Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][OH:14])[C:10](=[O:15])[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[CH2:24]1[O:26][CH2:25]1.[OH-].[NH4+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][OH:14])[C:10](=[O:15])[CH2:9][N:8]3[CH2:24][CH2:25][O:26][C:7]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: C1CO1
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CCO
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C1CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc2N1CCO
Reaction time: 0.33 h

Procedure:
A solution of 3.3 g (0.01 M) of 7-chloro-1-(2-hydroxyethyl)-5-(2-fluorophenyl)-1,3-dihyrdo-2H-1,4-benzodiazepin-2-one in 40 ml of 1,2-dichloro ethane under nitrogen was treated with 5.2 g (0.02 M) of stannic chloride with stirring. After 20 min, the mixture was cooled in an ice bath and 2.6 g (0.06 M) of ethylene oxide was added. After 1 hr at room temperature, the reaction mixture was made basic with ammonium hydroxide and filtered. The precipitate was washed with dichloromethane, and the combined filtrates were separated. The organic layer was washed with 40 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of ether and petroleum ether and recrystallized from toluene to give the above named product as white prisms, mp 142°-147°.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CCN(CC)CC>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(C)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
In a 1 L round-bottomed flask was added 2-amino-3-methylbenzoic acid (11.2 g, 74.1 mmol), N,O-dimethylhydroxylamine hydrochloride (14.45 g, 148 mmol) in CH2Cl2 (500 mL) to give a pale brown suspension. The reaction mixture was treated with Et3N (35 mL) to give a light brown/red solution. The solution was treated with HOBT (11.35 g, 74.1 mmol) and EDC (14.20 g, 74.1 mmol) and stirred at room temperature for 24 hours. The mixture was then washed with 10% LiCl aq acidified with 1N HCl. The organic layer was washed successively with 10% aqueous LiCl and aqueous NaHCO3. The organic layer was decolorized with charcoal, filtered and the filtrate dried over MgSO4. The mixture was filtered and concentrated to give 13.22 g (92% yield) of 2-amino-N-methoxy-N,3-dimethylbenzamide as an oil. MS(ES):m/z=195.1 [M+H+]; HPLC: RT=1.118 min. (H2O/MeOH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=4 min, wavelength=220 nm); 1H NMR (500 MHz, chloroform-d) δ 7.22 (dd, J=7.8, 0.8 Hz, 1H), 7.12-7.06 (m, 1H), 6.63 (t, J=7.5 Hz, 1H), 4.63 (br. s., 2H), 3.61 (s, 3H), 3.34 (s, 3H), 2.17 (s, 3H). This was used without further purification in next reaction.
Reaction SMILES: [N+]([CH2:4][CH:5](O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]CC)([O-])=O.[C:15]([O-:18])(=[O:17])[CH3:16].[Ca+2].[C:20]([O-:23])(=[O:22])[CH3:21]>C(O)(=O)C>[C:15]([O:18][CH:21]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:20]([OH:23])=[O:22])(=[O:17])[CH3:16]
Reactant: CCCCCCCCC(O)C[N+](=O)[O-]
Reactant: CC(=O)[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Product: CCCCCCCCC(OC(C)=O)C(=O)O
Temperature: 118 °C
Yield: 92.9 %

Procedure:
To 10.0 grams (0.05 mole) of 1-nitro-2-decanol and 7.9 grams (0.05 mole) of calcium acetate maintained at 10° C. was added 100 millilliters of acetic acid. Heating for 6 hours at 118° C. and extracting as in Example 1 above, provided 10.7 grams (approximately 90% yield) of 2-acetoxydecanoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](C=O)=[C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:35]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([OH:35])=[C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1ccc2c(c1C=O)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1O)OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of {(2R)-8-formyl-7-[(methoxycarbonyl)amino]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (8.46 g, 20.0 mmole) in methylene chloride (250 mL) was added dropwise to a solution of 57-86% m-chloro-peroxybenzoic acid (11.5 g, 40-48 mmole) in methylene chloride (120 mL). The reaction was stirred under nitrogen overnight. After dilution to 300 mL with methylene chloride, the solution was washed with saturated sodium aqueous sodium bicarbonate (2×200 mL) and with brine (100 mL), dried over magnesium sulfate, filtered and evaporated to dryness in vacuum. A H1 NMR spectra of the crude product was taken and it was determined to be the intermediate formate ester. Hydrolysis was effected by stirring in methanol over basic alumina for 15 hours. After filtration of the mixture and evaporation of the filtrate in vacuum, the residue was purified by column chromatography on silica gel with 20% hexane/methylene chloride to remove the impurities and methylene chloride to elute the product. Combination of the product fractions and concentration in vacuum gave the (R)-enantiomer of the title compound as a dark green foam (5.41 g, 66%). 1H (CDCl3) doublet, 7.8 δ (2 H); doublet, 7.3 δ (2 H); doublet, 7.2 δ (1 H); broad singlet, 6.8 δ (1 H); doublet, 6.4 δ (1 H); broad singlet, 6.0 δ (1 H); multiplet, 4.4 δ(1 H); multiplet, 4.2 δ (3 H); multiplet, 4.0 δ (1 H); singlet, 3.8 δ (3 H); singlet, 2.4 δ (3 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([N:12]([CH2:20][C:21]2([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:24][CH2:23][CH2:22]2)C(=O)OC(C)(C)C)=[CH:8][CH:7]=1)=[CH2:5])C.Cl/[C:33](=[N:39]/O)/[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O)(C(F)(F)F)=O>C1COCC1>[F:31][C:30]1[C:25]([C:21]2([CH2:20][NH:12][C:9]3[N:10]=[N:11][C:6]([C:4]4[O:3][N:39]=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:5]=4)=[CH:7][CH:8]=3)[CH2:24][CH2:23][CH2:22]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C=C(OCC)c1ccc(N(CC2(c3ncccc3F)CCC2)C(=O)OC(C)(C)C)nn1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
To t-butyl 6-(1-ethoxyvinyl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (439 mg, 1.02 mmol) in THF (5.0 mL) was added (E)-ethyl 2-chloro-2-(hydroxyimino)acetate (465 mg, 3.06 mmol) and TEA (1.4 mL, 10.2 mmol). The reaction mixture was stirred at rt for 30 min followed by addition of TFA (5 mL) and then heated to reflux overnight. The mixture was then concentrated and purified by reverse phase chromatography to give 415 mg of the title compound as a colorless oil, LRMS (M+H+) m/z 398.3.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([Cl:37])[C:28]3[C:38](=[O:46])[O:39][C:40]4([CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[C:27]=3[C:26]1=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>O1CCCC1.CCCCC>[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([Cl:37])[C:28]3[C:38]([C:2]4[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=4)([OH:46])[O:39][C:40]4([CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)[C:27]=3[C:26]1=2)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)OC3=O
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)OC3(O)c1ccc(C(F)(F)F)cc1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
2.31 g 1-Iodo-4-(trifluoromethyl)benzene are dissolved in 30 ml tetrahydrofurane, cooled to −65° C. and treated dropwise with 9.2 ml of a 1.6 M solution of tert.-butyllithium in n-pentan. The mixture is stirred for 30 minutes and then a solution of 1.9 g (S)-9-(tert-butyldimethylsilyloxy)-4-chloro-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3-one in 30 ml tetrahydrofurane is added dropwise. The mixture is stirred for 30 minutes at −65° C. and for 30 minutes at −50° C. Then the reaction is quenched by addition of 0.5 ml methanol. The mixture is partitioned between 0.1 M hydrochloric acid and ethylacetate. The aqueous phase is twice extracted with ethylacetate. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 80:20).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([OH:8])=O)(=[O:3])[CH3:2].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:24]([NH2:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>ClCCl>[C:1]([O:4][CH:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([NH:34][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:8])(=[O:3])[CH3:2]
