Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.CN(C=O)C>[C:13]([O:16][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4])(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)c1ccc(F)cc1F
Temperature: 20 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of Nal, and 3 L of DMF. Stir the mixture at 20° C. for 18 hr. then concentrate it to 1 L. Pour the residue into 6 L of cold dilute aqueous HCl and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2SO4, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluting with CH2Cl-2-hexane to obtain 198 g of the title compound. ##STR106##
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2.F[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])[CH2:8][CH2:7]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: N#Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1cccc(N2CCc3cc(Cl)ccc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A slurry of 2.64 g (0.11 mole, 1.1 equivalents) sodium hydride in 15.36 g (0.1 mole) 5-chloroindoline and 50 ml sieve dried DMSO was permitted to stir at room temperature under nitrogen for 2 hours. While cooling in an ice bath, a solution of 12.11 g (0.1 mole) 3-fluorobenzonitrile in 15 ml sieve dried DMSO was then added dropwise over 15 minutes. At the end of the addition, the ice bath was removed and the reaction mixture was permitted to warm to room temperature and stir overnight (20 hours). The product was poured onto ice and then extracted twice with CHCl3. The combined organic portions (400 ml) were washed four times with water (400 ml portions), 4 N HCl (three 300 ml portions) brine (300 ml), dried over Na2SO4, and concentrated to give 28.03 g (25.47 g theory) of a solid. Recrystallization from hot absolute ethanol containing 5-10% CHCl3 afforded 11.12 g (43.66% overall) of 3-(5-chloro-1-indolinyl)benzonitrile, m.p. 120°-121° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][Br:13])[CH3:2]
Reactant: CCOC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.2 %

Procedure:
2-Methylbenzoic acid ethyl ester (2.00 g, 11.9 mmol) was dissolved in carbon tetrachloride (60 ml), and the solution was added with N-bromosuccinimide (2.56 g, 14.4 mmol) and a catalytic amount of benzoylperoxide and then heated under reflux. After one hour, the reaction mixture was cooled to room temperature and added with hexane (40 ml) to remove insoluble solids by filtration. The filtrate was evaporated under reduced pressure to obtain the title compound 3.16 g as yellow oil. the product was used in the next reaction without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[C:14](=[O:18])[CH2:13][CH2:12]4)[N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: O=C1CCc2cc(Oc3cncc(Cl)n3)ccc21
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccc4c(c3)CCC4=O)n2)cc(OC)c1OC
Yield: 20 %

Procedure:
Using Method EE with 2-chloro-6-(indanone-5-oxy)-pyrazine (200 mg, 0.77 mmol) and 3,4,5-trimethoxyaniline (169 mg, 0.92 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (61 mg). Yield: 20%. 1H NMR (250 MHz, DMSO-d6) δ 2.68 (t, 2H, H3, J=5.6 Hz), 3.08 (t, 2H, H2, J=5.0 Hz), 3.39 (s, 6H, [CH3O]3+5), 3.55 (s, 3H, [CH3O]4), 6.77 (s, 2H, Harom2′+6′), 7.21 (dd, 1H, Harom 6, Jm=1.9 Hz, Jo=8.3 Hz), 7.40 (s, 1H, Harom 4), 7.68 (d, 1H, Harom 7, J=8.3 Hz), 7.84 (s, 1H, HPz 5), 8.02 (s, 1H, HPz 3), 9.62 (s, 1H, NH). m/z: 408.1 [(M+H)+, calcd for C22H21N3O5 407.1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Br:21])[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)n2)CC1
Yield: 77.9 %

Procedure:
A solution of 220 mg (0.793 mmol) 5-amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL CH2Cl2 was treated with 134 mg (0.753 mmol) N-bromosuccinimide at room temperature for 20 min. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography of the residue on a 50-g silica Varian MegaBond Elut column with 10-35% EtOAc-hexanes afforded 209 mg (74%) of the title compound as a colorless glassy solid. 1H-NMR (CDCl3; 400 MHz): δ 6.97 (d, 1H, J=8.0 Hz), 6.91 (d, 1H, J=8.0 Hz), 4.28-4.15 (br s, 2H), 4.06-3.90 (m, 2H), 2.85-2.75 (m, 2H), 2.77-2.68 (m, 1H), 1.92-1.83 (m, 2H), 1.68-1.54 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[CH3:19][O:20][C:21]([C:23]1[CH:27]=[C:26]([NH2:28])[NH:25][N:24]=1)=[O:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH3:19][O:20][C:21]([C:23]1[CH:27]=[C:26]2[NH:28][C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)=[C:4]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[C:3](=[O:18])[N:25]2[N:24]=1)=[O:22]
Reactant: COC(=O)c1cc(N)[nH]n1
Reactant: COC(=O)C(C(=O)c1ccco1)C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1
Product: COC(=O)c1cc2[nH]c(-c3ccco3)c(C3CCCCC3)c(=O)n2n1
Temperature: 120 °C
Yield: 32.1 %

