Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:15][NH:14][CH2:13]3)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:13][N:14]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:15]3)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)nn2C2CNC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CC(n2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(5-(4-fluorobenzyl)-1-(azetidin-3-yl)-1H-pyrazol-3-yl)pyridine (75 mg, 0.24 mmol) in CH2Cl2 (2 mL) was added propionyl chloride (22 μL, 0.24 mmol) and triethylamine (37 μL, 0.26 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The solution was then loaded directly onto a pre-wetted Biotage 25M column and purified by flash chromatography (0-5% MeOH/CH2Cl2) to give the title compound as a white solid, 68 mg, 78%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.57 (d, 2 H), 7.74 (d, 2 H), 7.26 (t, 2 H), 7.16 (t, 2 H), 6.72 (s, 1 H), 5.25-5.34 (m, 1 H), 4.32-4.45 (m, 2 H), 4.07-4.13 (m, 4 H), 2.09 (q, 2 H), 0.97 (t, 3 H); m/z (APCI+) for C21H21N4FO 365.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)=[O:29].C(C1C=C(NC(C2C=CC(N3CCN(C(C4CCC(C(O)=O)CC4)=O)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[CH3:26][O:27][C:28]([CH:30]1[CH2:35][CH2:34][CH:33]([C:36]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:12](=[O:25])[NH:11][C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=4)=[CH:14][N:15]=3)[CH2:20][CH2:21]2)=[O:37])[CH2:32][CH2:31]1)=[O:29]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)C4CCC(C(=O)O)CC4)CC3)nc2)c1
Product: COC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cn3)CC2)CC1

Procedure:
4-{4-[5-(4-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid methyl ester was prepared from N-(4-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide and trans-1,4-cyclohexane dicarboxylic acid monomethyl ester using a procedure similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid above. The product was isolated after silica gel column purification with 20-100% EtOAc in hexanes gradient. HRMS m/z calcd for C29H38N4O4 [M+H]+: 507.2966. Found: 507.2969.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>ClCCl>[CH3:1][CH:2]1[N:6]([C:28](=[O:31])[CH2:29][CH3:30])[CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1
Reactant: CCC(=O)O
Reactant: CC1NCC2(CCN(C)CC2)S1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC(=O)N1CC2(CCN(C)CC2)SC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a stirred solution of 2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (Example 1) (0.86 g, 4.62 mmol) in dichloromethane (90 ml) at room temperature was added dicyclohexylcarbodiimide (DCC) (1.28 g, 6.2 mmol) followed by addition of propionic acid (0.41 ml, 5.5 mmol). The resulting solution was stirred at room temperature overnight. During the reaction a white solid precipitated. After filtration the solvent was evaporated and the crude product was purified by flash chromatography (silica, CH2Cl2/MeOH/NH4OH 90/10/1) to give the title compound (0.5 g) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 5.51, 5.19 (2q, J=6.15 and J=6.22 Hz, 1H, CHCH3), 4.63, 3.74 (2d, J=11.88 and J=11.57 Hz, 1H, CHHNCO), 3.44, 3.08 (2d, J=11.55 and J=12.09 Hz, 1H, CHHNCO), 2.8-2.6 (m, 2H), 2.5-2.2 (m, 7H, CH2, CH2CH3, NCH3), 2.2-2.0 (m, 1H), 2.0-1.8 (m, 3H) 1.52, 1.48 (2d, J=630 and J=6.18 Hz, 3H, CH3—CH), 1.19-1.12 (m, 3H, CH3) ppm; 13C NMR (CDCl3, 300 MHz) δ 171.6 (C), 57.5, 57.2 (CH), 55.5 (C), 54.7, 54.3 (CH2), 53.2, 53.0 (CH2), 46.3 (CH3), 38.4, 37.7 (CH2), 37.0, 36.4 (CH2), 28.8, 26.8 (CH2), 25.6, 23.6 (CH3), 9.6, 9.4 (CH3) ppm.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.C(OC(C1C(C2C=CC=CN=2)=NOC=1)=O)C>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][N:6]=2)=[CH:16][O:15][N:14]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccccn2)nc1
Agent: CCOC(=O)c1conc1-c1ccccn1
Product: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 96.3 %

Procedure:
As described for example 358b, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (510 mg, 1.6 mmol), instead of 3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester, was converted to the title compound (458 mg, 94%) which was obtained as a white solid. MS: m/e=296.5 [M−H]−.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([N:10](CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[Cl:15][CH2:16][C:17]([NH2:1])=[O:18].[Cl:15][CH2:16][C:17]([NH2:10])=[O:18].[NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCl
Reactant: CCN(CC)CC
Agent: C1CNCCNC1
Solvent: ClC(Cl)Cl
Product: NC(=O)CCl
Temperature: -30 °C
Reaction time: 8 h

