Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1.[NH:29]1[CH:33]=[N:32][C:31]([NH2:34])=[N:30]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[NH:34][C:31]3[N:32]=[CH:33][NH:29][N:30]=3)[CH:17]=2)=[O:13])[NH:3]1
Reactant: O=C(O)CCCOc1cccc(CNC(=O)c2nc3ccccc3c(=O)[nH]2)c1
Reactant: Nc1nc[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCCOc1cccc(CNC(=O)c2nc3ccccc3c(=O)[nH]2)c1)Nc1nc[nH]n1
Temperature: 40 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
A solution of 4-{[3-({[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl]amino}methyl)phenyl]oxy}butanoic acid obtained in Reference Example 44 (100 mg, 0.262 mmol), 1H-1,2,4-triazol-3-amine (26.4 mg, 0.314 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (60.3 mg, 0.314 mmol) and 1-hydroxybenzotriazole (42.5 mg, 0.314 mmol) in DMF (5 mL) was stirred at 40° C. for 5 hr. Water was added to the reaction mixture, and the resulting solid was collected by filtration, washed with water and IPE, and dried to give the title compound as a white powder (95.0 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[C@@H:7](O)[C@@H:6]([OH:9])[C@@H:5]([NH:10][C:11](=[O:13])[CH3:12])[C@H:4]([O:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:3]=1.C(OC(C)(C)C([Br:27])=O)(=O)C.C1C[O:33][CH2:32][CH2:31]1>>[C:32]([O:9][C@H:6]1[C@@H:5]([NH:10][C:11](=[O:13])[CH3:12])[C@H:4]([O:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:3]=[C:2]([Br:1])[C@@H:7]1[Br:27])(=[O:33])[CH3:31]
Reactant: CCC(CC)O[C@@H]1C=C(Br)[C@@H](O)[C@@H](O)[C@H]1NC(C)=O
Reactant: C1CCOC1
Reactant: CC(=O)OC(C)(C)C(=O)Br
Product: CCC(CC)O[C@@H]1C=C(Br)[C@H](Br)[C@@H](OC(C)=O)[C@H]1NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diol 23 (7.42 g, 22.1 mmol) in THF (150 mL) at 0° C. under nitrogen atmosphere, α-acetoxyisobutyryl bromide (4.1 mL, 27.8 mmol) was added dropwise over a period of 10 min. The reaction mixture was stirred at same temperature for 30 min, and warmed to room temperature with stirring for 3.5 h. The solvent was evaporated, and the residual oil was partitioned between EtOAc (200 mL) and 5% aqueous NaHCO3 (50 mL). The organic layer was washed with water (100 mL), dried over MgSO4, filtered and concentrated to afford the crude bromoacetate 24 (9.05 g). The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][NH2:12])=[N:9][CH:10]=1)(=[O:4])=[O:3].OS(O)(=O)=O.[F:18][CH:19]([F:31])[C:20](=O)[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O.C(O)(C)C.FC(F)C(=O)CC(C1C=CC=CC=1)=O>C(O)(C)C.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][C:20]([CH:19]([F:18])[F:31])=[N:12]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Reactant: O=C(CC(=O)C(F)F)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2ccccc2)nc1
Temperature: 22 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a clean and dry nitrogen purged 1 L round-bottom flask under nitrogen atmosphere was charged 25.6 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (0.14 moles), 512 mL water (20 volumes) and 16 mL of concentrated H2SO4 (0.063 volumes). In a separate 500 mL 1-neck round-bottom flask, was prepared a solution of 384 mL of isopropanol (15 volumes) and 26.01 g (0.13 moles) of 4,4-difluoro-1-phenyl-1,3-butanedione. The isopropanol/4,4-difluoro-1-phenyl-1,3-butanedione solution was added to the 5-(methylsulfonyl)-2-hydrazinyl-pyridine reaction mixture keeping the pot temperature less than 25° C. After addition, the mixture was stirred at 22° C. for 2.0 hours and sampled for disappearance of starting material. When the starting materials had disappeared (less than 15 remaining), the pot was then heated to 40° C. for 5.5 hours until disappearance of the intermediate. The resulting slurry was filtered and washed with water to achieve a pH 6-7 of the filtrate. The solids were then charged to a 250 mL 3-neck round-bottom flask. To the flask was added: 31.25 mL water (1.2 volumes) and 31.25 mL isopropanol (1.2 volumes). The mixture was heated to reflux (85° C.) for 30 minutes. The pot was allowed to cool to 28° C. and the solids were isolated by filtration and washed with 20 mL isopropanol. The solids were dried in a vacuum oven at 45° C. The product was obtained with 87% yield and contained 0.54% of the compound of formula 6 (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45.
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].C[O:6][CH:7]1[CH2:15]C2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=O.ClCCl.C([O:23][CH2:24][CH3:25])(=O)C.Cl>C1C=CC=CC=1>[OH:6][C:7]1[CH:15]=[C:25]2[C:10]([CH2:11][CH:12]([CH3:13])[C:24]2=[O:23])=[CH:9][CH:8]=1
Reactant: CCOC(C)=O
Reactant: COC1Cc2ccccc2C1=O
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC1Cc2ccc(O)cc2C1=O