Reactant: CSCCC(OC(C)=O)C(=O)O
Reactant: CCCCCCCCCCN
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCNC(=O)C(CCSC)OC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-acetoxy-4-(methylthio)butanoic acid (17.1 g, 89 mmol) in dichloromethane (350 mL) at 0° C. was added thionyl chloride (32.4 mL, 445 mmol) dropwise over 1 hr. The reaction was stirred at 0° C. for 1.5 hrs then the cooling bath was removed and the reaction was warmed to room temperature with stirring for 3 hrs. The solvent was evaporated and the resulting oil was dried under high vacuum for 1 hr to give an orange oil. A solution of the resulting oil in dichloromethane (˜30 mL) was added to a solution of triethylamine (24.8 mL, 178 mmol) and decylamine (17.8 mL, 89 mmol) in dichloromethane (150 mL) at 0° C. and the reaction was allowed to warm to room temperature with stirring overnight. The reaction was evaporated, redissolved in EtOAc (300 mL) and washed with 1N HCl (3×150 mL), saturated sodium bicarbonate (3×150 mL), and brine(1×150 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography with 0-40% EtOAc/heptane to give a yellow oil. (21.1 g, 71%). m/z 332 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH:5]=[C:4]([CH3:8])[O:3]1.[CH:18]#[N:19]>N1C=CC=CC=1>[CH3:8][C:4]1([C:18]#[N:19])[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:3]1
Reactant: CC1=CCCC(C)(COCc2ccccc2)O1
Reactant: C#N
Solvent: c1ccncc1
Product: CC1(C#N)CCCC(C)(COCc2ccccc2)O1
Reaction time: 16 h

Procedure:
A mixture of 15.0 g, 3,4-dihydro-2,6-dimethyl-2-[(phenylmethoxy)-methyl]-2H-pyran, 1.75 g liquid hydrogen cyanide, and 0.1 g pyridine sealed in a 30 ml glass bomb was kept at 150° C. for 16 hours. The resulting dark brown solution was distilled (Kugelrohr) to give 15.7 g colorless product, bp 112°-118° C. (0.01 torr), as an isomeric mixture, ca 4:6, cis:trans, based on NMR spectrum in CDCl3.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH:25]=O>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH:25]=[N:15][C:13]1[C:12]2[C:7]([N:6]=[C:5]3[C:14]=1[CH2:1][CH2:2][CH2:3][CH2:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: Clc1cccc(Cl)c1C=Nc1c2c(nc3ccccc13)CCCC2

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (3.23 g) was suspended in 400 ml of toluene to which morpholine (2.8 g) and 2,6-dichlorobenzaldehyde (3.5 g) were successively added. The reaction mixture was refluxed overnight and then an additional 1.7 g of aldehyde was added. Reflux was continued for an additional sixteen (16) hours and then the reaction mixture was concentrated and purified by flash chromatography (CH2Cl2, then 20% EtOAc/CH2Cl2). Fractions containing the product were concentrated and recrystallized from benzene/hexane to give 2.18 g of analytically pure product, m.p. 200°-202° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:3]2[C:2]([Cl:1])=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:16][CH:15]=1
Reactant: Clc1c2ccccc2nn1-c1ccc(OC[C@@H]2CCCN2)cc1
Reactant: COC(=O)CCCBr
Product: COC(=O)CCCN1CCC[C@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 74.6 %

Procedure:
The title compound was prepared from product from 3-chloro-2-[4-((S)-1-pyrrolidin-2-ylmethoxy)-phenyl]-2H-indazole (0.33 g, 0.94 mmol) and methyl 4-bromobutyrate (0.25 g, 1.4 mmol) using the procedure of Step 1 of the Example 17 to provide the title compound (0.30 g, 75%).