Procedure:
Homopiperazine (10 g; 100 mmol) was dissolved in chloroform (150 mL) and triethylamine (28 mL; 500 mmol) was added to the mixture. The solution was cooled to -30° C. under nitrogen and chloroacetyl chloride (17 mL, 213 mmol) was added over a period of 1 hour. The solution was stirred at -30° C. for 1 hour, at 0° C. for 2 hour and at ambient temperature overnight. The solution was washed with water (4×50 mL), dried over anhydrous MgSO4, filtered and concentrated. The oily residue was purified by column chromatography on silica gel (5% methanol in chloroform) to yield the title product as an oil which solidified on prolonged standing (10.3 g; 41%). 1H NMR (CDCl3): 4.04 (m, 4 H), 3.62 (m, 8 H), and 1.94 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:20])[CH3:19])[CH:13]=2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[NH:39][C:38](=[O:40])[O:37][N:36]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[C:18]([C:14]1[CH:13]=[C:12]([N:8]2[C:7](=[O:21])[C:6]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]4[NH:39][C:38](=[O:40])[O:37][N:36]=4)=[CH:27][CH:28]=3)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:10]=[C:9]2[CH3:11])[CH:17]=[CH:16][CH:15]=1)(=[O:20])[CH3:19]
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCc1nc(C)n(-c2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of 6-butyl-3-[3-(1-hydroxyethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.3 g) in acetonitrile (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.36 g), and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate, water and sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.21 g, 71%).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[CH3:13][Si:14]([CH3:50])([CH3:49])[CH2:15][CH2:16][O:17][CH2:18][N:19]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:20]1[N:25]2[N:26]=[CH:27][CH:28]=[C:24]2[N:23]=[C:22]([CH:29]2[CH2:34][CH2:33][C:32](=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31][CH2:30]2)[CH:21]=1.[NH4+].[Cl-]>CS(C)=O.[Na+].[Cl-]>[CH3:46][Si:45]([CH3:48])([CH3:47])[CH2:44][CH2:43][O:42][CH2:41][N:19]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:13])([CH3:49])[CH3:50])[C:20]1[N:25]2[N:26]=[CH:27][CH:28]=[C:24]2[N:23]=[C:22]([CH:29]2[CH2:34][CH2:33][C:32]3([CH:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7]3)[CH2:31][CH2:30]2)[CH:21]=1
Reactant: CCOC(=O)C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC12CCC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 50 mL roundbottom flask containing trimethylsulfoxonium iodide (3.57 mmol, 785 mg) in DMSO (8 mL) was added potassium tert-butoxide (3.57 mmol, 401 mg). This suspension was allowed to stir at room temperature for 3 hours. After 3 hours, ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate (1.78 mmol, 1.00 g) was added in 2 mL DMSO. The resulting solution was stirred at room temperature for 18 hours. After 18 hours, the reaction was diluted with saturated NaCl(aq) (30 mL). The pH was adjusted to ˜7 with saturated NH4Cl(aq) and extracted with DCM (50 mL) 4 times. The combined organics are dried over Na2SO4 and reduced in vacuo. The resulting residue was purified via flash chromatography to yield the title compound.
Reaction SMILES: [I-:1].[Na+].[CH2:3]([N:7]([CH3:17])[S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Cl)(=[O:10])=[O:9])[CH2:4][CH2:5][CH3:6]>C(C(C)=O)C>[CH2:3]([N:7]([CH3:17])[S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][I:1])(=[O:10])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCN(C)S(=O)(=O)CCCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCN(C)S(=O)(=O)CCCCCI
Yield: 93.8 %

Procedure:
526 mg of sodium iodide were added to a solution of 449 mg of the product of Step A in 4.5 ml of methyl ethyl ketone, and the mixture was stirred at reflux for 4 hours. After cooling, the methyl ethyl ketone was evaporated under reduced pressure and water was added. Extraction was carried out with ethyl acetate and the extracts were washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 572 mg of the expected product.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C.C(OC(=O)C)(=O)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:2]2[O:1][CH2:6][C:5](=[O:7])[NH:4][C:3]=2[N:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C1COc2cccnc2N1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1COc2ccc([N+](=O)[O-])nc2N1
Reaction time: 8 h