Procedure:
To a stirred solution of anhydrous aluminum bromide (69.82 g, 0.261 mole) in anhydrous benzene (250 mL) kept under nitrogen is added dropwise over 30 minutes a solution of the methoxy indanone (18 g, 0.102 mole) of Step C, in benzene (60 mL). The mixture is gently refluxed for 3 hours (TLC, dichloromethane-ethyl acetate 8:2, UV), cooled in an ice bath and treated dropwise with 6N-HCl (ca. 200 mL) to decompose the aluminum complex. The aqueous phase is extracted with ether (3 times), the extracts are concentrated at reduced pressure and extracted with 2.5N-NaOH (2×75 mL and 1×50 mL). The basic extracts are neutralized (ice bath) with concentrated HCl and the oil that separates is extracted with ether (3 times). The combined extracts are washed with brine, dried (MgSO4) and evaporated to yield an oil that readily solidifies. The crude material is flash chromatographed (on silica Merck-60, gradient CH2Cl2, CH2Cl2 -ethyl acetate 85:15 ) to provide the pure title compound (13.60 g, nearly colorless solid, 82%).
Reaction SMILES: FC(F)(F)C(O[I:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)OC(=O)C(F)(F)F)=O.II.C1([C:30]23[CH2:37][CH2:36][C:33]([C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH2:34][CH2:35]2)[CH2:32][CH2:31]3)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[I:6][C:14]1[CH:15]=[CH:16][C:17]([C:30]23[CH2:37][CH2:36][C:33]([C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH2:32][CH2:31]2)[CH2:34][CH2:35]3)=[CH:18][CH:19]=1
Reactant: CCOC(=O)C12CCC(c3ccccc3)(CC1)CC2
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C12CCC(c3ccc(I)cc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
[Bis(trifluoroacetoxy)iodo]benzene (3.78 g, 8.78 mmol) and iodine (1.061 g, 4.18 mmol) were added to a stirred solution of ethyl 4-phenylbicyclo[2.2.2]octane-1-carboxylate (prepared according to the procedure described in WO 2007/071966) (2.16 g, 8.36 mmol, CAS 10207-26-8) in CHCl3 (50 mL). The resulting solution was stirred at ambient temperature for 90 minutes. The reaction mixture was poured into sodium thiosulfate (100 mL), extracted with DCM (2×100 mL), the organic layer was washed with aqueous sodium thiosulfate (2×80 mL), separated, dried over MgSO4, filtered and evaporated to afford a yellow oil which solidified on standing. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (2.78 g, 87%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:26])[CH2:18][N:19]1[CH:23]=[C:22]([CH:24]=O)[CH:21]=[N:20]1)[CH3:15].N1CCCC1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12]/[C:11](=[CH:24]\[C:22]2[CH:21]=[N:20][N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:26])[CH:23]=2)/[C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CCOC(=O)Cn1cc(C=O)cn1
Solvent: C1CCNC1
Solvent: CCO
Product: CCOC(=O)Cn1cc(/C=C2\CN(C(=O)OC(C)(C)C)CC2=O)cn1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 34.8 %

