Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O/[C:2](=[CH:8]\[C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)/[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[CH:26]1([NH:32][NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CCO.CCOC(C)=O>[CH:26]1([N:32]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:12][CH:11]=3)=[CH:8][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:33]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NNC1CCCCC1
Reactant: CCOC(=O)/C(O)=C/C(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Yield: 98.6 %

Procedure:
The butenoate 1.2 (5.00 g, 15.3 mmol) and cyclohexylhydrazine hydrochloride (2.77 g, 18.4 mmol) were heated at refluxed in EtOH (60 ml) for 2 h. Concentration in vacuo resulted in formation of a solid which was suspended in EtOAc and filtered through a 1″ pad of SiO2, elution with ethyl acetate. The filtrate was concentrated to afford 6.10 g (98%) of the desired pyrazole ester 1.3. MS (ESI) 405.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.ClC(Cl)C.[CH3:13][O:14][C:15]([C:17]1([CH2:23][CH:24]=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:13][O:14][C:15]([C:17]1([CH2:23][CH2:24][NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)=[O:16]
Reactant: COC(=O)C1(CC=O)CCOCC1
Reactant: Nc1ccc(Br)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)C1(CCNc2ccc(Br)cn2)CCOCC1
Temperature: 25 °C

Procedure:
To a solution of 5-bromopyridin-2-amine (0.488 g, 2.82 mmol) in 1-2 dichloroethane (DCE, 10 mL) was added desired 4-(2-oxo-ethyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (0.529 g, 2.82), acetic acid (3.1 eq) and allowed to stir at room temperature for an hour. NaBH(OAc)3 (3 eq) was then added in one portion and reaction mixture allowed to stir at room temperature for 16 hours. The reaction mixture was then diluted with DCM (10 mL), quenched with 2 M of NH4OH in water. The aqueous layer was extracted with DCM (10 mL×2). The combined organic layers were washed with aqueous NaHCO3 (30 mL), brine (30 mL), and dried over Na2SO4, and concentrated under vacuum.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([CH2:11][CH2:12][C@H:13]([NH2:17])[C:14]([OH:16])=[O:15])=[O:10])=[CH:3][CH:2]=1.[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>C1(C)C=CC=CC=1>[CH2:7]([O:8][C:9]([CH2:11][CH2:12][C@H:13]([N:17]1[C:21](=[O:22])[C:20]2[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]1=[O:23])[C:14]([OH:16])=[O:15])=[O:10])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C(CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Yield: 60.5 %

Procedure:
16 g of L-glutamic acid γ-benzyl ester and 11 g of phthalic anhydride, both finely powdered, were stirred in 20 ml of toluene at reflux temperature for 2 hours. 50 ml of toluene were added and the mixture was evaporated. A further 80 ml of toluene were then added and the mixture was left to crystallize. Recrystallization from toluene yielded 15 g of α(S)-(2-benzyloxycarbonylethyl)-1,3-dihydro-1,3-dioxo-2-isoindoleacetic acid of melting point 96°-98° C.; [α]D20 =-50.4° (c=1 in methanol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.CO.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=[O:16])[CH3:15].N1CCCCC1>CC(O)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:15]/[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:16])=[CH:2]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(=O)c1ccccn1
Solvent: CO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C(/C=C/c1c[nH]c2ccccc12)c1ccccn1

Procedure:
Indole-3-carboxaldehyde (200 mg, 1.38 mmol) was added to a dried 100 mL round bottom flask under argon and anhydrous methanol (8 mL) was added. 2-Acetyl-pyridine (232 μL, 2.07 mmol) and piperidine (69 μL, 0.7 mmol) were added and the reaction was stirred under reflux for 24 hours, after which still no precipitate had formed (AcOH did not lead to precipitation). The crude reaction mixture was concentrated and directly applied to a silica column for chromatography (ethyl acetate:hexanes 1:1). The product was partially separated from the aldehyde starting material (some product coeluted with aldehyde and was discarded), and 80 mg (23%) of purified product was isolated. NMR: 1H NMR (600 MHz, d6-DMSO): δ 11.989 (s, 1H, N—H), 8.831-8.819 (m, pyr-H2), 8.220-8.194 (d, J=15.6, 1H, C═CH), 8.154-8.105 (m, 3H, C═CH, indole-H2, pyr-H3), 8.052-8.027 (m, 1H, pyr-H4), 7.976-7.962 (m, 1H, indole-H4), 7.679-7.656 (m, 1H, pyr-H5), 7.522-7.508 (m, 1H, indole-H7), 7.285-7.262 (m, 2H, indole-H5,6). 13C NMR (150 MHz, d6-DMSO): δ 188.2, 154.3, 149.1, 139.3, 137.7, 137.6, 134.2, 127.1, 125.1, 122.3, 122.2, 121.4, 120.1, 114.3, 113.1, 112.7. Melting Point: 141-145° C. TLC: (ethyl acetate:hexanes 4:1) Rf=0.40. Elemental analysis calculated for C16H12N2O.0.1C4H8O2: C, 76.62; H, 5.02; N, 10.90. found: C, 76.41; H, 5.03; N, 10.80.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[OH-].[Na+].[C:12](O)(=[O:14])[CH3:13]>C(OC(=O)C)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[N:3][CH:4]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(Br)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(Br)cn1
Reaction time: 1 h