Procedure:
2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one (2.5 g) was dissolved in acetic acid (6 mL) and acetic anhydride (30 mL). Fuming nitric acid (3 mL) was added dropwise to the reaction solution in ice-bath. The reaction solution was stirred in ice-bath overnight. Solution was poured into crashed ice. The light yellow precipitation was collected by filtration, washed with water and dried to give a mixture of nitrated products (regio-isomers). The mixture was crystallized from dichloromethane to give 6-nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (1 g) as a light yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:12]([O-:14])=[O:13])=[N:9][C:10]=1[CH3:11])([CH3:3])[CH3:2].[Li+].[OH-].O.CCOC(C)=O>C1COCC1.O>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[N:9][C:10]=1[CH3:11])([CH3:3])[CH3:2]
Reactant: Cc1nc(C(=O)[O-])ccc1OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
5-Isopropoxy-6-methylpicolinate (1.3 g, 6.22 mmol) was dissolved in THF/water 2:1 (9 mL). LiOH*H2O (0.26 g, 6.22 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was poured into a mixture of water and EtOAc and the layers were separated. The aqueous layer was acidified to pH 4 with 2 N HCl and was extracted with EtOAc (2×). The combined organics were dried (Na2SO4) and concentrated in vacuo to give 5-isopropoxy-6-methylpicolinic acid (860 mg, 74%) as a beige solid. 1H-NMR (300 MHz, DMSO) 1.31 (d, 6H), 4.73 (m, 1H), 7.44 (d, 1H), 7.86 (d, 1H).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:38]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Cl:40][C:41]1[CH:46]=[C:45]([NH2:47])[CH:44]=[CH:43][C:42]=1[C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:38][NH:47][C:45]2[CH:44]=[CH:43][C:42]([C:48]3[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=3)=[C:41]([Cl:40])[CH:46]=2)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (2.7 g, 12.7 mmol) was added to a DCE solution (22 mL) of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate, prepared as in Example 6, (2.3 g, 6.3 mmol), 2,4′-dichloro-[1,1′-biphenyl]-4-amine (1.7 g, 7.0 mmol), and AcOH (1.5 mL, 25.4 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([N:16]1[C:20](=[O:21])[C:19](Cl)=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:17]1(=[O:30])=[O:29])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([N:16]1[C:20](=[O:21])[C:19]([NH:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:17]1(=[O:29])=[O:30])([CH3:15])([CH3:13])[CH3:14]
Reactant: NCCCOc1ccccc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 73 %

Procedure:
The title compound was prepared as described for Example 24 from (3-phenoxypropyl)amine and 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide. The residue was purified by silica gel column chromatography (Horizons Biotage) using 17-20% EtOAc in hexane as eluent to give the title compound (0.152 g, 73%). 1H NMR (500 MHz CDCl3): δ 7.52-7.47 (m, 2H), 7.44-7.38 (m, 3H), 7.32-7.24 (m, 2H), 6.95 (t, 1H), 6.84 (d, 2H), 5.74 (t, 1H), 3.87 (t, 2H), 3.12-3.04 (m, 2H), 1.86-1.78 (m, 2H), 1.72 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 158.8, 135.3, 131.8, 129.7, 128.7, 125.3, 121.3, 114.6, 107.2, 65.9, 61.7, 42.5, 29.0, 27.8; Mass Spectrum M+H+ 415.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH:21]=[CH:20][N:19]=3)[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[Li+].[OH-]>CO.O>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([C:14]3[CH:13]=[C:12]([C:9]4[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=4)[CH:17]=[CH:16][CH:15]=3)[CH:23]=2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1ccc(-c2cccc(-c3cc(N4CCN(C)CC4)ccn3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCN(c2ccnc(-c3cccc(-c4ccc(C(=O)O)cc4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3′-[4-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-biphenyl-4-carboxylic acid ethyl ester (182 mg, 0.4 mmol) in MeOH/water (3:1, 4 mL) was added LiOH (48 mg, 2 mmol). The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated and the resulting aqueous solution was adjusted to pH 7 by the addition of 1 N HCl. The resulting mixture was concentrated and the resulting residue was dissolved in MeOH, dried, and concentrated to yield the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:32])[C:5]([CH2:8][N:9]2[C:18]3[C:17]([F:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=3[C:12]3=[N:21][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[C:23](=[O:24])[C:11]3=[CH:10]2)=[N:6][CH:7]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CS(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][C:17]1[C:18]2[N:9]([CH2:8][C:5]3[C:4]([F:32])=[CH:3][C:2]([C:37]4[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=4)=[CH:7][N:6]=3)[CH:10]=[C:11]3[C:23](=[O:24])[N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[N:21]=[C:12]3[C:13]=2[C:14]([F:20])=[CH:15][CH:16]=1
Reactant: O=c1c2cn(Cc3ncc(Br)cc3F)c3c(F)ccc(F)c3c-2nn1-c1ccccc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(-c2cnc(Cn3cc4c(=O)n(-c5ccccc5F)nc-4c4c(F)ccc(F)c43)c(F)c2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-[(5-Bromo-3-fluoropyridin-2-yl)methyl]-6,9-difluoro-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 103, 63 mg, 0.13 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (45 mg, 0.21 mmol, 1.7 equiv), potassium carbonate (52 mg, 0.38 mmol, 3 equiv), palladium(II) acetate (5.7 mg, 0.025 mmol, 0.2 equiv) and 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (28 mg, 0.058 mmol, 0.46 equiv) were combined in dimethylsulfoxide (0.9 mL) and water (0.2 mL). The mixture was sparged under an atmosphere of nitrogen, the vessel was sealed and placed into a preheated oil bath at 88° C. for 4 hours. The mixture was cooled to ambient temperature, poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed once with water (10 mL) and brine (10 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 98:2; chloroform:methanol), providing the titled compound: high resolution mass spectrometry (ES+) m/z 505.1385 [(M+H)+; calculated for C26H17F4N6O: 505.1395].
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(OC(OCC)OCC)C>C1COCC1.C(Cl)Cl>[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([N:17]2[C:4](=[O:12])[C:5]3[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:7]=[C:2]2[CH3:1])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: Cc1c(N)cccc1Br
Solvent: CCOC(OCC)OCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(Br)cccc1-n1c(C)nc2ccccc2c1=O
Temperature: 25 °C
Yield: 19.6 %