Procedure:
To a solution of 1-(t-butoxycarbonyl)pyrrolidin-3-one (6.8 g) in ethanol (200 ml) were added ethyl(4-formyl-1H-pyrazol-1-yl)acetate (8.0 g) and pyrrolidine (600 μl). The resulting mixture was stirred at 80° C. for 45 minutes, cooled to room temperature, and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (2:1:1) as the eluent to afford the title compound as a yellow amorphous solid (4.47 g, yield: 35%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:33])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)[CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:40][CH2:41][C:42](Cl)=[O:43]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:33])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:42](=[O:43])[CH2:41][Cl:40])=[CH:29][CH:30]=3)[CH2:19][CH2:18]4)(=[O:13])=[O:14])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(C(=O)N2CCc3cc(S(=O)(=O)n4cc(-c5ccccc5)[nH]c4=O)ccc32)cc1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(C(=O)N2CCc3cc(S(=O)(=O)n4cc(-c5ccccc5)[nH]c4=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
4-Phenyl-1-[N-(4-aminobenzoyl)indoline-5-sulfonyl]-2-imidazolone (150 mg, 0.3 mmol) prepared in Example 10 was dissolved in 10 ml of dichloromethane. Pyridine (73 μl, 0.9 mmol) and chloroacetylchloride (36 μl, 0.45 mmol) were added thereto one after another, and then the reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. After stirring, the reaction mixture was diluted with 30 ml of dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1, v/v) to afford 130 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:27](O)[CH2:28][OH:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:10]3[N:19]=[C:18]([NH:20][C:21]4[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=4)[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)[O:29][CH2:28][CH2:27][O:9]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Nc2nc(C3(c4ccc(F)cc4)OCCO3)nc3ccccc23)n[nH]1
Yield: 1 %

Procedure:
To (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 3 (0.20 g, 0.58 mmol) in toluene (20 mL) were added ethylene glycol (0.2 mL) and p-toluenesulfonic acid monohydrate (catalytic quantity). The mixture was heated under reflux overnight while collecting water in a Dean-Stark trap. Additional ethylene glycol (1.5 mL) and p-toluenesulfonic acid monohydrate (50 mg) were added and mixture was heated at reflux overnight with collection of water. After cooling, the mixture was evaporated to dryness, and then dissolved in DMSO (8 mL). A 5 mL aliquot of this solution was purified by preparative reverse-phase HPLC (Varian diphenyl reverse phase column eluting with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O) followed by additional purification by preparative reverse-phase HPLC (Phenomenex C-18 reverse phase column, eluted with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(2-(4-fluorophenyl)-1,3-dioxolan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (2 mg, 1%). 1H NMR (300 MHz, DMSO-d6) δ 2.20 (s, 3H) 4.05-4.22 (m, 4H) 6.2 (s, 1H) 7.19 (t, 2H) 7.5-7.65 (m, 3H) 7.81 (m, 2H) 8.59 (d, 1H) 10.38 (s, 1H) 12.08 (s, 1H); LC-MS (ESI) m/z 392 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:10][C:11]=1[F:12]>>[Cl:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[C:8]([C:13]([F:14])([F:15])[F:16])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1C(F)(F)F
Temperature: 40 °C
Reaction time: 5 h

Procedure:
About 500 parts of aqueous nitric acid was added slowly, with stirring, to about 400 parts of 3-chloro-4-fluorobenzotrifluoride. The temperature of the reaction mixture was maintained at about 40° C. during the addition, then raised to about 60° C. and maintained thereat for about 5 hours. The reaction mixture was allowed to settle. The aqueous layer was removed and the organic layer washed twice with 500 parts of water, treated several times with a saturated solution of sodium bicarbonate, washed with water again, dried over anhydrous magnesium sulfate, and filtered. The filtrate was vacuum distilled to yield 347 parts of 5-chloro-4-fluoro-2-nitrobenzotrifluoride.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](I)[CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH2:22][CH2:23][CH3:24])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Yield: 62.2 %