Procedure:
A mixture of 1.1 g (4.4 mmol) of 2-cyclohexyl-3-furan-2-yl-3-oxo-propionic acid methyl ester, 0.592 g (4.2 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester, 76 mg (0.4 mmol, 10 mol %) of p-toluenesulfonic acid monohydrate (PTSA), and 50 mL of chlorobenzene was heated at 120° C. overnight. The reaction mixture was then concentrated to a residue which was chromatographed on silica gel (7% methanol in dichloromethane) to afford 0.46 g (32% yield) of desired 6-cyclohexyl-5-furan-2-yl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as indicated by 1H NMR; LC-MS—calcd for C18H19N3O4 [M++H]+: 342.14, found: 342.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH2:11]([CH2:13][NH2:14])[OH:12].C(=O)(O)[O-].[Na+]>C(#N)C>[OH:12][CH2:11][CH2:13][NH:14][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cccc(CBr)c1
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cccc(CNCCO)c1
Reaction time: 4 h
Yield: 44.5 %

Procedure:
3-(Bromomethyl)benzonitrile (20.0 g, 0.125 mol) was added portion wise into a mixture of ethanolamine (11.4 g, 0.19 mol) and sodium bicarbonate (21.0 g, 0.25 mol) in ACN (200 mL) at 0° C. The resulting mixture was stirred for 4 hours. The reaction mixture was concentrated under vacuum. The residue was taken up with water and extracted with DCM (200 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to afford the title compound as white solid (9.8 g, 54%). 1H NMR (DMSO-d6, 400 MHz) δ 7.76 (s, 1H), 7.67 (m, 2H), 7.51 (m, 1H), 4.47 (brs, 1H), 3.74 (s, 2H), 3.44 (m, 2H), 2.51 (m, 2H), 2.12 (brs, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH:15]=1)[C:10]([OH:12])=O)[OH:6])[CH3:2].Cl.Cl.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([C@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[CH:15]=1)[C:10]([NH:36][C@@H:34]([C:31]1[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=1)[CH3:35])=[O:12])[OH:6])[CH3:2]
Reactant: CCN(CC)CC(O)c1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CC(O)c1cc(C(=O)N[C@H](C)c2ccc(C)nc2)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2-(diethylamino)-1-hydroxyethyl)-5-(5-methylpyridin-2-yl)benzoic acid (30 mg, 0.075 mmol) in N,N-dimethylformamide (5 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (100 mg, 0.48 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (160 mg, 0.42 mmol) and N,N-diisopropylethylamine (300 μL, 1.7 mmol). The reaction mixture was stirred for 16 hours at 25° C. and purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford the title product.
Reaction SMILES: [C:1]12([C:8]3[C:13](Cl)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][OH:31].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O>CN(C)C=O>[C:1]12([C:8]3[C:13]([O:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: OCc1ccccn1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2nnc3cc(C45CCC(CC4)C5)c(OCc4ccccn4)nn23)cc1
Reaction time: 3 h

Procedure:
To a solution of 7-(bicyclo[2.2.1]hept-1-yl)-6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (0.08 g, 0.25 mM, Example 1, step b) and 2-pyridylcarbinol (0.06 ml, 0.5 mM) in N,N-dimethylformamide (2 ml) under nitrogen was added lithium bis(trimethylsilyl)amide as a 1 mol solution in hexanes (0.375 ml). The reaction was stirred for 3 hours. Water was added until the solution became cloudy and after stirring for a further 15 minutes a solid was collected by filtration. This solid was recrystallised from ethyl acetate-hexane to give the required product (0.050 g, m.p.=166-168° C.). 1H NMR (360 MHz, DMSO) δ1.55 (2H, m), 1.91 (4H, m), 1.97 (2H, m), 2.13 (2H, m), 2.49 (1H, m), 5.77 (2H, s), 7.54 (1H, m), 7.69 (4H, s), 8.00 (1H, t, J=7.6 Hz), 8.28 (1H, s), 8.34 (2H, dd, J=7.6 and 1.5 Hz), 8.80 (1H, m); MS (ES+) m/e 398 [MH]+. Anal. Found C, 72.16; H, 5.59; N, 17.41. C24H23N5O. 0.1H2O requires C, 72.20; H, 5.86; N, 17.54%.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4](=O)[C:3]1=O.[CH:13]1([NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[NH2:19].O>C(O)(=O)C>[CH3:1][C:2]1([CH3:12])[C:3]2[C:4](=[N:19][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[N:20]=2)[C:5]([CH3:9])([CH3:8])[CH2:6][CH2:7]1
Reactant: NC1CCCCC1N
Reactant: CC1(C)CCC(C)(C)C(=O)C1=O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2nc3c(nc21)CCCC3