Procedure:
A solution of 2-methyl-4H-benzo[d][1,3]oxazin-4-one (300 mg, 1.862 mmol), 3-bromo-2-methylaniline (346 mg, 1.862 mmol), and triethoxymethane (276 mg, 1.862 mmol) in THF (2 mL) was heated overnight in a sealed tube at 100° C. The mixture was cooled to rt and diluted with DCM. The solution was washed with water and NaHCO3 (aq), and dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 to 50:50 hexane-EtOAc) and the crude product was triturated in hexane to give 3-(3-bromo-2-methylphenyl)-2-methylquinazolin-4(3H)-one as an off-white solid (120 mg, 20%). 1H NMR (400 MHz, chloroform-d) δ 8.28 (1H, dd, J=7.92, 1.10 Hz), 7.77-7.82 (1H, m), 7.68-7.73 (2H, m), 7.47-7.52 (1H, m), 7.22-7.25 (1H, m), 7.13-7.17 (1H, m), 2.20 (6H, s). Mass spectrum m/z 329, 331 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH2:11](Br)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:12][CH2:11][CH:9]([C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH3:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCc1ccncc1CC
Reactant: BrCCc1ccccc1
Product: CCc1cnccc1C(C)CCc1ccccc1
Yield: 57.2 %

Procedure:
1.26 g (9.35 mmol) of 3,4-diethylpyridine and 1.73 g (9.35 mmol) of phenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.28 g of the desired compound (yield: 57.2).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH:5]([C:10]1[CH:11]=[C:12]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:18]2[CH2:19][CH2:20][CH2:21][CH:16]([C:14]3[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:45])=[O:3])[CH:11]=[C:12]([C:35]4[CH:36]=[CH:37][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:39][CH:40]=4)[CH:13]=3)[CH2:17]2)=[CH:24][C:25]=1[C:31]([F:34])([F:33])[F:32]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(OC)c(C(F)(F)F)c3)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CN2CCCC(c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(CC(C)C)C(=O)O)c3)C2)cc1C(F)(F)F
Temperature: 78 °C

Procedure:
To compound 51a, 2-{5-[1-(4-Methoxy-3-trifluoromethyl-benzyl)-piperidin-3-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl ester (62.0 mg, 0.10 mmol) in EtOH (5.0 ml) was added 2M KOH (0.50 ml, 1.0 mmol). The reaction was heated to 78° C. for 3 hour, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, salt exchange with 1N HCl (aqueous) gave the product as a white lyophilate, (45.5 mg, 71%). 1H NMR (300 MHz, MeOD) δ ppm 0.95 (d, J=6.41 Hz, 6 H) 1.49 (dq, J=13.33, 6.61 Hz, 1 H) 1.67 (ddd, J=13.75, 7.16, 6.97 Hz, 1 H) 1.89-2.14 (m, 6 H) 3.00-3.14 (m, 1 H) 3.14-3.26 (m, 2 H) 3.47-3.60 (m, 2 H) 3.76 (t, J=7.72 Hz, 1 H) 3.94 (s, 3 H) 4.30-4.43 (m, 2 H) 7.27-7.34 (m, 2 H) 7.50 (s, 1 H) 7.58 (s, 1 H) 7.72-7.83 (m, 5 H) Calcd for C33H35F6NO3 (M+H) 607.63, Found 608.4.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:26]4[CH2:25][CH2:24][C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([OH:22])[CH2:28][CH2:27]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-hydroxy4-phenylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=463.