Procedure:
The reaction procedure of Example 11 was followed except that 939 mg (3.24 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 26 mg of lithium hydride and 551 mg of propyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 669 mg of 2-[(4-chlorophenyl)imino]-2,3-dihydro-3-propyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (62%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 112 mg of 2-[N-(4-chlorophenyl)-N-propylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (10%, recrystallized from ether) as a high polarity substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([C:19]2[CH:20]=[N:21][C:22]([C:25]([CH:27]3[CH2:32][CH2:31][CH:30]([C:33]([O:35]C)=[O:34])[CH2:29][CH2:28]3)=O)=[CH:23][CH:24]=2)[CH:3]=1.[OH-].[K+].NN>CS(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][C@H:27]3[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]3)=[CH:23][CH:24]=2)[CH:3]=1.[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][C@@H:27]3[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]3)=[CH:23][CH:24]=2)[CH:3]=1
Reactant: COC(=O)C1CCC(C(=O)c2ccc(-c3cc(C)cc(Nc4cc(C(F)(F)F)ccn4)n3)cn2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(C[C@H]3CC[C@@H](C(=O)O)CC3)nc2)c1
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(C[C@H]3CC[C@H](C(=O)O)CC3)nc2)c1
Temperature: 140 °C

Procedure:
To a flask containing methyl 4-[(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)carbonyl]cyclohexanecarboxylate (50 mg, 0.10 mmol) in DMSO (1 mL) was added potassium hydroxide (113 mg, 2.01 mmol) and hydrazine (57 μL, 1.81 mmol). The reaction was heated in a sealed vessel to 140° C. for 3 hours. The reaction mixture was then cooled to ambient temperature and filtered. The solution was then purified directly by reverse phase column chromatography (acetonitrile/water with 0.1% TFA modifier) to afford trans-4-[(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)methyl]cyclohexanecarboxylic acid and cis-4-[(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)methyl]cyclohexanecarboxylic acid.
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:9][C:10]1[CH:15]=[C:14]([CH3:16])[O:13][C:12](=[O:17])[CH:11]=1.Cl>C1C=CC=CC=1>[OH:9][C:10]1[CH:15]=[C:14]([CH3:16])[O:13][C:12](=[O:17])[C:11]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: ClSc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Product: Cc1cc(O)c(Sc2ccccc2)c(=O)o1
Yield: 99 %

Procedure:
Benzenesulfenyl chloride (7.2 g., 0.050 mol) dissolved in benzene (15 ml.) was added to a rapidly stirred slurry of 4-hydroxy-6-methyl-2-pyrone (6.3 g., 0.050 mol) in benzene (135 ml.). There was no apparent reaction at ambient temperature, but upon heating hydrogen chloride was evolved. After heating at reflux for 2 hours, the mixture was cooled and filtered to give 11.6 g. colorless crystals, m. 160°-162.5°C., 99 percent yield.
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[CH:5]=[C:6]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][C:32]2[C:35]([C:38](O)=[O:39])=[N:36][NH:37][C:31]=2[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:21][C:3]([F:2])([F:20])[C:4]1[CH:5]=[C:6]([CH:14]2[CH2:19][CH2:18][N:17]([C:38]([C:35]3[C:32]4[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:30][C:31]=4[NH:37][N:36]=3)=[O:39])[CH2:16][CH2:15]2)[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1
Reactant: FC(F)(F)c1cc(C2CCNCC2)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)O)n[nH]c2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)n[nH]c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(3,5-bis(trifluoromethyl)phenyl)piperidine hydrochloride (20, 100 mg, 0.31 mmol), 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (96 mg, 0.36 mmol), and diisopropylethylamine (0.16 mL, 0.90 mmol) in DMF (5.6 mL) was added EDCI (69 mg, 0.36 mmol) and HOBt (49 mg, 0.36 mmol). The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with a saturated brine solution (4×30 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% CH3OH in CH2Cl2 with 0.1% NH4OH in CH2Cl2) to provide tert-butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (51) as a white film (76 mg, 45%): 1H NMR (300 MHz, DMSO-d6) δ 13.13-12.77 (m, 1H), 8.02-7.98 (m, 2H), 7.96-7.91 (m, 1H), 4.91-4.59 (m, 2H), 4.53-4.41 (m, 2H), 3.60-3.46 (m, 2H), 3.21-3.03 (m, 2H), 2.85-2.69 (m, 1H), 2.63-2.54 (m, 2H, overlaps with solvent), 1.97-1.78 (m, 2H), 1.77-1.58 (m, 2H), 1.42 (s, 9H); ESI MS m/z 547 [M+H]+.
Reaction SMILES: [O-:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].C1([I+][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C=CC=CC=1.[C:22]1([S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[C:29]1([S+:28]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: c1ccc(Sc2ccccc2)cc1
Agent: [Cu+2]
Agent: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 125 °C
Reaction time: 1 h

