLC and GC analyses. Hexane was added to the reaction mixture and the layers were separated. The organic layer was washed successively with 10% HCl (aqueous), saturated NaHCO3 (aqueous) and brine. The resulting organic layer was dried with MgSO4, filtered, and concentrated. The brown oil was distilled under vacuum to give 2-cyclopentylidenecyclopentan-1-one (155 g, 52% yield). The structural formula of 2-cyclopentylidenecyclopentan-1-one is shown in FIG. 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6].Cl[C:14]1[N:23]=[C:22]([NH2:24])[C:21]2[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[CH:20]=2)[N:15]=1>>[NH2:24][C:22]1[C:21]2[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[CH:20]=2)[N:15]=[C:14]([N:10]2[CH2:9][CH2:8][N:7]([C:5](=[O:6])[CH2:4][CH2:3][O:2][CH3:1])[CH2:12][CH2:11]2)[N:23]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: COCCC(=O)N1CCNCC1
Product: COCCC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(3-methoxypropionyl) piperazine (6.4 g) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (8.9 g) in 100 ml of isoamylalchohol is refluxed with stirring for 6 hours. The reaction mixture is cooled at room temperature for 12 hours. The crystallized product is separated and wet recrystallized by dissolving in warm methanol, with the subsequent addition of ether to the beginning of turbidity. The yield is 13.4 g of the title compound in the form of a hydrochloride monohydrate, which melts at 268°-272° C. with decomposition. Another crystallization from a methanol-ether mixture yields the analytically pure product melting at 273°-278° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11](Br)Br)=[CH:7][N:6]=1)=[O:4].C([OH:16])C>C1COCC1.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=[O:16])=[CH:7][N:6]=1)=[O:4]
Reactant: CCO
Reactant: COC(=O)c1cnc(C(Br)Br)cn1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(C=O)cn1
Temperature: 80 °C

Procedure:
A solution of 5-dibromomethyl-pyrazine-2-carboxylic acid methyl ester (1.00 g, 3.23 mmol) in a mixture of ethanol (20 mL) and THF (10 mL) was heated to 80° C. A solution of silver nitrate (2.20 g, 12.9 mmol) in H2O (4 mL) was added. The reaction mixture was heated at 80° C. for 1.25 h and was filtered while hot. The filtrate was concentrated to yield the title compound (1.36 g). This material was carried to the next step without purification.
Reaction SMILES: C([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)C.[OH-].[K+:14]>C(O)C>[K+:14].[N:6]1([CH2:5][C:4]([O-:12])=[O:3])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)CN1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CN1CCOCC1
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of morpholin-4-yl-acetic acid ethyl ester (117 mg, 0.67 mmol) in ethanol (4 mL) was added 6N KOH (110 μL, 0.67 mmol) via syringe and stirring was continued for 3 h. Concentration in vacuo afforded 122 mg (100%) of morpholin-4-yl-acetic acid potassium salt. To a mixture of morpholin-4-yl-acetic acid potassium salt (29 mg, 0.15 mmol), 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (65.1 mg, 0.13 mmol, as prepared in Example 14, step (b)) and PyBroP (93 mg, 0.19 mmol) in CH2Cl2 (4 mL) was added DIEA (51 μL, 0.29 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with CH2Cl2 (50 mL), washed with H2O (2×25 mL), dried (Na2SO4) and concentrated in vacuo. Purification of the crude product by silica gel preparative TLC afforded 8.1 mg (12%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.68-2.04 (m, 5H), 2.20-2.29 (m, 4H), 2.53-2.78 (m, 5H), 3.09-3.23 (m, 6H), 3.35-3.40 (m, 1H), 3.72 (br s, 4H), 4.16-4.22 (m, 1H), 4.73-4.77 (m, 1H), 5.82 (s, 1H), 7.00 (s, 1H), 7.12 (dd, 1H, J=0.6, 8.0 Hz), 7.73 (s, 1H), 8.27 (d, 1H, J=8.1 Hz), 9.48 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C28H34N6O3, 503.27 (M+H). found 503.1.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CCCC>[Cu]>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: COc1ccc(N)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: COc1ccc(Nc2ccccc2C(=O)O)cc1
Reaction time: 4 h

Procedure:
A mixture of 80 g. 2-chlorobenzoic acid, 80 g. 4-anisidine, 80 g. potassium carbonate, 4 g. activated copper powder, and 800 ml. amyl alcohol was heated under reflux with efficient stirring for 4 hours. The amyl alcohol was removed by steam distillation and the remaining aqueous phase was filtered and made neutral by addition of 1:1 concentrated hydrochloric acid-water. The resulting solid (102 g.) was collected by filtration to give after recrystallization from isopropyl alcohol N-(4-methoxyphenyl)anthranilic acid; m.p. 183°-184° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(OCC)(=O)C>[Pd].C(O)(=O)C>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([CH:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]3[NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1cnn2c1NCCC2c1cccc(C(F)(F)F)c1
Reaction time: 4.5 h

Procedure:
A mixture of 1.5 parts of 4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 50 parts of ethyl acetate, 10 parts of acetic acid and 0.2 parts of 5% palladium-on-carbon catalyst was shaken on a Parr hydrogenator under about 30 pounds of hydrogen pressure for 4.5 hours. The reaction mixture was filtered, and the mother liquor was concentrated to remove the solvent. The yellow oil which was obtained was crystallized by trituration in ether. The crystalline product was recrystallized from ethyl acetate by addition of hexane. The product 4,5,6,7-tetrahydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile melted at 181°-183° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[NH2:5].F[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([NH:5][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1)[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: CC(C)C[C@H](N)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(N[C@@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cn3)cc2)nc1
Temperature: 107.5 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
A mixture of crude (S)-3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butan-1-amine (66.34 g, 192.4 mmol), methyl 6-fluoronicotinate (32.8 g, 212 mmol), and freshly pulverized and dried (150 C, vacuum oven, 12 h) tripotassium phosphate (75.6 g, 356 mmol) was purged with dry nitrogen then diluted with N,N-dimethylacetamide (320 ml). The mixture was heated to 110° C. (107-108° C. internal temperature) for 24 hours. The reaction was diluted with water (˜1.5 L) and the resulting mixture was stirred vigorously for 15 minutes. The aqueous portion was decanted, leaving behind a thick amorphous solid. This material was washed with water (2×1 L). The resulting solid was dissolved in ethyl acetate and the remaining water was removed via azeotropic distillation (rotary evaporator, approximately 2×1 L ethyl acetate). The combined aqueous layers were stirred vigorously for 12 hours resulting in the precipitation of an additional aliquot (approximately 500 mg) of the crude product that was combined with the originally recovered material. The crude material was purified via ISCO MPLC (SiO2, 0-75% ethyl acetate in heptane) to yield the product (53.0 g, 62%) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.93 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.97 (dd, J=8.5, 2.1 Hz, 1H), 7.92 (dd, J=8.9, 2.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 6.25 (d, J=8.8 Hz, 1H), 5.79 (d, J 6.5 Hz, 1H), 4.73-4.85 (m, 1H), 3.84 (s, 3H), 1.77-1.86 (m, 1H), 1.65-1.77 (m, 2H), 1.01 (d, J=6.1 Hz, 3H), 0.97 (d, J=6.1 Hz, 3H). MS (M+1): 444.5.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][Zn+]>C1COCC1.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>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: Fc1ccc(C[Zn+])cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccc(F)c(F)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
Methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen. (3,4-Difluorobenzyl)zinc(II) bromide (0.5 M in THF) (100 mL, 50.00 mmol) was added and the brown solution was stirred at 60° C. overnight. The reaction was quenched by addition of methanol (50 mL). The solution was diluted with EtOAc and washed with NH4Cl (aq). The organic layer was dried over MgSO4, filtered and evaporated to yield a yellow oil. The compound was purified via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 6 CV to yield methyl 2-(3,4-difluorobenzyl)isonicotinate (7.7 g, 90%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.93 (s, 3H), 4.16 (s, 2H), 6.94-7.01 (m, 1H), 7.02-7.12 (m, 2H), 7.66-7.71 (m, 2H), 8.70 (dd, 1H). MS m/z 264 (M+H)+
