Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1.[OH-].[Na+].CCO>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=1[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccc(Br)cc1
Reactant: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(-c2ccc(CO)cc2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 2.80 g (9.36 mmol ) of 2-(N-t-butylsulfamoyl)-5-n-propylphenylboronic acid (from Step B) and 4-bromobenzyl alcohol (5.25 g, 3 equiv) in toluene (125 mL) was added 1.25N NaOH (32 mL), EtOH (86 mL) and tetrakis(triphenylphosphine)palladium(0) (325 mg, 3 mol %). The mixture was stirred at 100° C. under N2 for 3 hours. The reaction was concentrated and the residue was extracted with ethyl acetate. The organic solution was washed with 1N NaOH, H2O and brine. Next, the organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The product was purified by flash chromatography, eluting with 2:1 hexane-EtOAc, to provide the titled compound; Rf =0.42 (1:1 EtOAc-hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH:15]([CH3:17])[O:14][CH:13]([CH3:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[O:20]=[C:21](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[CH3:18][CH:13]1[O:14][CH:15]([CH3:17])[CH2:16][N:11]([C:8]2[CH:7]=[C:3]3[C:4]([O:6][C:21](=[O:20])[NH:1][C:2]3=[CH:10][CH:9]=2)=[O:5])[CH2:12]1
Reactant: CC1CN(c2ccc(N)c(C(=O)O)c2)CC(C)O1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CC1CN(c2ccc3[nH]c(=O)oc(=O)c3c2)CC(C)O1

Procedure:
To the mixture of 8.9 g of 2-amino-5-(2,6-dimethylmorpholin-4-yl)benzoic acid in 60 ml of dioxane, under stirring and external cold water cooling 10 ml of diphosgene is added dropwise. The mixture is heated under reflux conditions for 4 hours. From the cold reaction mixture the solid material is filtered off, washed with 50 ml of ether. The product is stirred for 5 minutes in the mixture of 50 ml of methanol and 5 ml of triethylamine, then filtered off and washed with 30 ml of methanol. After drying 7 g of the title product is obtained (MH+: 277).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]1[C:30]([CH2:35]Br)=[CH:31][CH:32]=[CH:33][CH:34]=1.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C(#N)C.C(O)C>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]4[CH2:35][C:30]5[C:29](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: BrCc1ccccc1CBr
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCN4Cc5ccccc5C4)CC3)noc2c1

Procedure:
A stirred mixture of 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46 g, 12.5 mmol), K2CO3 (4 g, 29 mmol) and α,α'-dibromo-o-xylene (3.3 g, 12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours. The mixture was cooled and the insolubles were filtered. The dark red solution was concentrated down to a dark oil. This oil was purified by flash chromatography over a silica gel column (SiO2, 45 g; eluted with dichloromethane and MeOH in dichloromethane). The product thus obtained weighed 1.95 g as an oil. This oil was dissolved in ethanol and was treated with a solution of fumaric acid (600 mg) in ethanol. The resulting crystals were collected as an off white solid and weighed 1.44 gm, m.p. 206°-209° C.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:13]2[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:20][N:21]1[C:30](=[O:31])[C:29]2[C:24](=[C:25]([C:32](Cl)=[O:33])[CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1.Cl>O1CCOCC1>[CH3:20][N:21]1[C:30](=[O:31])[C:29]2[C:24](=[C:25]([C:32]([NH:19][C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([N:8]4[CH2:9][CH2:10][CH2:11][CH2:12]4)[N:18]=3)=[O:33])[CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:42])[F:44])[CH:36]=1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)Cl)cccc2c1=O
Reactant: Nc1cccc(N2CCCC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)Nc3cccc(N4CCCC4)n3)cccc2c1=O
Temperature: 70 °C
Reaction time: 48 h
Yield: 59.6 %

