Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([O:17][CH3:18])[CH2:15][C:14](=[O:19])[CH2:13][CH:12]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N-:27]=[N+]=[N-].[Na+]>C(#N)C.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([O:17][CH3:18])[CH2:15][C:14](=[O:19])[NH:27][CH2:13][CH:12]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: COC1CC(=O)NCC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 15.6 %

Procedure:
In a manner similar to the method described in example 2 (method A), rac-(1R,2S,6S)-6′-chloro-2-(3-chlorophenyl)-6-methoxyspiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (156 mg, 0.4 mmol) was reacted with NaN3 (52 mg, 0.8 mmole) in the presence of TiCl4 (1.0 M in CH2Cl2, 0.8 mL) (Aldrich) in acetonitrile (10 mL) to give rac-(3S,4R,5S)-6′-chloro-3-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-5-methoxy-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (25.3 mg): HRMS (ES+) m/z Calcd for C20H18Cl2N2O3+H [(M+H)+]: 405.0767, found: 405.0765 and rac-(3R,4R,5S)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-methoxy-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione: HRMS (ES+) m/z Calcd for C20H18Cl2N2O3+H [(M+H)+]: 405.0767, found: 405.0768.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[N:14][CH:15]=1.O.O.[OH-].[Li+]>CO>[CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)OC)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
Methyl 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyrazine-2-carboxylate (423 mg, 0.907 mmol) synthesized in Example (62c) was dissolved in methanol (10 mL), and water (2 mL) and lithium hydroxide monohydrate (76.2 mg, 1.82 mmol) were added, followed by stirring at 50° C. for 1 hour under nitrogen atmosphere. To the reaction solution, water (30 mL) was added, and extraction was carried out twice with ethyl acetate (30 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: dichloromethane/methanol=0%-10%) to afford the desired compound (269 mg, yield 66%) as a pale yellow solid.
Reaction SMILES: C[C:2]([CH3:5])([O-])C.[K+].[CH:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:12][C:13]([NH2:15])=[S:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[NH2:15][C:13]1[S:14][C:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:12]=1
Reactant: NC(N)=S
Reactant: CCOC=O
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc(N)s1
Temperature: -2.5 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a -10° C. solution of potassium tert-butoxide (150 g, 1.3 mol) in THF (1.35 L) was added a solution of ethyl chloroacetates (139 mL, 1.3 mol) and ethyl formate (103 mL, 1.27 mol) in THF (150 mL) dropwise over 75 minutes, with good mechanical stirring. A THF rinse (25 mL) was added over 5 minutes. The thick solution was stirred another 3 hours at ca. -5 to 0° C., then the reaction was quenched by addition of a solution of NaCl (240 g) and conc. HCl (90 mL) in water (960 mL). The mixture was allowed to warm to 15° C. and the lower aqueous layer was discarded. Thiourea (97 g, 1.27 mol) was dissolved in the crude THF solution of chloroaldehyde. The solution was warmed to 65° C. and refluxed for 1 hour, then cooled to 30° C. Addition of a solution of K2CO3 (88 g, 0.64 mol) in 1500 mL water produced two layers (aqueous pH=7). The THF was removed under vacuum at ≤45° C., causing the product to precipitate as a yellow solid. The slurry was cooled to 15° C., and the product was collected on a fritted Buchner funnel and washed with 3×200 mL water, then dried 24 hours in a vacuum oven at 55° C. to provide 151 g of title compound as a yellow solid, m.p. 155-158° C. 1H NMR (DMSO-d6) δ 7.8 (brs, 2H, NH2), 7.62 (s, 1H), 4.13 (q, 2H), 1.18 (t, 3H). 13C NMR (DMSO-d6) δ 173.4, 161.3, 147.9, 114.5, 60.1, 14.3.