Procedure:
20.0 g of 3,3,6,6-tetramethyl-1,2-cyclohexanedione and 20 ml of 1,2-cyclohexanediamine were dissolved in 20 ml of acetic acid. The obtained solution was heated under reflux for 6 hours, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated acueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 5% ethyl acetate/hexane) to give 16.0 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH2:44])[CH:42]=2)[N:37]([CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[N:36]=1>CN(C=O)C>[NH:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:26]=[C:27]1[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH:44][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])[CH:42]=2)[N:37]([CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[N:36]=1
Reactant: O=C(O)C1CC1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.4 %

Procedure:
Cyclopropanecarboxylic acid (6.46 mg, 0.075 mmol), HOBT (15.20 mg, 0.112 mmol), EDC (21.56 mg, 0.112 mmol) and sodium bicarbonate (6.30 mg, 0.075 mmol) was added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (25 mg, 0.075 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash column chromatography (6% CH3OH/CH2Cl2) afforded the title compound (20 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.50 (d, 1H, J=1.6 Hz), 7.96 (s, 1H), 7.75 (dd, 1H, J=2.0 and 8.8 Hz), 7.65 (m, 2H), 7.26 (m, 2H), 5.86 (dd, 1H, J=2.0 and 9.2 Hz), 3.97 (m, 1H), 3.81 (m, 1H), 2.63 (m, 1H), 2.14 (m, 2H), 1.82 (m, 2H), 1.68 (m, 2H), 0.99 (m, 2H), 0.87 (m, 2H); ESI-MS [M+H]+: 402.22.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19]C2.ClC1C=CC(C2CCNCC2)=CC=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[NH:15][N:14]=[C:22]4[CH2:21][CH2:20][CH2:19][C:17]=34)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Agent: Clc1ccc(C2CCNCC2)cc1
Product: Cc1ccc(N2CCN(CCCc3[nH]nc4c3CCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(2,4,5,6-tetrahydrocyclopentapyrazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 4 and 1-(4-methylphenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-2,4,5,6-tetrahydrocyclopentapyrazole was obtained, m.p. 101-102° C.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:20])[C:7](=[O:19])[N:8]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(OCC)(=O)C>CS(C)=O>[O:24]1[CH2:25][CH2:26][N:21]([C:2]2[CH:10]=[C:9]3[C:5]([C:6](=[O:20])[C:7](=[O:19])[N:8]3[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccc(F)cc21
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 2-(6-fluoro-2,3-dioxoindolin-1-yl)acetate (0.400 g, 1.432 mmol) in DMSO (10 ml), morpholine (1.248 ml, 14.32 mmol) was added drop wise at room temperature. The resulting orange mixture was stirred at room temperature for 24 hours. Ethyl acetate (50 ml) was added and the solution was washed with brine (3×30 ml); the organic phase was dried over sodium sulfate, filtered and concentrated under vacuum. The crude was purified by silica gel flash chromatography (DCM:MeOH=98:2) affording tert-butyl 2-(6-morpholino-2,3-dioxoindolin-1-yl)acetate (0.400 g, 1.155 mmol, 81% yield 0. MS/ESI+ 347.1 [MH]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:44])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:42][CH3:43])([C:27]3[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[C:29]([CH3:41])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH:17]=1.[C:45]([C:47]1([OH:52])[CH2:51][CH2:50][CH2:49][CH2:48]1)#[CH:46]>C(#N)C.[Cu]I>[CH3:8][O:9][C:10](=[O:44])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([CH2:42][CH3:43])([C:27]3[CH:32]=[CH:31][C:30]([C:46]#[C:45][C:47]4([OH:52])[CH2:51][CH2:50][CH2:49][CH2:48]4)=[C:29]([CH3:41])[CH:28]=3)[CH2:25][CH3:26])=[CH:22][CH:23]=2)[CH:17]=1
Reactant: C#CC1(O)CCCC1
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Temperature: 160 °C
Yield: 33.6 %