Procedure:
Triethylamine (100 μL) and 6-pyrollidin-1-ylpyridin-2-amine 35 (0.136 mmol) was added to a solution of 3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazoline-8-carbonyl chloride 34 (50 mg, 0.136 mmol) in dioxane (1 mL). The reaction was stirred at 70° C. for 2 d, after which 1N HCl (4 mL) was added. The resulting precipitate was collected by filtration, rinsed with 5 mL H2O, 5 mL pentane, and dried under vacuum to give Compound 350 (40 mg, 56% yield). MS (ESI) calc. for C26H22F3N5O2: 493.17. found: 494 [M+H].
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]3[N:15]([CH3:28])[C:16](=[O:27])[N:17]([CH2:18][C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[C:9]=23)[CH2:3]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(OCC)(=O)C>ClCCl>[C:21]([C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[CH2:18][N:17]1[C:9]2[C:10](=[N:11][C:12]([CH3:14])=[CH:13][C:8]=2[N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:36](=[O:38])[CH3:37])[CH2:3]2)[N:15]([CH3:28])[C:16]1=[O:27])#[N:22]
Reactant: Cc1cc(N2CCC[C@@H](N)C2)c2c(n1)n(C)c(=O)n2Cc1ccccc1C#N
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCCN(c2cc(C)nc3c2n(Cc2ccccc2C#N)c(=O)n3C)C1
Temperature: -5 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
430 mg (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile (1.14 mmol) was dissolved in 5 mL dichloromethane at 0° C. 0.35 mL (2.5 mmol) triethylamine and 123 mg (1.2 mmol) acetic anhydride were added dropwise. After the reaction was continued for 1 h at 0° C., ethyl acetate was added until turbidity appeared. It was cooled at −5° C., and a lot of solid was precipitated. 270 mg white powder was obtained after filtration, with a yield of 56.6%.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[OH:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2>>[OH:6][C:7]12[CH2:8][CH:9]3[CH2:15][CH:13]([CH2:12][C:11]([OH:2])([CH2:10]3)[CH2:16]1)[CH2:14]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=S(=O)(O)O
Product: OC12CC3CC(C1)CC(O)(C3)C2
Temperature: 0 °C

Procedure:
To 324 ml of 70% sulfuric acid was added 0.33 mole of the 1-hydroxyadamantane obtained in Comparative Example 5, and the resultant mixture was stirred at the temperature of 95° C. for 4 hours. The reaction product was poured into ice water extracted with ethanol. The water phase was neutralized by sodium hydroxide and extracted with n-butanol, then the solvent was distilled off from the extract under reduced pressure. The crude product was recrystallized from n-hexane to obtain a powderly 1,3-dihydroxyadamantane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C(OC)=NN=NC=1OC.CN1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:46]([O:53][C:54](=[O:58])[CH2:55][CH2:56][NH2:57])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1COCC1>[CH2:46]([O:53][C:54](=[O:58])[CH2:55][CH2:56][NH:57][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: NCCC(=O)OCc1ccccc1
Agent: COc1nnnc(OC)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NCCC(=O)OCc2ccccc2)C1

Procedure:
rac-N-(t-butoxycarbonyl)piperidine-3-carboxylic acid (Can. J. Physiol. Pharmacol. 57, 1979, 763) in THF was activated with chlorodimethoxytriazine and N-methyl-morpholine and then coupled with β-alanine benzyl ester p-toluenesulphonate (J. Org. Chem. 17, 1952, 1564) and N-methylmorpholine to give rac-N-[[1-(t-butoxycarbonyl)-3-piperidinyl]carbonyl]-β-alanine benzyl ester, m.p. 57°-59° C.
Reaction SMILES: [C:1]([C:4]1[CH:32]=[CH:31][C:7]([C:8]([C:10]2[CH:30]=[CH:29][C:13]([CH2:14][S:15][C:16]3[N:25]([CH3:26])[C:24](=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH3:28])[N:17]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.CCOC(OC(OCC)=O)=O.[OH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C>[CH3:26][N:25]1[C:24](=[O:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:28])[N:17]=[C:16]1[S:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([C:1]([N:48]3[CH2:49][CH2:50][CH:45]([OH:44])[CH2:46][CH2:47]3)=[O:3])=[CH:32][CH:31]=2)=[CH:30][CH:29]=1
Reactant: OC1CCNCC1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(C(=O)O)cc4)cc3)n(C)c(=O)c12
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(C(=O)N5CCC(O)CC5)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-[4-(4-carboxybenzoyl)benzyl]thio-3,5-dimethyl-4(3H)-quinazolinone (1.00 g, 2.26 mmol) in DMF (10.0 ml) was added DEPC (0.755 g, 4.63 mmol) and the mixture was stirred at room temperature for 10 minutes. Then, 4-hydroxypiperidine (0.522 g, 5.16 mmol) was added and the mixture was stirred at room temperature for 4 hours. The solvent was then distilled off and the residue was dissolved in ethyl acetate and washed with saturated aqueous NaCl solution. The organic layer was dried over MgSO4 and then concentrated under reduced pressure, and the residue was recrystallized from THF to provide colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[C:4]([CH3:28])[CH:3]=1.O[C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][N:31]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH3:37][O:36][C:34](=[O:35])[C:33]1[CH:38]=[CH:39][C:30]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:28])[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:31][CH:32]=1
Reactant: COC(=O)c1ccc(O)nc1
Reactant: Cc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1C(CO)C1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3C)nc3cc(F)c(F)cc32)nc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 200 mg (0.494 mmol) 2-[2-(4-chloro-2-methyl-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol in 5 ml tetrahydrofuran were added 83 mg (0.543 mmol) methyl 6-hydroxynicotinate (commercially available) and 120 mg (0.593 mmol) tri-n-butylphosphin. The reaction mixture was cooled down to 0° C. 102 mg (0.593 mmol) N,N,N′,N′-tetramethylazodicarboxamide were added. The reaction mixture was stirred for 18 hours at room temperature and then concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Light yellow solid (29%). MS (Turbo Spray): m/z=540.2 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][C@H:9]1[C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([O-:35])(=[S:34])[CH3:33].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([S:34][C:32](=[O:35])[CH3:33])[CH2:10][C@H:9]1[C:24]([N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)=[O:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)N3CCCCC3)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCCCC2)N(C(=O)OC(C)(C)C)C1
Yield: 71.3 %

