Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)[N:4]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[N:4]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(Oc2cccc(C=C3CCNCC3)c2)n1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnc4)CC3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
2-Methyl-6-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (500 mg, 1.42 mmol, from Step 5), phenyl pyridin-3-ylcarbamate (333 mg, 1.56 mmol) and triethylamine (0.79 mL, 5.66 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4OH):CH2Cl2) to afford the title compound (399 mg) as a foamy white solid. MS (APCI 10V) AP+ 401.5, 281.2 1H NMR (400 MHz, CD3OD) d ppm 2.42 (s, 3H) 2.45 (td, J=5.74, 1.04 Hz, 2H) 2.56 (td, J=5.80, 1.15 Hz, 2H) 3.51-3.58 (m, 2H) 3.61-3.67 (m, 2H) 6.44 (s, 1H) 6.64 (d, J=8.24 Hz, 1H) 6.91-6.97 (m, 2H) 6.99 (d, J=7.19 Hz, 1H) 7.07 (d, J=7.65 Hz, 1H) 7.29-7.40 (m, 2H) 7.63-7.74 (m, 1H) 7.90 (ddd, J=8.38, 2.53, 1.39 Hz, 1H) 8.16 (dd, J=4.79, 1.40 Hz, 1H) 8.58 (d, J=2.31 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:29])=[C:7]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[F:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:29])=[C:7]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(F)cc2C2(CCOCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CNC(=O)C1=C(O)c2ccc(F)cc2C2(CCOCC2)C1=O
Yield: 39.2 %

Procedure:
1,1-Dimethylethyl N-((7-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (703 mg, 1.73 mmol) was stirred in TFA (2 mL, 26.9 mmol) at room temperature for 25 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as an off-white solid (237 mg). MS (m/e)=350.1 (M+H)+. Calculated for C18H16F3NO6 349.10.
Reaction SMILES: [CH:1]1([O:7][C:8]2[C:9](=[O:14])[NH:10][CH:11]=[CH:12][N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O1CCOCC1.[Cu]I>[CH:1]1([O:7][C:8]2[C:9](=[O:14])[N:10]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:11]=[CH:12][N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1[nH]ccnc1OC1CCCCC1
Reactant: Fc1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=c1c(OC2CCCCC2)nccn1-c1ccc(F)cc1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
Copper (I) iodide (0.98 g, 5.1 mmol) was added to a suspension of 3-(cyclohexyloxy)-2(1H)-pyrazinone (1.0 g, 5.1 mmol, prepared according to the method described in the Journal of Medicinal Chemistry, 52(7), 2076-2089; 2009), 1-bromo-4-fluorobenzene (0.85 mL, 7.7 mmol), N,N′-dimethylethylenediamine (0.55 mL, 5.1 mmol) and K3PO4 (2.18 g, 10.3 mmol) in a mixture of DMF (2 mL) and 1,4-dioxane (8 mL). The reaction mixture was stirred at 180° C. for 15 minutes under microwave irradiation. The solid was filtered off and washed with DCM, the filtrate was treated with a 32% solution of NH4OH. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 1/99 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-cyclohexyloxy-1-(4-fluoro-phenyl)-1H-pyrazin-2-one (1.13 g, 76% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:2]=1.O.NN>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCc1cnc2ccccc2c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCCc1cnc2ccccc2c1
Yield: 89.2 %

Procedure:
3-Quinolinehexanamine was prepared in the same manner as described in Example 110, starting from 4.4 g of 2-[6-(3-quinolinyl)hexyl]-1H-isoindole-1,3(2H)-dione and 2.5 g of hydrazine hydrate in 60 ml of ethanol. The crude product was evaporatively distilled to give 2.5 g (89%) of 3-quinolinehexanamine, bp 144°-155° C./0.1 mm. Bis picrate mp 225°-226° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[OH:10][CH:11]([CH3:15])[C:12](O)=O.Cl.N>CO>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:12]([CH:11]([OH:10])[CH3:15])[NH:9][C:5]2=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1N
Reactant: CC(O)C(=O)O
Agent: Cl
Agent: N
Solvent: CO
Product: CC(O)c1nc2nc(Cl)ccc2[nH]1