Procedure:
Triethylamine (0.078 mL, 0.560 mmol), tetrakistriphenylphosphine palladium (43.0 mg, 0.036 mmol) and copper (I) iodide (7.0 mg, 0.037 mmol) were added to a solution of (5-{4-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-phenyl}-pyridin-3-yl)-acetic acid methyl ester (Example 144-(2); 0.1 g, 0.186 mmol) and 1-ethynyl-cyclopentanol (61.6 mg, 0.56 mmol) in acetonitrile (0.9 mL), and the mixture was stirred with microwave heating at 160° C. for three minutes. The reaction solution was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (31.0 mg, 33%).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:22]1([CH3:39])[CH:27]=[CH:26][C:25](S(OCC2CCCCC2)(=O)=O)=[CH:24][CH:23]=1>>[CH:22]1([CH2:39][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCC2)cc1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2CCCCC2)c1
Yield: 55.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclohexyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (212 mg, yield: 55.4%).
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:13][C:12]=2[CH2:28][CH3:29])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH2:38][OH:39]>C(O)C.O>[CH2:28]([C:12]1[CH:13]=[C:14]([C:18]([F:27])([C:19]([F:22])([F:20])[F:21])[C:23]([F:25])([F:24])[F:26])[CH:15]=[C:16]([CH3:17])[C:11]=1[NH:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([C:1](=[N:38][OH:39])[CH3:2])=[CH:31][CH:30]=1)[CH3:29]
Reactant: NO
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)=NO)cc1
Yield: 104.8 %

Procedure:
4-Acetyl-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-benzamide (2.2 g) was dissolved in ethanol (15 ml) and water (15 ml). To the solution, sodium acetate (0.6 g) and hydroxylamine hydrochloride (0.30 g) were added and the mixture was refluxed under heating for 4 hours. The reaction solution was extracted twice with ethyl acetate. The organic phases were combined, washed with water and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-4-[N-hydroxyethaneimidoyl]benzamide (2.1 g, yield 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=2)[C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:31]1C=C(S(Cl)(=O)=O)C=C[CH:36]=1>>[CH2:31]([O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:27]=[CH:28][CH:29]=[C:12]([NH:11][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:9])=[O:10])[CH:13]=2)=[CH:19][CH:20]=1)[CH3:36]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(Cl)c3)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(Cl)c3)c2)cc1

Procedure:
4-[3-(3-Chloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=429.2 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 3-chloro-benzensulfonyl chloride and yielded 4-[3-(3-chloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]1.[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:7]([O:8][CH2:23][C:22]#[CH:21])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]1
Reactant: C#CCBr
Reactant: Nc1c(O)c(Cl)cc(F)c1-n1nnn(CCCF)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1c(Cl)cc(F)c(-n2nnn(CCCF)c2=O)c1N
Yield: 104.8 %

Procedure:
The mixture of 1-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)(3-fluoropropyl)-tetrazolinone (0.28 g), propargyl bromide (0.13 g), and potassium carbonate (0.14 g) in acetonitrile (5 ml) was heated under reflux for 0.5 hour. The solvent and excess reagent were removed under reduced pressure. The residue was purified by a silica gel column, eluted with ethyl acetate to give the desired product (0.33 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20](O)=[O:21])[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:65]1([NH2:68])[CH2:67][CH2:66]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=2)[C:20]([NH:68][C:65]2([C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=3[C:58]([F:57])([F:69])[F:70])[CH2:67][CH2:66]2)=[O:21])[N:10]=1
Reactant: NC1(c2ccccc2C(F)(F)F)CC1
Reactant: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1C(=O)NC1(c2ccccc2C(F)(F)F)CC1
Yield: 16.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 5-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-2-methoxybenzoic acid (Intermediate-11, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropyl ethyl amine (1.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[2-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-12, 0.066 g, 0.329 mmol) to afford 0.025 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.26-1.28 (m, 4H), 3.91 (s, 3H), 7.24 (d, J=9.3 Hz, 1H), 7.11-7.48 (m, 6H), 7.98 (t, J=7.5 Hz, 2H), 8.27 (s, 1H), 8.74 (s, 1H), 12.56 (br s, 1H); MS (m/z): 545.31 (M−H)−.