Reaction SMILES: C([C@@:4]1([OH:37])[C@@:9](C(=O)C)([OH:10])[C@@:8](C(=O)C)([OH:14])[C@@H:7]([CH:18](C(=O)C)[OH:19])[O:6][C@H:5]1[O:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35])[C:27]([O:29][CH3:30])=[O:28])(=O)C.CO>C(N(CC)CC)C>[C@@H:5]1([O:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=2[N+:34]([O-:36])=[O:35])[C:27]([O:29][CH3:30])=[O:28])[O:6][C@H:7]([CH2:18][OH:19])[C@H:8]([OH:14])[C@H:9]([OH:10])[C@H:4]1[OH:37]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O[C@@H]2O[C@H](C(O)C(C)=O)[C@@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@]2(O)C(C)=O)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1

Procedure:
The tetraacetate IV (119 g, 0.226 mole) was added to methanol (1000 ml). The mixture was heated at 60° until the solid dissolved. Triethylamine (25 ml) was then added, and the solution was heated at 60° for an additional two hours. The crude solid product was obtained in several crops by evaporation of the solution, the final crop being taken from a 20 ml volume. The crude material was used in the next reaction without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7].FC(F)(F)S(O[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=O)=O.N1C(C)=CC=CC=1C>ClCCl>[Si:23]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CON(C)C(=O)[C@H](CCCO)CCC(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CON(C)C(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)CCC(C)C

Procedure:
A solution of Example 8F (2.58 g, 11.1 mmol), tert-butyldimethylsilyl trifluoromethanesulfonate (2.8 mL, 12 mmol), and 2,6-lutidine (1.5 mL, 13 mmol) in dichloromethane (100 mL) at 0° C. was stirred for 2 hours, diluted with dichloromethane, washed sequentially with 10% KHSO4, aqueous NaHCO3, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 346 (M+H)+.
Reaction SMILES: ClCCl.[C:4]([Si:8]([CH3:24])([CH3:23])[O:9][C@@H:10]([C@@H:12]1[C@@H:15]([C@H:16]([C:18]([S:20][CH3:21])=[S:19])[CH3:17])[NH:14][C:13]1=[O:22])[CH3:11])([CH3:7])([CH3:6])[CH3:5].[Si](O[C@@H]([C@@H]1[C@@H]([C@@H](C(SC)=S)C)NC1=O)C)(C(C)(C)C)(C)C.Cl[C:47](=[O:54])[C:48]([O:50][CH2:51][CH:52]=[CH2:53])=[O:49]>C(N(CC)CC)C>[CH2:51]([O:50][C:48](=[O:49])[C:47]([N:14]1[C@H:15]([C@H:16]([C:18]([S:20][CH3:21])=[S:19])[CH3:17])[C@@H:12]([C@H:10]([O:9][Si:8]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:23])[CH3:24])[CH3:11])[C:13]1=[O:22])=[O:54])[CH:52]=[CH2:53]
Reactant: CSC(=S)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)C(=O)Cl
Agent: CSC(=S)[C@@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=S)SC
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
To a mixture of dichloromethane (32.6 mg) and a mixture (33.1 mg) of (3S,4S)-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine and (3S,4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1S)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine were added triethylamine (30.4 mg) and allyl chloroglyoxylate (32.6 mg) successively at 0° C. After stirring for 10 minutes at the same temperature, the solution was washed with water, 1N hydrochloric acid, brine, and dried. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (5% diethyl ether-hexane) to afford a mixture (23 mg) of (3S,4S)-1-(allyloxyoxalyl)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine and (3S,4S)-1-(allyloxyoxalyl)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1S)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine.