Procedure:
6.39 g (14.12 mmol) (2S,4R)-2-(Piperidine-1-carbonyl)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester in 50 ml DMF were treated with 2.42 g (21.18 mmol, 1.5 eq) potassium thioacetate at 100° C. for 4 h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc, NaHCO3 solution, the phases were separated and the inorganic layer was extracted with EtOAc. The combined organic phases were washed with water and brine, dried over Na2SO4. Column chromatography gave 3.59 g (71%) (2S,4S)-4-Acetylsulfanyl-2-(piperidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as light pink solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:25])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Br:26]Br>C(O)(=O)C>[BrH:26].[Br:26][CH:9]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=1)[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:25]
Reactant: BrBr
Reactant: Cc1cccc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)c1
Solvent: CC(=O)O
Product: Br
Product: Cc1cccc(C(=O)C(Br)c2ccnc(NC(=O)c3ccccc3)c2)c1
Reaction time: 2 h
Yield: 180.2 %

Procedure:
To a solution of N-[4-[2-(3-methylphenyl)-2-oxoethyl]-2-pyridyl]benzamide (19.0 g, 57.5 mmol) in acetic acid (60 mL) was added dropwise bromine (3.0 mL, 57.5 mmol) at room temperature over 1 hr., and the reaction mixture was stirred for 2 hrs. The precipitated crude crystals were collected by filtration and washed with ethyl acetate to give the title compound (25.4 g, yield 90%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[C:6](C(O)=O)[N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1>[Cu]=O.CN(C)C=O>[Cl:2][C:3]1[CH:7]=[CH:6][N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1
Reactant: O=C(O)c1cc(Cl)nn1-c1cccnc1
Agent: O=[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: Clc1ccn(-c2cccnc2)n1

Procedure:
In step e of Scheme 9, 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride (6e) is decarboxylated in the presence of copper (II) oxide in polar solvents such as N,N-dimethylformamide at temperatures from about 80° C. to about 140° C. to yield 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b). It was surprisingly discovered that this decarboxylation only occurs in the presence of copper (II) oxide. Several known decarboxylation agents from the literature such as, for example, hydrochloric acid (See alternate synthetic route, Example 17), sulfuric acid, and palladium (II) trifluoroacetate/trifluoroacetic acid (See “CE-7”) did not yield the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[N:4][C:5]([CH3:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:13][C:14]([F:28])([F:27])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OC(C)C)=O)(C(OC(C)C)=O)=[N-]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[N:4][C:3]=1[O:12][CH:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=1)[C:14]([F:28])([F:27])[F:13]
Reactant: OC(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Reactant: Cc1nc(O)c(Br)cc1[N+](=O)[O-]
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(OC(c2ccc(C(F)(F)F)cc2)C(F)(F)F)c(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 6 h
Yield: 36.6 %