Procedure:
A flask was charged with 2.0 g (4.8 mmol) of diphenyliodonium triflate, 0.93 g (5.0 mmol) diphenyl sulfide and 37 mg of copper benzoate. The mixture was heated under argon for 3 h (bath 125° C.). After cooling, the mixture was triturated with hot ether and stirred 1 h. The solid was filtered and recrystallized from 1:1 butyl acetate-isopropanol (1.6 g, 80%, mp 134°-6° C.).
Reaction SMILES: [C:1]([N:4]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=[O:28])=[C:19]([F:33])[CH:18]=2)=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1.O>[C:1]([N:4]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([OH:29])=[O:28])=[C:19]([F:33])[CH:18]=2)=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCCC(C)(C)C(=O)O)c(F)c2)c2ccccc21
Temperature: 40 °C
Yield: 82.6 %

Procedure:
Methyl 5-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-fluorophenyl)-2,2-dimethylpentanoate (70 mg, 0.12 mmol, 1 eq.) was dissolved in methanol/tetrahydrofuran (2/1) (3 ml). A solution of sodium hydroxide (8 mg, 0.20 mmol, 1.7 eq.) in water (1 ml) was added and reaction mixture heated to 40° C. for 8 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude acid. Purification by silica gel chromatography (methylene chloride/methanol: 99/1 to 98/2 gradient) gave pure 5-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-fluorophenyl)-2,2-dimethylpentanoic acid (56 mg, 84%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[N:4]1([CH:9](Cl)[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH2:11][CH3:12])[CH:8]=[N:7][CH:6]=[N:5]1.O>CO.[I-].[K+]>[N:4]1([CH:9]([O:2][CH3:1])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH2:11][CH3:12])[CH:8]=[N:7][CH:6]=[N:5]1
Reactant: C[O-]
Reactant: CCC(c1ccc(Cl)cc1Cl)C(Cl)n1cncn1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(c1ccc(Cl)cc1Cl)C(OC)n1cncn1
Yield: 23.7 %

Procedure:
9.4 g of sodium methylate and 0.2 g of potassium iodide are added to a solution of 26.6 g of 1-(1,2,4-triazol-1-yl)-1-chloro-2-(2,4-dichlorophenyl)-butane in 200 ml of methanol. The reaction mixture is refluxed for 48 hours, after which 100 ml of water are added to the solution and the mixture is extracted several times with methyl tert-butyl ether. The organic phase isolated is washed twice with water, then dried over sodium sulfate and evaporated down and the remaining residue is purified by chromatography over silica gel (9:1 ethyl acetate/n-hexane). 6.2 g (24%) of 1-(1,2,4-triazol-1-yl)-1-methoxy-2-(2,4-dichlorophenyl)-butane are obtained as a 1:1 diastereomer mixture [compound No. 1).