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([Cl:24])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:25]([C:27]3[O:31][N:30]=[C:29]([CH3:32])[CH:28]=3)[OH:26])[CH:14]=2)[N:9]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:7][C:8]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([Cl:24])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:25]([C:27]3[O:31][N:30]=[C:29]([CH3:32])[CH:28]=3)=[O:26])[CH:14]=2)[N:9]=1
Reactant: Cc1cc(C(O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)on1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C(=O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)on1
Temperature: 100 °C

Procedure:
1,4-dioxane (7.5 mL) and manganese (IV) dioxide (447 mg, 5.14 mmol) were added to crude (2,4-dichloro-3-phenylquinolin-6-yl)(3-methylisoxazol-5-yl)methanol (Intermediate 3: step a, 1.03 mmol assuming theoretical yield in prior step). The resulting black suspension was heated in a 100° C. oil bath in a sealed tube for 3 hours then cooled to room temperature. The mixture was then diluted with DCM, and filtered through Celite®. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 3-15% EtOAc-heptane) to afford slightly impure title compound which was used without further purification.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]([CH3:19])[NH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.[CH2:20]=O>C(O)(=O)C.CO>[CH3:20][N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]([CH3:19])[NH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1NC(=O)NN=C1c1ccc(N(C)C)cc1
Reaction time: 0.5 h

Procedure:
Sodium cyanoborohydride (0.62 g) was added portionwise to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1 g) and 36% aqueous formaldehyde (0.92 ml) in a mixture of acetic acid (20 ml) and methanol (30 ml) at room temperature. After stirring for 0.5 hours at the same temperature, the reaction mixture was evaporated in vacuo. To the oily residue was added an aqueous solution of sodium bicarbonate, and the resultant solid was collected by filtration and recrystallized from 70% aqueous ethanol to give 6-(4-dimethylaminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.8 g).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:22])[CH2:6][CH:7]([CH3:21])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=1>O.CO>[C:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH:7]([CH3:21])[CH2:6][C:5]([OH:22])=[O:4])=[CH:11][CH:12]=1)([OH:19])=[O:18]
Reactant: COC(=O)Cc1ccc(CCC(C)CC(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CCc1ccc(CC(=O)O)cc1)CC(=O)O

Procedure:
A solution of 20 g of potassium hydroxide in 40 cc of water is added to a solution of 19.3 g of 5-(4-carbomethoxymethylphenyl)-3-methylvaleric acid methyl ester in 200 cc of methanol and the mixture is heated at reflux for 2 hours. The solution is subsequently concentrated, diluted with water, acidified with 2 N hydrochloric acid and extracted with ether. The crude 5-(4-carboxymethylphenyl)-3-methylvaleric acid obtained after concentrating the ether extract, is recrystallized from ether/hexane. M.P. 100°-102°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[H-].[Na+].Cl[C:16]1[C:21]([NH2:22])=[C:20](Cl)[N:19]=[CH:18][N:17]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[C:21]([NH2:22])=[C:20]([O:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]([F:12])([F:10])[F:11])[CH:4]=3)[N:19]=[CH:18][N:17]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1c(Oc2ccc(F)c(C(F)(F)F)c2)ncnc1Oc1ccc(F)c(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Dissolved in 70 ml DMF, 40.8 g 4-fluoro-3-(trifluoromethyl)-phenol are stirred under an inert gas atmosphere and cooled to 10° C. To this, 5.8 g sodium hydride are added slowly under vigorous stirring. The mixture is then allowed to warm up to room temperature and stirred for 1 h. Then, a solution of 19.9 g 4,6-Dichloro-5-aminopyrimidine in 50 ml DMF is added dropwise and the reaction mixture is heated for 24 h at 80° C. After quenching with water and concentration under reduced pressure the crude mixture is extracted twice with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride and finally dried over magnesium sulfate and charcoal. The dark brown oily residue is dissolved in 100 ml diethylether and treated with 100 ml hexane. The resulting title compound crystallizes as a colorless solid with a melting point of 104-105° C.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+]>C(O)C>[CH2:11]([O:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCOc1ccc(C(=O)O)cn1
Yield: 59.8 %

Procedure:
Separately, 5 g of 6-hydroxypyridine-3-carboxylic acid and 10 g of n-octyl bromide were dissolved in 50 ml of ethanol, 50 ml of a 3N aqueous solution of potassium hydroxide was added to the solution, and the mixture was refluxed for 24 hours. Ethanol was removed from the reacted liquid by distillation, and the residue was neutralized with dilute hydrochloric acid and extracted with ethanol. The excess of n-octyl bromide was separated from the extract by the silica gel column chromatography using n-hexane as the developing solvent. Recrystallization from a mixed solvent of hexane and chloroform gave 5.4 g of 6-octyloxypyridine-3-carboxylic acid.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:39]2=[O:52])=[CH:30][C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[CH:37]=1>>[OH:16][CH2:5][C:38]1([C:29]2[C:28]([OH:27])=[CH:37][C:32]3[N:33]=[C:34]([CH3:36])[S:35][C:31]=3[CH:30]=2)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:39]1=[O:52]
Reactant: CCCCCN1C(=O)C(c2cc3sc(C)nc3cc2O)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCCCCN1C(=O)C(CO)(c2cc3sc(C)nc3cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 367.5 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].[OH:37][CH:38]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39]1.O>CN(C)C=O>[OH:37][CH:38]1[CH2:43][CH2:42][CH2:41][N:40]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]5[C:24]([CH:25]=4)=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:29][CH3:30])[CH2:39]1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCl
Reactant: OC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCN1CCCC(O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone (46 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare a solution. Potassium carbonate (45 mg) and 3-hydroxypiperidine (33 mg) were added to the solution, and the mixture was stirred at 80° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (37 mg, yield 70%).