Procedure:
A solution of 25.0 g (144 mmol) of 2-amino-5-bromopyridine in 50 mL of acetic acid and 250 mL of acetic anhydride was heated at reflux for about 2 hours. The reaction mixture was then cooled and poured into 750 mL of water with stirring. After about 1 hour, the solution was adjusted to pH=10 with 50% sodium hydroxide solution and the precipitate was filtered, washed with water and dried to give 26.5 g of the title product as a white flaky solid, mp 175-176° C. 1H nmr (deuteriochloroform): δ=8.29 (d, 1 H); 8.12 (d, 1 H); 7.96 (br, 1 H); 7.78 (d of d, 1 H); 2.19 (s, 3 H). MS (El): m/z =214, 216 (M+, Br isotopes).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:14]([CH:16]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17]O)[CH3:15].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.CN(C)C=O>[C:1]([O:9][CH2:17][CH:16]([CH2:14][CH3:15])[CH2:19][CH2:20][CH2:21][CH3:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: CCCCC(CC)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCC(CC)COC(=O)c1cccnc1
Yield: 48.3 %

Procedure:
A mixture of 10 g of nicotinic acid (0.08 mol), 25 g of thionyl chloride (0.21 mol), 1.5 ml of dimethylformamide and 200 ml of benzene was refluxed in an eggplant type flask for 3 hours. The solvent was removed by distillation. To the residue were added 20.8 g (0.16 mol) of 2-ethylhexyl alcohol and benzene, and the mixture was refluxed for 4 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate. The benzene layer was separated, washed successively with a saturated sodium bicarbonate aqueous solution, water and a saturated sodium chloride aqueous solution, dried over sodium sulfate and distilled to remove the solvent. The residue was purified by distillation under reduced pressure and column chromatography to obtain 9.1 g (70%) of 2-ethylhexyl nicotinate.
Reaction SMILES: [C:1]([CH2:3][C:4](=[NH:8])OCC)#[N:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(=O)([O-])O.[Na+].Br[CH:21]([CH3:31])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=O>C(O)C.NC(N1CCOCC1)=CC#N>[C:1]([C:3]1[C:21]([CH3:31])=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[NH:8][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)#[N:2]
Reactant: C1COCCN1
Reactant: CC(Br)C(=O)c1ccc(F)cc1
Reactant: CCOC(=N)CC#N
Agent: N#CC=C(N)N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2ccc(F)cc2)[nH]c(N2CCOCC2)c1C#N
Temperature: 25 °C
Yield: 4.7 %