Procedure:
6-Chloropyridine-2,3-diamine (150 mg, 1.05 mmol) and 2-hydroxypropanoic acid (277 mg, 2.61 mmol) were heated to 110° C. for 4 hours. To the cooled mixture was then added 1 N hydrochloric acid, followed by 7N ammonia in methanol to neutralize the acid. The aqueous solution was then evaporated under reduced pressure and the resulting oil was purified via flash chromatography (silica, 0-3% methanol/ethyl acetate) to afford the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.O=[C:13]1[NH:18][CH2:17][C@H:16]([C:19](OC)=[O:20])[C@@H:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:14]1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:23]1([C@H:15]2[CH2:14][CH2:13][NH:18][CH2:17][C@@H:16]2[CH2:19][OH:20])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@H]1CNC(=O)C[C@@H]1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CNCC[C@@H]1c1ccccc1
Temperature: 75 °C
Reaction time: 35 h
Yield: 84.6 %

Procedure:
To a suspension of 1.8 g of lithium aluminum hydride in 40 mL of toluene—40 mL of THF was added 6.3 g of methyl rel-(3R,4S)-6-oxo-4-phenylpiperidine-3-carboxylate at room temperature. The reaction mixture was stirred at 75° C. for 35 hours. After completion of the reaction, it was cooled to room temperature, and 1.0 mL of water, 1.0 mL of a 1 M aqueous sodium hydroxide solution, and 1.0 mL of water added thereto in this order, followed by stirring for 10 minutes. This mixture was dried over anhydrous sodium sulfate, the insolubles were removed by filtration, and the filtrate was then concentrated under reduced pressure to obtain a white solid of 4.37 g of rel-[(3R,4S)-4-phenylpiperidin-3-yl]methanol as a crude product. ESI+: 192
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([CH3:18])=[C:16]([Br:17])[C:3]=12.[OH-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([CH3:18])=[C:16]([Br:17])[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc(C)c(Br)c2c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2sc(C)c(Br)c2c(N)c1C(=O)O
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a solution of ethyl 4-amino-3-bromo-2,6-dimethylthieno[2,3-b]pyridine-5-carboxylate (5 g, 15.19 mmol) (Description 6) in ethanol (50 mL) was added aqueous NaOH (3M) (20.25 mL, 60.8 mmol) and the mixture stirred at 100° C. for 1 h. The reaction mixture was cooled and combined with material (4.43 g) from a similar reaction. The combined solution was acidified with aqueous HCl (1M) to pH 6-7. Ethanol was removed in vacuo. Water (50 mL) was added and the mixture extracted with DCM (5×50 mL). The combined organics were dried over MgSO4, filtered and solvent removed in vacuo, to afford the title compound (2.98 g). LCMS (A) m/z: 301/303 [M+1]+, Rt 0.73 min (acidic).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])C([O-])=O.[K+]>>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:23]([F:28])([F:27])[C:22]([F:30])([F:29])[F:21])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Agent: [K+]
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21

Procedure:
Using 2,2-bis(fluoromethyl)-6-iodo-2H-1-benzopyran-4-carboxylic acid ethyl ester and potassium pentafluoropropionate, an oily product of 6-pentafluoroethyl-2,2-bis(fluoromethyl)-2H-1-benzopyran-4-carboxylic acid ethyl ester was obtained according to the same method as in Example 23 (4).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[CH2:14](O)[CH3:15]>C(Cl)Cl>[CH2:14]([O:12][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1)=[O:13])[CH3:15]
Reactant: Cn1ccc2ccc(C(=O)O)cc21
Reactant: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc2ccn(C)c2c1
Reaction time: 15 h
Yield: 89 %

Procedure:
A solution of 1.05 g (6.0 mmol) of 1-methyl-1H-indole-6-carboxylic acid in 15 mL of methylene chloride was added to a stirring solution of 1.905 g (10 mmole) of 1-ethyl-3-(3dimethyl-aminopropyl)carbodiimide hydrochloride, 1.20 g (10 mmole) of 4-dirmethylaminopyridine in 20 mL of methylene chloride at room temperature. Ethanol was added and the reaction stirred for 15 h. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with brine and dried on anhydrous magnesium sulfate. Chrorriatographic purification of this material gave 1.08 g (89%) of 1-methyl-1H-indole-6-carboxylic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]O)[CH2:17][CH2:16]1>>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:22][CH2:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC1CCNCC1
Reactant: OC(c1ccccc1)c1ccccc1
Product: c1ccc(C(OCCC2CCNCC2)c2ccccc2)cc1
Yield: 94 %

Procedure:
Using benzhydrol and 4-piperidineethanol, the procedure of Reference Example 23 was otherwise repeated to provide the title compound. Yield 94%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6]S([O-])(=O)=O)[CH3:3].[Na+].[CH3:12][N:13]([CH:15]([CH3:17])[O-])[CH3:14].[Na+]>>[CH3:1][N:2]([CH2:4][CH2:5][O:6][CH2:17][CH2:15][N:13]([CH3:14])[CH3:12])[CH3:3]
Reactant: CC([O-])N(C)C
Reactant: CN(C)CCOS(=O)(=O)[O-]
Agent: [Na+]
Product: CN(C)CCOCCN(C)C