Reaction SMILES: [S:1](Cl)([OH:4])(=O)=[O:2].[CH:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.O>O1CCCC1>[C:6]1([S:1]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:4])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccccc1
Reactant: O=S(=O)(O)Cl
Reactant: Nc1ccccn1
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccccn1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 264 g of benzene sulphochloride was added dropwise at 10° to 25° C. to a solution of 282 g of 2-aminopyridine in 1200 ml of tetrahydrofuran. After two hours continuous stirring without further cooling, the mixture was poured into water. The reaction product was suction filtered and washed first with water and then with methanol.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH:10][C:11](=[O:13])[CH3:12])[CH2:4][C:3]1([CH3:15])[CH3:14].C(OO)(C)(C)C.[CH2:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>[Mo](=O)(=O)=O>[CH:22]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([NH:10][C:11](=[O:13])[CH3:12])[CH2:4][C:3]2([CH3:15])[CH3:14])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCCCC1
Reactant: CC(=O)NC1CC(C)(C)N(O)C(C)(C)C1
Agent: O=[Mo](=O)=O
Agent: CC(C)(C)OO
Product: CC(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 10.0 grams (47 mmol) of N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)acetamide, 15.2 grams (118 mmol) of 70% aqueous tert-butyl hydroperoxide, 0.67 gram of molybdenum trioxide, and 75 ml of cyclohexane is heated at reflux and water is collected in a Dean-Stark trap. The reaction mixture is then transferred to a Fischer-Porter pressure bottle and heated at 140° C. (bath temperature) for four hours to discharge the red color of the nitroxyl starting material. The reaction mixture is filtered, and the filtrate is diluted with ethyl acetate (150 ml). The organic solution is stirred with 5% aqueous sodium sulfite (150 ml) for one hour to decompose any residual hydroperoxide, then washed with brine (150 ml), dried over anhydrous magnesium sulfate, and concentrated to obtain 12.6 grams of of white solid. Recrystallization from heptane affords 10.4 grams of the title compound as a white solid melting at 139°-144° C.