Procedure:
In anhydrous ethanol (10 ml) was dissolved 3-amino-3-morpholinoacrylonitrile, as prepared from ethyl 2-cyano-acetimidate (1.0 g) and morpholine (0.78 g) as in Reference Example 3, followed by addition of sodium hydrogen carbonate (0.95 g). Then, a solution of 2-bromo-4′-fluoropropiophenone (2.06 g) in ethanol was added dropwise thereto at room temperature with stirring. The mixture was refluxed for 10 minutes and, then, stirred at room temperature overnight. The separated crystal crop was collected by filtration and recrystallized from ethanol to provide the title compound as colorless crystals (0.12 g). m.p. 245-247° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][CH3:18])[CH:10]=1)=[O:2].[CH2:19]1[CH2:23]OC[CH2:20]1>>[CH:20]1([CH:1]([OH:2])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH2:19][CH2:23]1
Reactant: C1CCOC1
Reactant: COc1cc(-c2cnccc2C=O)ccc1C#N
Product: COc1cc(-c2cnccc2C(O)C2CC2)ccc1C#N
Temperature: -36 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-formylpyridin-3-yl)-2-methoxybenzonitrile (100 mg, 0.42 mmol) in THF (4 mL) at −36° C. was added 0.5M c-PrMgCl in THF (2.27 mL, 1.13 mmol) dropwise and the mixture was stirred at −36° C. for 1 hr. The mixture was quenched with water at −36° C., silica gel was added, and the mixture was concentrated in vacuo. The residue was purified by silica chromatography eluting with a 40 to 100% EtOAc-heptane gradient. The product obtained was re-purified by Xbridge C18 eluting with a 10 to 100% acetonitrile-water gradient to give 4-(4-(cyclopropyl(hydroxy)methyl)pyridin-3-yl)-2-methoxybenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.13-−0.05 (m, 1H), 0.20-0.29 (m, 1H), 0.29-0.41 (m, 2H), 0.91-1.06 (m, 1H), 3.95 (s, 3H), 4.16 (dd, J=6.6, 4.3 Hz, 1H), 5.39 (d, J=4.5 Hz, 1H), 7.12 (dd, J=7.8, 1.3 Hz, 1H), 7.27 (d, J=1.3 Hz, 1H), 7.66 (d, J=5.3 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 8.42 (s, 1H), 8.62 (d, J=5.3 Hz, 1H). HRMS: (ESI) m/z 281.1280 [(M+H)+ Calcd for C17H16N2O2 281.1290].
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][NH:24][OH:25])=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1>O1CCOCC1.O>[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][N:24]([OH:25])[C:3]([NH:2][CH3:1])=[S:4])=[C:13]2[CH3:26])=[O:11])=[CH:8][CH:7]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CN=C=S
Solvent: O
Solvent: C1COCCO1
Product: CNC(=S)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A solution of methyl isothiocyanate (1.36 g, 18.56 mmol) in 2 ml of dioxane is added dropwise to a suspension of 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine (2.01 g, 5.84 mmol) in 60 ml of dioxane and 60 ml of H2O at 0° C. The ice bath is removed. After one hour 0.5 g (6.84 mmol) additional methyl isothiocyanate is added and the reaction mixture is stored in a freezer overnight. The solids are collected by filtration and recrystallized from THF/hexane, rinsed with ether, and dried under high vacuum over P2O5 to give pure 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(methylamino)thioxomethyl]-1H-indole-3- methanamine (1.32 g, 54%); mp 198°-198.5° C. (dec).
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:7][CH2:6][CH:5]([C:8]([O:10]CC)=[O:9])[CH2:4][CH2:3]1.O.O.[OH-].[Li+].Cl>C1COCC1.CCOC(C)=O>[F:1][C:2]1([F:13])[CH2:3][CH2:4][CH:5]([C:8]([OH:10])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A solution of ethyl 4,4-difluorocyclohexanecarboxylate (0.385 g, 2.003 mmol) in THF (12 mL) was treated with H2O (6 mL) followed by lithium hydroxide monohydrate (0.420 g, 10.02 mmol) and the mixture stirred vigorously at RT overnight. The mixture was treated with EtOAc, acidified with 1M HCl until pH 4, the layers separated and the aqueous layer extracted with additional EtOAc (1×). The combined organics were washed with brine, dried over MgSO4 and concentrated to dryness to afford 4,4-difluorocyclohexanecarboxylic acid (318 mg, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.28 (s, 1H), 2.40 (m, 1H), 2.02-1.75 (m, 6H), 1.59 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](S([O-])=O)=[CH:5][CH:4]=1.[Na+].II.[C:15]([C:18]([CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[N:28]([CH3:34])[C:27]1=[O:35])=[CH:19][S:20]([O-:22])=[O:21])([OH:17])=[O:16].[Na+].C(N(CC)CC)C.S(=O)(=O)(O)O>O.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:20](/[CH:19]=[C:18](\[CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]([CH3:32])([CH3:33])[N:28]([CH3:34])[C:27]1=[O:35])/[C:15]([OH:17])=[O:16])(=[O:22])=[O:21]
Reactant: COc1ccc(S(=O)[O-])cc1
Reactant: CN1C(=O)N(CCCC(=CS(=O)[O-])C(=O)O)C(=O)C1(C)C
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1S(=O)(=O)/C=C(\CCCN1C(=O)N(C)C(C)(C)C1=O)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Sodium 4-methoxyphenylsulfinate (10.0 g, 51.49 mmol) was dissolved in water (100 ml). This solution was shaken with iodine (9.8 g, 36.61 mmol) in dichloromethane (100 ml). The dichloromethane layer turned from deep pink to orange. The dichloromethane layer was dried over magnesium sulfate and filtered into a flask containing sodium 2-carboxy-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)pent-1-ene-1-sulfinate (6.47 g, 25.74 mmol). The solution was stired overnight at room temperature and then cooled to 0° C. Triethylamine (11.0 ml, 77.23 mmol) was added and the solution was allowed to warm to room temperature over 2 hours. Sulfuric acid (2M, 50 ml) was added to quench the reaction. The organic phase was washed with 10% aqueous sodium bisulfite (50 ml), then extracted with sodium hydroxide (2M, 3×50 ml). The aqueous layer was washed with dichloromethane (50 ml) and the acidifed with sulfuric acid (2M) to pH 1. The product was extracted into dichloromethane (3×50 ml) and the combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and evaporaed to give the title compound in 88% yield. This yellow oil was crystallised from MTBE/DCM 40:1 to give the title compound as a white solid (5.6 g, 51%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([Cl:12])[CH:6]=1)(=[O:3])[CH3:2].[Br:13]Br.O>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:10]([Br:13])=[CH:9][C:8]([CH3:11])=[C:7]([Cl:12])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc(C)c(Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)c(C)cc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To a solution of 4-acetamido-2-chlorotoluene (89.2 g, 0.486 mol) in glacial acetic acid (480 ml) that was stirred with an overhead mechanical stirrer and under argon was dropwise added bromine (28.5 ml) during a period of 2 h while the temperature of the reaction mixture was kept below 15° C. by using an ice-bath. Stirring was continued for a further 1.5 h after the addition of bromine, under an argon atmosphere. Then the brownish reaction mixture was poured into ice-water (1.8 lt), with the aid of water (1 lt), washed with water (6 lt), and dried in vacuo over P2O5. Purification by recrystallisation from acetonitrile afforded the desired product as a white crystals (61.5 g, 48%), mp 154-155° C.; 1H-NMR (CDCl3) 2.24, 2.32 (2×s, 6H, 2×CH3), 7.40, 7.73 (2×s, 2H, 3-H, 6-H), 7.49 (br s, 1H, CONH); MS (FAB, m/z): 262, 264, 266 [(M+H)+, 80%, 100%, 25% respectively; BrCl isotopic pattern];
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:13]([Cl:25])=[CH:14][C:15]([Cl:24])=[C:16]([CH:23]=2)[O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[CH3:26][NH:27][CH3:28].N1C=CC=N1.C(OCC)(=O)C>O1CCCC1>[CH3:26][N:27]([CH3:28])[C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:23]=[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:10])[F:9])[N:5]([CH3:11])[N:4]=2)[C:13]([Cl:25])=[CH:14][C:15]=1[Cl:24])[CH3:22]
Reactant: CC(Oc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl)C(=O)Cl
Reactant: CNC
Agent: c1cn[nH]c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(Oc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl)C(=O)N(C)C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
A solution of 2-[5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole-3-yl)-2,4-dichlorophenoxy]propionyl chloride (0.80 g, 1.78 mmoles) in 20 ml anhydrous tetrahydrofuran was added dropwise to a solution of 50% dimethylamine (0.32 g, 3.56 mmoles) in 20 ml tetrahydrofuran at room temperature to react the pyrazole derivative with dimethylamine. After the addition was finished, the reaction was continued further for 1 hour. Then ethyl acetate was added to the reaction product solution, and the mixture was washed with water. The separated organic layer was dehydrated, concentrated under reduced pressure, and purified by silica gel chromatography, giving crystals (0.24 g) of the title compound, m.p. 148.9° C., yield 27%.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[CH:7]=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][CH2:31][NH2:32].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][CH2:31][NH:32][C:16]([C:13]([CH3:14])([O:12][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([O:19][CH3:20])[C:3]([OH:2])=[O:21])[CH:11]=[CH:10][CH:9]=1)[CH3:15])=[O:18]
Reactant: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)O)c1)OC
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1cccc(OC(C)(C)C(=O)NCCc2ccc(Cl)cc2Cl)c1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (EXAMPLE 56, step 2) and 2-(2,4-dichloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:21][CH3:22])[C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH:23]1([C@@H:29]([NH2:31])[CH3:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:23]1([C@@H:29]([NH:31][C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][CH3:6])[C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH3:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: C[C@H](N)C1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1c(OC)cc(C(=O)N[C@@H](C)C2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
To a mixture of 5 ml of THF and 0.38 g of 3,5-dimethoxy-4-(2-propynyloxy)benzoyl chloride were added 0.21 g of (1S)-1-(cyclohexyl)ethylamine and 0.23 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.42 g of N-((1S)-1-cyclohexylethyl)-4-(2-propynyloxy)-3,5-dimethoxybenzamide (hereinafter, described as the compound 23 of the present invention) represented by the formula:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[CH3:8])=[CH:4][F:5].[FH:15]>>[F:1][C:2]([F:13])([F:14])[CH:3]([C:6]([F:11])([F:12])[C:7]([F:10])([F:9])[CH3:8])[CH:4]([F:15])[F:5]
Reactant: F
Reactant: CC(F)(F)C(F)(F)C(=CF)C(F)(F)F
Product: CC(F)(F)C(F)(F)C(C(F)F)C(F)(F)F