Reaction SMILES: [F:1][C:2]([F:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.[H-].[Na+].[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26]([CH:38]=O)[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]>C1COCC1>[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26](/[CH:38]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (0.453 g, 1.75 mmol) in anhydrous THF (7 ml), sodium hydride (60%, dispersion in mineral oil, 70 mg, 1.75 mmol) was added and stirred for 15 minutes at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.175 g, 439 mmol) in anhydrous THF (3 ml) was added thereto, and the mixed solution was heat refluxed for approximately 4 hours. Only a trace amount of the target product (3) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:16][CH2:15]2)=O)=[CH:5][C:4]=1[CH3:24].O>C(Cl)(Cl)Cl>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1([C:12]2[C:7]3[C:6](=[CH:5][C:4]([CH3:24])=[C:3]([O:2][CH3:1])[CH:8]=3)[CH2:9][CH2:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: COc1ccc(CCNC(=O)C2(c3ccccc3Cl)CC2)cc1C
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2c(cc1C)CCN=C2C1(c2ccccc2Cl)CC1

Procedure:
A mixture of the amide and 82% w/w solution of polyphosphate ester in chloroform (170 g) was heated gently for 16 hours, then poured into water (1200 ml) and the mixture washed with ether. The aqueous phase was basified by addition of aqueous ammonia solution and the product was extracted with ethyl acetate. The extracts were dried and concentrated to give 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-6-methyl-3,4-dihydroisoquinoline as a solid. Yield 14.7 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH:12]([OH:14])[CH3:13].C[N+]1([O-])CCOCC1.CC#N>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CC(O)c1cc(C(F)(F)F)ccc1Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)c1cc(C(F)(F)F)ccc1Br

Procedure:
1-(2-Bromo-5-trifluoromethyl-phenyl)-ethanol (0.914 g, 3.40 mmol), N-methylmorpholine N-oxide (0331 g, 6.24 mmol), and tetrapropylammonium perruthenate (0.109 g, 0.31 mmol) were combined in CH2Cl2 (18 mL) and MeCN (0.9 mL) and stirred at room temperature for 30 minutes. Once no starting material was seen by analytical LCMS, the mixture was filtered through Celite and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2Cl)=[O:5])[CH3:2].[CH3:19][CH:20]([CH3:25])[CH2:21]B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COC(OC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[CH2:19][CH:20]([CH3:25])[CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(Cl)c2c1
Reactant: CC(C)CB(O)O
Agent: COC(C)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1ccc2ncc(C#N)c(CC(C)C)c2c1
Temperature: 100 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
The mixture of 4-chloro-3-cyano-quinoline-6-carboxylic acid ethyl ester (example 46c, 1.3 g, 5 mmol), (2-methylpropyl)boronic acid (1.0 g, 10 mmol), sodium carbonate (3.18 g, 30 mmol) and POPd (bis[bis(1,1-dimethylethyl)phosphinous acid-κP]dichloropalladium, CAS: 391683-95-7) (75 mg, 0.15 mmol) in dimethyloxyethane (DME) (20 mL) was stirred at 100° C. for 2 days. After cooling to room temperature, the product was extracted with ethylacetate. The combined organic layers were successively washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-50% ethyl acetate in hexanes in 30 min) afforded 3-cyano-4-isobutyl-quinoline-6-carboxylic acid ethyl ester (1.1 g, 79%) as a clear oil. LC-MS m/e 283 (MH+).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2>>[CH3:21][CH:17]([C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])[CH:8]=2)[CH:13]=1)[C:18]([OH:20])=[O:19]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: CCCCI