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)(Cl)Cl>[C:14]1([C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][Cl:5])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)CCCCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCCCCCl)c1ccccc1
Reaction time: 0.25 h
Yield: 34.6 %

Procedure:
Aluminum chloride (16 g, 0.12 mol) is suspended in carbon tetrachloride (80 ml) and 6-chlorohexanoyl chloride (20 g, 0.12 mol) is added dropwise to the suspension with ice-cooling. After completion of addition, the mixture is stirred for 15 minutes and benzene (7.8 g, 0.1 mol) is added dropwise to the mixture with ice-cooling. After stirring with ice-cooling for 1 hour, the mixture is poured into ice-hydrochloric acid and extracted with carbon tetrachloride. The carbon tetrachloride extract is washed with water, saturated aqueous sodium bicarbonate, water and then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The dried solution is distilled to obtain 5-chloropentyl phenyl ketone (7.3 g), b.p. 143°-150° C./0.5 mmHg.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH4+].[OH-:9]>[Cu]I.C1COCC1>[O:9]1[CH2:4][CH2:3][CH2:2][CH2:1][CH:6]1[CH2:5][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[OH:7]
Reactant: [OH-]
Reactant: C1CCC2OC2C1
Agent: [Cu]I
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1CCCCC1CC1CCCCO1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirring THF solution of the Grignard reagent (formed from 2-(bromomethyl)tetrahydro-2H-pyran, 16a and powdered magnesium, 20 milligram-atoms) and cooled to -30° C., CuI is added as a bolus. After approx. 10 min., a solution of cyclohexene oxide (10 mmol) is added slowly, maintaining the reaction temperature below -25° C. until the addition is complete. The mixture is then stirred at 0° C. for 2 hours and checked by TLC and/or GC. The reaction is quenched by pouring into concentrated NH4Cl solution (if starting material remains, the reaction may be warmed to r.t. and followed by TLC or GC until no additional starting material is observed). Also, the addition of some concentrated NH4OH solution combined with vigorous stirring may be used to remove suspended CuI from the mixture. This mixture is then extracted with 2 portions of ether or 1:1 EA-hexane. The combined extracts are then washed with brine and dried (MgSO4). The product may be sufficiently pure at this point for use in the next reaction. Otherwise, it may be purified by distillation or flash chromatography.
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7](=[O:21])[C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[C:9]=1[F:20])([CH3:5])[CH3:4].S(Cl)(Cl)=O.[H-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[F:20][C:9]1[C:10]([C:16]([F:17])([F:18])[F:19])=[C:11]([F:15])[C:12]([F:14])=[CH:13][C:8]=1[C:7]1[O:21][CH2:5][C:3]([CH3:4])([CH3:2])[N:6]=1
Reactant: CC(C)(CO)NC(=O)c1cc(F)c(F)c(C(F)(F)F)c1F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)COC(c2cc(F)c(F)c(C(F)(F)F)c2F)=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
A solution of 5.81 g (18.4 mmol) of N-(2-hydroxy-1,1-dimethylethyl)-2,4,5-trifluoro-3-(trifluoromethyl)-benzamide in 100 ml of chloroform at 0° C. was treated dropwise with 5 ml of thionyl chloride. The mixture was allowed to warm to room temperature overnight. The solution was concentrated to a yellow oil which was dissolved in 20 ml of DMF and treated with 0.8 g (21.6 mmol) of 60% sodium hydride. This reaction mixture was stirred at room temperature for 18 hours, then poured into 50 ml of dilute NaHCO3. The solution eas extracted with ethyl acetate; the organic phase was washed with water and dried over magnesium sulfate. Concentration in vacuo gave an orange oil which was chromatographed on silica, eluting with 2% methanol in chloroform, to give 2.62 g of a yellow oil.