Procedure:
As another example, 4-difluoromethyl-2,3,5,5,5-pentafluoro-1-pentene may be prepared by fluorinating commercially available 2,3-pentanedione to form 2,2,3,3-tetrafluoropentane which may then be dehydroqenated to form 3,3,4,4-tetrafluoro-1-pentene. CF3 may then be added to the 3,3,4,4-tetrafluoro-1-pentene to form 2-trifluoromethyl-1,3,3,4,4-pentafluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluoropentane which may then be dehalogenated to form 4-difluoromethyl-2,3,5,5,5-pentafluoro-1-pentene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][CH2:14]3)[CH:12]=1)[NH:9][C:8]([C:21]([OH:23])=O)=[CH:7][C:6]2=[O:24].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[O:66]1[CH2:71][CH2:70][N:69]([C:72]2[CH:78]=[CH:77][C:75]([NH2:76])=[CH:74][CH:73]=2)[CH2:68][CH2:67]1>CN(C)C=O.CO>[N:69]1([C:72]2[CH:73]=[CH:74][C:75]([NH:76][C:21]([C:8]3[NH:9][C:10]4[C:5]([C:6](=[O:24])[CH:7]=3)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:11]=4[N:13]3[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][CH2:14]3)=[O:23])=[CH:77][CH:78]=2)[CH2:68][CH2:67][O:66][CH2:71][CH2:70]1
Reactant: COc1cc(N2CCCN(C)CC2)c2[nH]c(C(=O)O)cc(=O)c2c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(N2CCCN(C)CC2)c2[nH]c(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 69.2 %