Product: CCCCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-iodobutane and racemic 6-hydroxy-α-methyl-2-naphthalene acetic acid. White crystals are obtained having a melting point of 125°-127° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH2:8][NH:9][C:10]2[C:11]([F:18])=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=2[F:16])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH2:8][NH:9][C:10]2[C:11]([F:18])=[C:12]([CH:13]=[CH:14][C:15]=2[F:16])[O:17][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:7]=1
Reactant: Oc1ccc(F)c(NCc2cc(Br)ccc2F)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(Br)ccc2F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution of 3-[(5-bromo-2-fluoro-phenyl)methylamino]-2,4-difluoro-phenol (5.26 g, 15.8 mmol, 1.0 eq) in DMF (50 mL) was added Na2CO3 (2.35 g, 22.2 mmol, 1.4 eq). The reaction was stirred at room temperature for 30 min then ethyl bromoacetate (2.91 g, 17.4 mmol, 1.1 eq) was added. The reaction mixture was stirred at room temperature for 1 h then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 40:1 to 30:1) to give the title compound as a colorless oil (5 g, 75%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([Si:15]([CH3:29])([CH3:28])[O:16][CH:17]1[CH:22]([O:23][CH3:24])[CH:21]([CH3:25])[CH2:20][O:19][CH:18]1[CH2:26][OH:27])([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl>[CH3:11][C:12]([Si:15]([CH3:29])([CH3:28])[O:16][CH:17]1[CH:22]([O:23][CH3:24])[CH:21]([CH3:25])[CH2:20][O:19][CH:18]1[CH:26]=[O:27])([CH3:13])[CH3:14]
Reactant: COC1C(C)COC(CO)C1O[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC1C(C)COC(C=O)C1O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
Into a stirred solution of oxalylchloride (0.07 ml, 0.81 mmol) in dry dichloromethane (3 ml) was dropped a solution of dry dimethylsulfoxide (0.11 ml, 1.49 mmol) in dry dichloromethane at -60° C. and stirring was continued at this temperature (-60° C.) for 15 minutes. Then a solution of the title compound of Example 39 (180 mg, 0.62 mmol) in dry dichloromethane (1 ml) was added slowly. After being stirred for additional 15 minutes at -60° C. triethylamine (0.43 ml, 3.1 mmol) was added slowly, the mixture was stirred for 10 minutes at -60° C. and then allowed to come to ambient temperature and stirred for 40 minutes at this temperature. The solvent was removed on a rotary evaporator, and the residue was partitionated between ether and ice-water. The organic phase was separated, dried over sodium sulfate and evaporated in vacuo to leave an oil (157 mg) which was chromatographed on silica gel eluting with ethyl acetate/petroleum ether (1:4). The relevant fractions were combined and then evaporated in vacuo to yield the desired title aldehyde as a pale yellowish oil. Yield 108 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:7]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])O[C:4](=[O:5])[CH2:3]1.[CH3:19][OH:20].S(Cl)([Cl:23])=O>>[CH3:19][O:20][C:4](=[O:5])[CH2:3][C:2]([CH3:18])([CH3:1])[CH:7]([Cl:23])[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10]
Reactant: CC1(C)CC(=O)OC1CC(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)CC(C)(C)C(Cl)CC(=O)c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
134 g of 3,3-dimethyl-4-(4'-chloro-phenacyl)-γ-butyrolactone were dissolved in 215 g of thionyl chloride in a 0.7 liter autoclave with a glass liner. 100 g of methanol were then pumped in and the mixture was heated to 50° C. for 4 hours. After working up as in Example 10, 6-(4'-chloro-phenyl)-6-oxo-4-chloro-3,3-dimethyl-hexanoic acid methyl ester was obtained.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:6][CH:5]=[N:4][CH:3]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cncs1
Product: Fc1ccc(-c2cncs2)cc1

Procedure:
Using 5-bromothiazole (1.0 g, 6.09 mmol) and (4-fluorophenyl)boronic acid (1.0 g, 7.31 mmol) and following the procedure described in example 7 step 1, the title compound was obtained after purification by purified by Biotage IsoleraOne® column (10% ethyl acetate in hexane) as yellow viscous liquid (0.4 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.25 (s, 1H), 7.73-7.69 (m, 2H), 7.27 (t, 2H); LC-MS m/z calculated for [M+H]+ 180.02, found 180.1.