Procedure:
subsequently, heating the resulting sodium dimethylaminoethylsulfate in the presence of sodium dimethylaminoethoxide to produce bis(N,N-dimethylaminoethyl)ether.
Reaction SMILES: C([O:3][C:4](=[O:21])[C@@H:5](O)[C:6](=[O:19])[CH2:7][CH:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:9]([CH3:11])[CH3:10])C.[OH-].[Na+]>C1COCC1>[OH:19][C:6]1[CH2:7][C@:8]([CH:9]([CH3:11])[CH3:10])([CH2:12][CH2:13][C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[O:3][C:4](=[O:21])[CH:5]=1
Reactant: CCOC(=O)[C@@H](O)C(=O)CC(CCc1ccsc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@]1(CCc2ccsc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 8 using (S)-hydroxy-6-methyl-3-oxo-5-(2-thiophen-3-yl-ethyl)-heptanoic acid ethyl ester (6.4 mmol), 0.1N NaOH (400 mL), and THF (40 mL). The product was triturated from Et2O, mp 117-123° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH:11]([OH:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[CH:17]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[OH:16][CH:11]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:17][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: COc1ccc(N)c(CC(O)C(C)(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CNc2ccc(OC)cc2CC(O)C(C)(C)C)c1
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a solution of 1-(2-amino-5-methoxyphenyl)-3,3-dimethylbutan-2-ol (155 mg) and methyl 3-formylbenzoate (137 mg) in acetic acid (2 mL) was added sodium triacetoxyborohydride (294 mg) at room temperature, and the mixture was stirred for one hour. The reaction mixture was diluted with ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (205 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl[CH2:14]/[CH:15]=[C:16]1/[C:17]2[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[CH:28]=[CH:27][C:18]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]/1=2>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:14]/[CH:15]=[C:16]2/[C:17]3[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[CH:28]=[CH:27][C:18]=3[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]/2=3)[CH:2]=1
Reactant: c1ccncc1
Reactant: COC(=O)c1ccc2c(c1)/C(=C/CCl)c1ccccc1CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)/C(=C/Cc1cccnc1)c1ccccc1CO2
Temperature: 25 °C

Procedure:
To 50 ml of pyridine was added to 2.0 g of lithium aluminum hydride, and the mixture was stirred at room temperature for one night. Then, 90 ml of tetrahydrofuran solution containing 5.0 g of Compound h was dropwise added thereto under ice-cooling. The mixture was stirred at room temperature for 5 hours, and the solvent was distilled off under reduced pressure. The residue was washed with tetrahydrofuran, and the washings were concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate:triethylamine=10:10:1) to give 1.7 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.C1([SiH3])C=CC=CC=1.C([OH:38])(C)C.C(Cl)Cl>[Co]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@:13]([CH2:23][C:24]([OH:38])([CH3:26])[CH3:25])([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Reactant: CC(C)O
Agent: [Co]
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-methylallyl)-4-phenyl-1,3-diazepan-2-one (23 mg, 0.054 mmol) in 2:1 i-Propanol/CH2Cl2 (2 mL) was added the cobalt catalyst A, prepared as described below, (c.a. 1 mg, cat. amount) and phenylsilane (250 μL, excess). The mixture was stirred vigorously in open air for 1 h. LC-MS found the reaction completed. The mixture was quenched with 1% aq HCl, concentrated and purified by prep HPLC to afford the title compound (9.1 mg, 38%). LC-MS Method 1 tR=2.12 min., m/z 445, 447(M+1); 1H NMR (CDCl3) δ 7.48 (d, 2H), 7.37-7.22 (m, 5H), 6.97 (d, 2H), 5.52 (q, 1H), 2.84 (td, 1H), 2.65 (dt, 1H), 2.28-2.07 (m, 3H), 1.89 (d, 1H), 1.45 (d, 3H), 1.21 (s, 3H), 1.07 (m, 1H), 0.62 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)[OH:4].[CH2:17]([N:19]1[C:23]2=[N:24][C:25]([CH2:47][CH3:48])=[C:26]([CH2:35][NH:36][C:37](=[O:46])[C:38]3[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][CH:39]=3)[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:22]2[CH:21]=[N:20]1)[CH3:18]>>[CH2:17]([N:19]1[C:23]2=[N:24][C:25]([CH2:47][CH3:48])=[C:26]([CH2:35][NH:36][C:37](=[O:46])[C:38]3[CH:39]=[CH:40][C:41]([CH2:44][NH:1][CH2:2][C@H:3]([OH:4])[C:5]4[CH:14]=[CH:13][C:12]([OH:15])=[C:11]5[C:6]=4[CH:7]=[CH:8][C:9](=[O:16])[NH:10]5)=[CH:42][CH:43]=3)[C:27]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:22]2[CH:21]=[N:20]1)[CH3:18]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C=O)cc1
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 43, using Intermediate 4 in place of Intermediate 8 and Intermediate 31 in place of Intermediate 29.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([OH:17])=O)[CH2:12][C:11]2([Cl:14])[Cl:13])=[CH:6][CH:5]=1)[CH3:2].S(Cl)([Cl:20])=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([Cl:20])=[O:17])[CH2:12][C:11]2([Cl:14])[Cl:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(C2(C(=O)O)CC2(Cl)Cl)cc1
Product: CCOc1ccc(C2(C(=O)Cl)CC2(Cl)Cl)cc1