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]([NH:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[CH:3]=1.CCN(C(C)C)C(C)C.[F:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[CH:47][C:46]([C:52](O)=[O:53])=[CH:45]2.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CN(C=O)C.CS(C)=O>[F:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[CH:47][C:46]([C:52]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:22]3[N:21]=[CH:20][C:19]([C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]5[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=5)[N:5]=4)=[CH:24][CH:23]=3)[CH2:27][CH2:28]1)=[O:53])=[CH:45]2
Reactant: O=C(O)c1cnc2ccc(F)cc2c1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCNCC3)nc2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCN(C(=O)c4cnc5ccc(F)cc5c4)CC3)nc2)c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
4-Methyl-N6′-(piperidin-4-yl)-N6-(4-(trifluoromethyl)pyridin-2-yl)-2,3′-bipyridine-6,6′-diamine (30 mg, 0.07 mmol) was dissolved in DMF (500 μL). The solution was then treated with DIEA (24 μL, 0.14 mmol), 6-fluoroquinoline-3-carboxylic acid (20 mg. 0.11 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (42 μL, 0.07 mmol). The reaction was warmed to 40° C. and stirred for 16 hours. The reaction was allowed to cool to room temperature: The mixture was diluted with DMSO (1.0 mL) and purified by mass-triggered reverse phase high pressure liquid chromatography, eleuting with a 1% ammonium hydroxide buffered water/acetonitrile gradient over a Waters X-Bridge C-18 column, to afford (6-fluoroquinolin-3-yl)(4-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)-2,3′-bipyridin-6′-ylamino)piperidin-1-yl)methanone. MS ESI calcd. for C32H28F4N7O [M+H]+ 602. found 602. 1H NMR (600 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.60 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.11 (dd, J=5.4, 9.2 Hz, 1H), 8.00 (dd, J=2.4, 8.8 Hz, 1H), 7.86 (dd, J=2.9, 9.3 Hz, 1H), 7.73 (m, 1H), 7.20 (s, 1H), 7.14 (d, J=5.1 Hz, 1H), 7.07 (s, 1H), 6.87 (d, J=7.6 Hz, 1H), 6.56 (d, J=8.8 Hz, 1H), 4.37 (s, 1H), 4.06 (s, 1H), 3.32 (s, 1H), 2.47-2.45 (m, 1H), 2.27 (s, 3H), 2.04 (s, 1H), 1.90 (s, 1H), 1.49 (s, 1H), 1.42 (s, 2H). rhSyk IC50=8 nM.
Reaction SMILES: [Li+].CCC[CH2-].[F:6][C:7]([F:19])([F:18])[C:8]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH2:9][CH:10]([OH:12])[CH3:11].[CH:20]12[CH2:29][CH:23]([CH:24]([C:26](Cl)=[O:27])[CH2:25]1)[CH:22]=[CH:21]2>C1COCC1>[CH:20]12[CH2:29][CH:23]([CH:24]([C:26]([O:12][CH:10]([CH3:11])[CH2:9][C:8]([OH:13])([C:14]([F:15])([F:16])[F:17])[C:7]([F:18])([F:19])[F:6])=[O:27])[CH2:25]1)[CH:22]=[CH:21]2
Reactant: CC(O)CC(O)(C(F)(F)F)C(F)(F)F
Reactant: O=C(Cl)C1CC2C=CC1C2
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CC(O)(C(F)(F)F)C(F)(F)F)OC(=O)C1CC2C=CC1C2
Reaction time: 8 h
Yield: 87.3 %

Procedure:
N-butyllithium (1600 ml) (2.56 mol, 1.6M solution in hexanes) was added to a 3-L, three-necked round bottomed flask equipped with an overhead stirrer, a digital thermometer, a 500-mL capacity constant-pressure dropping funnel and a nitrogen inlet. The dropping funnel was charged with a solution of 1,1,1-trifluoro-2-trifluoromethyl-2,4-pentanediol (289 g, 1.28 mol) in anhydrous THF (250 ml). The flask was cooled in ice and the THF solution was slowly added over about 2 hours, while maintaining a temperature below 10° C. Once the addition was complete, the dropping funnel was recharged with a solution of norbornene-5-carbonylchloride (201 g, 1.28 mol) in anhydrous THF (250 ml), which was then slowly added over about 1.5 hours, while maintaining a temperature below 10° C. The solution was allowed to reach room temperature with stirring overnight. The resulting suspension was transferred to a 4-L separatory funnel and washed once with water (1 L). The organic layer was separated and the aqueous wash was adjusted to pH 6 (litmus) with concentrated HCl and extracted twice with ether (1 L). The combined organic solutions were washed once with water and once with brine and dried over anhydrous magnesium sulfate. The suspension was filtered, the solvent removed on a rotary evaporator and the resulting oil distilled twice at 120° C. and 0.5 mm Hg to yield 387 g of the title compound as an oil.