Procedure:
To a solution of 6-methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (2.10 mmol) (Reference Example 25b) and diisopropylethyl amine (1.4 mL, 8.6 mmol) in 34 mL dimethylformamide was added TBTU (1.40 g, 4.36 mmol) and HOBt (0.588 g, 4.35 mmol) followed by the addition of 4-morpholinoaniline (0.463 g, 2.60 mmol). The resulting dark brown solution was stirred at room temperature under nitrogen for 19 hours. The reaction was concentrated in vacuo and the resulting crude product was taken up in methylene chloride/methanol. Filtration of the resulting mixture afforded some product as a yellow solid. The filtrates were concentrated and partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated sodium bicarbonate, dried (MgSO4), and concentrated under vacuum to afford a brown solid. This was suspended in methanol and filtered to afford the desired product as a yellow solid (0.714 g, 69%). 1H NMR (300 MHz, DMSO, d6) δ 9.97 (bs, 1 H, NH), 7.67 (d, 2 H, Jo=8.8 Hz, ArH2′& H6′), 7.47 (bs, 1 H, ArH5), 7.00 (s, 1 H, C═CH), 6.99 (d, 2 H, Jo=8.8 Hz, ArH3′& H5′), 6.71 (bs, 1 H, ArH7), 3.85 (s, 3 H, OCH3), 3.75 (t, 4 H, J=4.6 Hz, OCH2CH2N), 3.70 (bs, 2 H, ArNCH2CH2CH2NCH3), 3.55 (bs, 2 H, ArNCH2CH2NCH3), 3.09 (t, 4 H, J=4.6 Hz, OCH2CH2N), 2.95 (bs, 2 H, ArNCH2CH2NCH3), 2.73 (bs, 2 H, ArNCH2CH2CH2NCH3), 2.36 (s, 3 H, NCH3), 2.07 (bs, 2 H ArNCH2CH2CH2NCH3); Mass Spec.: calc. for [C27H33N5O4+H]+ Theor. m/z=492; Obs. 492.