Procedure:
To a stirring suspension of 3-bromo-6-methyl-5-nitro-pyridin-2-ol (0.25 g, 1.07 mmol) in THF (7 mL), 2,2,2-trifluoro-1-[4-(trifluoromethyl)phenyl]ethanol (0.39 g, 1.61 mmol, 1.5 equiv) and triphenylphosphine (0.42 g, 1.61 mmol, 1.5 eq) were added at room temperature under inert atmosphere (Ar). To this mixture, DIAD (diisopropyl diazodicarboxylate) (0.33 mL, 1.61 mmol, 1.5 eq) was added dropwise over 10 minutes while keeping the temperature below 40° C. The reaction mixture was stirred for 6 h under heating at 60° C. After this time, TLC indicted that the starting material was consumed and the reaction mixture was allowed to reach room temperature before quenching with water (10 mL). The water phase was extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give a brown residue, which was purified by combiflash column chromatography (silica gel, heptane/ethyl acetate, v/v=95/5). Fractions containing the pure compound were collected and concentrated in vacuo to give the title compound (0.18 g, 41% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][N:15]([CH2:18][CH3:19])[C:14](=[O:20])[CH:13]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:18]([N:15]1[CH:16]=[CH:17][C:12]([C:4]2[S:3][C:2]([NH:1][C:21]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[O:28])=[N:6][C:5]=2[C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[CH:13][C:14]1=[O:20])[CH3:19]
Reactant: CCn1ccc(-c2sc(N)nc2-c2ccco2)cc1=O
Reactant: O=C(O)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCn1ccc(-c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)cc1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
2-Amino-5-(1-ethyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(2-furyl)thiazole (167 mg, 0.582 mmol) obtained in Step 1 was dissolved in DMF (8 mL), and isonicotinic acid (143 mg, 1.16 mmol), PyBOP (664 mg, 1.28 mmol) and triethylamine (0.356 mL, 2.55 mmol) were added thereto, followed by stirring at 80° C. for 1 hour. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=17:1), followed by reslurrying with a mixed solvent of methanol and diethyl ether to afford the entitled Compound 124 (83.5 mg, 37%) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[CH:35]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH2:37][CH2:36]1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH:35]3[CH2:37][CH2:36]3)(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22]
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: NS(=O)(=O)C1CC1
Product: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 62.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.30 g, 0.66 mmol) obtained in Example 39, step 2 and cyclopropanesulfonamide (0.40 g, 3.3 mmol), the title compound (0.23 g, 63%) was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=O.Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.P(=O)(O)(O)O>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[C:14]2[C:13](=[CH:12][CH:11]=[C:10]([F:9])[CH:15]=2)[NH:16][CH:6]=1
Reactant: O=CCCCCCl
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: O=P(O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc2[nH]cc(CCCCl)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound 5-chloropentan-1-ol (16.2 mL) was dissolved in cold 5 mM 2,2,6,6-tetramethylpiperidine-1-yloxy (tempo) in dichloromethane (240 mL) and cooled down to 0° C. with an ice bath. Potassium bromide (0.5 M in water, 24 mL) was added, and this was followed by the addition (in one portion at 5° C. under vigorous stirring) of a solution of sodium hydrogencarbonate (24 g) in aqueous sodium hypochlorite (0.3 M, 500 mL). The resulting mixture was stirred at 5° C. for 20 min, and the phases were separated. The water phase was extracted with dichloromethane (200 mL), and the combined organic phases were evaporated in vacuo giving 5-chloropentanal as a clear oil (16 g). Subsequently, 5-chloropentanal was suspended in water (100 mL) followed by addition of 4-fluorophenylhydrazine hydrochloride (19.5 g) and toluene (800 mL), and the mixture was stirred at room temperature for 15 min. Phosphoric acid (85%, 100 mL) was added and the mixture was boiled under reflux for 2 h. The mixture was cooled to room temperature and the phases were separated. The organic phase was washed with saturated aqueous sodium hydrogencarbonate, dried (MgSO4) and evaporated in vacuo to yield an orange oil. The crude product was purified by flash chromatography on silicagel (eluent:ethylacetate/heptane 1:4) to give the title compound as an orange oil (14 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[F:13][C:14]1[C:15]([O:23][CH3:24])=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH:17]=O.C(O)(=O)C>C1(C)C=CC=CC=1>[F:13][C:14]1[C:15]([O:23][CH3:24])=[C:16]([CH:17]=[N:1][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([CH3:12])=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: COc1c(F)cc(F)cc1C=O
Reactant: Cc1ccc2c(N)cccc2n1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1c(F)cc(F)cc1C=Nc1cccc2nc(C)ccc12
Yield: 87.2 %

Procedure:
To 2.0 g (12.6 mmol) 5-amino-2-methylquinolin and 2.2 g (12.6 mmol) 3,5-difluoro-2-methoxybenzaldehyde in 38 ml toluene are added 0.1 ml acetic acid and 5 g molecular sieve. The mixture is heated over 5 hours under reflux and filtrated through a path of cellites after cooling. The solvent is evaporated and the residue is two times azeotrophed with small portions of toluene. 3.43 g of [(3,5-difluoro-2-methoxyphenyl)methylene]-2-methylquinolin-5-amine are obtained as a yellow solid. 1.93 ml (22.3 mmol) 1,1,1-trifluoroepoxypropane in 40 ml THF and 10 ml hexane are cooled to −100° C. and 14 ml of a 1.6 M n-butyl lithium solution in hexane are added over 2 hours while the temperature does not exceed −96° C. 10 Minutes after complete addition 3.44 g (11.2 mmol) [(3,5-difluoro-2-methoxyphenyl)methylene]-2-methylquinolin-5-amine in 50 ml THF are added over 1.5 hours while the temperature temperature does not exceed −95° C. After one hour at −100° C. the reaction mixture is warmed to 0° C. over two hours. The reaction was quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer was extracted twice with diethyl ether, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (isopropanol in hexane 5% to 20%) yields 1.68 g of the desired epoxide.