Procedure:
The 1-p-ethoxyphenyl-2,2-dichlorocyclopropane-1-carboxylic acid (1.38 g) was refluxed on a water bath with thionyl chloride (1.19 g) for 15 minutes. The excess thionyl chloride was then evaporated under vacuum (1 Torr.) and the residue of carbonyl chloride reacted without further purification with one of the alcohols (a), (b), (c) or (d). ##STR11##
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][CH:16]([OH:19])[CH2:17][CH3:18]>>[CH:16]([O:19][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH2:17][CH3:18])[CH3:15]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CCC(C)O
Product: CCC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) and rac-butan-2-ol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 271.4 ([M−H]−, 100%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[CH:12]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:11]
Reactant: CCOC(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 1.2 eq oxalyl chloride (12.69 g, 0.10 mol) in dichloromethane (150 mL) was cooled to approximately −78° C. and treated dropwise, under nitrogen, with a solution of 2.4 eq anhydrous dimethylsulfoxide (15.63 g, 0.20 mol) in dichloromethane (50 mL). 15 minutes after the addition was complete, a solution of 1.0 eq ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate (15.60 g, 83.3 mmol) in dichloromethane (50 mL) was added dropwise. 30 minutes after the addition was complete, a solution of 3.0 eq triethylamine (25.30 g, 0.25 mol) in dichloromethane (50 mL) was added dropwise and the reaction warmed to room temperature. The reaction was stirred at room temperature for 1 hour, then quenched with saturated sodium bicarbonate (500 mL). The layers were separated and the aqueous layer extracted once with dichloromethane (200 mL). The pooled organic layers were washed with H2O (3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine, then dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to afford 13.84 g ethyl 4-formylpiperidine-1-carboxylate as a viscous amber oil. Yield=90%. 1H-NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 4.10 (q, J=7.2 Hz, 2H), 4.00 (br m, 2H), 2.97 (m, 2H), 2.40 (m, 1H), 1.87 (br m, 2H), 1.54 (m, 2H), 1.23 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[C:25]([Cu])#[N:26].O.Cl>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: COC(=O)c1nc(I)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-1-iodo-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (136 mg, 0.31 mmol) and CuCN (56 mg, 0.62 mmol) in 5 mL of DMF was refluxed for 8 min. The mixture was cooled to r.t. and poured into a mixture of water and CH2Cl2. 4 M HCl was added to the mixture with vigorous stirring until no solid was present. The aqueous layer was extracted with additional CH2Cl2, and the combined organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-10% EtOAc/CH2Cl2) to give 88 mg of the title compound. MS: (+) m/z 336.00 (M+1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:28][CH2:29][O:30][CH3:31])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[CH2:32][CH2:33][CH3:34])[CH:9]=[CH:8][N:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:23][C:20]([F:21])([F:22])[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[CH:11]=2)=[C:14]([CH2:32][CH2:33][CH3:34])[CH:15]=1)([O:28][CH2:29][O:30][CH3:31])[C:24]([F:27])([F:26])[F:25]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(COC(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(CO)c1
Yield: 82.6 %

Procedure:
To a solution of (4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)pyridin-2-yl)methyl acetate (221 mg, 446 μmol) in methanol (3 mL), potassium carbonate (123 mg) was added at room temperature and the resultant mixture was stirred. After completion of the reaction, the reaction solution was concentrated in vacuo. The residue was neutralized by adding water and 2 mol/L of hydrochloric acid at room temperature, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (167 mg, yield 83%) was obtained as a colorless oil.