Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[NH:7]2.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[NH:7]2
Reactant: COc1cccc2c1CC(=O)N2
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1Cc2c(O)cccc2N1
Temperature: 235 °C
Yield: 94 %

Procedure:
A mixture of 4-methoxy-2-oxindole (3.5 g, 21.4 mmol) and 3.0 g of aluminum chloride was heated at 235° C. for 10 minutes with stirring. On cooling the sludge was triturated with H2O. The solids were filtered washed with H2O and dried to give 3.0 g of product as an orange solid. Purified by flash chromatography (hexane-ethyl acetate 3:1) to give 1.1 g of pure title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].C1(C)C=CC(S([N:27]=[N+:28]=[N-])(=O)=O)=CC=1>C(#N)C>[N+:27](=[C:9]([C:10](=[O:11])[CH3:12])[C:8]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[N-:28]
Reactant: C=CCOC(=O)CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCOC(=O)C(=[N+]=[N-])C(C)=O
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 94.9 %

Procedure:
55.4 ml (0.4 mole - 2 equivalents) of triethylamine were added dropwise to a solution, which had been cooled to 0° C., of 28.43 g (0.2 mole) of allyl acetoacetate and 43.39 g (0.22 mole - 1.1 equivalents) of p-toluenesulphonyl azide in 400 ml of anhydrous acetonitrile. The mixture was stirred at 0° C. for 3.5 h, then 50 g of kieselguhr were added, evaporation in vacuo was carried out and then chromatography on 400 g of silica gel (toluene:ethyl acetate 96:4). 31.9 g (95%) of the title compound were obtained as a pale yellow oil, Rf: 0.36 (toluene:ethyl acetate 9:1).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[CH:9][N:10]([CH2:18][CH2:19][S:20]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]2[C:6](=[O:40])[N:5]([CH2:41][CH3:42])[C:4]1=[O:43])[CH3:2].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:8]2=[CH:9][N:10]([CH2:18][CH2:19][SH:20])[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]2[C:6](=[O:40])[N:5]([CH2:41][CH3:42])[C:4]1=[O:43])[CH3:2]
Reactant: CCn1c(=O)c2c(-c3ccccc3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(CC)c1=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c2c(-c3ccccc3)n(CCS)cc2n(CC)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,3-Diethyl-5-phenyl-6-(2-(tritylthio)ethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 4) (1.45 g, 2.475 mmol) was dissolved in DCM (50 mL) and treated with TFA (5 mL, 64.9 mmol) followed by triethylsilane (0.791 mL, 4.95 mmol). The mixture was stirred at RT for 16 h. The reaction mixture was basified by slow addition of sat. NaHCO3(aq) and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated under vacuum. The residue was dissolved in DCM, evaporated onto silica and the silica deposited onto a 10 g silica cartridge. The system was eluted with 20%-60% EtOA in iso-hexane to yield the title compound as a pale yellow oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[O:15].[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:28]=1[CH2:29]Br>C1COCC1.CS(C)=O>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[C:28]=1[CH2:29][N:19]1[CH:20]=[CH:21][C:17]([NH:16][C:14](=[O:15])[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[CH3:11])=[N:18]1
Reactant: Cc1ccccc1C(=O)Nc1cc[nH]n1
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccccc1C(=O)Nc1ccn(Cc2c(F)cccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 M lithium bis(trimethylsilyl)amide (100 μl, 0.1 mmol, Aldrich) was slowly added to a solution of 2-methyl-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 46)(22 mg, 0.1 mmol) in THF (400 μl). The resulting solution was then transferred to a solution of 2-fluoro-6-(trifluoromethyl)benzyl bromide (26 mg, 0.1 mmol, Aldrich) in THF (200 μl) and stirred for 1 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using a Sunfire C18 (Method D) column using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg); LCMS (System 3) MH+=378, tRET=1.13 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[CH:14]=[C:13]([F:15])[C:12]([NH:16]C(=O)OCC)=[C:11]([F:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:23]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:10]=[C:11]([F:22])[C:12]([NH2:16])=[C:13]([F:15])[CH:14]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)Nc1c(F)cc(N(Cc2ccccc2)Cc2ccccc2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(F)cc(N(Cc2ccccc2)Cc2ccccc2)cc1F

Procedure:
2.10 g (5.30 mmol) of ethyl [4-(dibenzylamino)-2,6-difluorophenyl]carbamate are dissolved in 40 ml of ethanol. 3.0 g (53 mmol) of powdered potassium hydroxide are added, and the mixture is heated at reflux for 20 hours. The solvent is then removed, and water and dichloromethane are added to the residue. The organic phase is separated off, washed three times with water, dried over sodium sulfate and concentrated. The residue is taken up in ethyl acetate and clarified over activated carbon. Using pentane, crystals are obtained which are filtered off with suction.
Reaction SMILES: Cl.Br[C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.CC1(C)C(C)(C)OB([C:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:39])[CH3:38])[CH2:33][CH:32]=2)O1.C([O-])(=O)C.[K+].CC(N)CC1C=CC=CC=1.OP(O)(O)=O>O.C(#N)C>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:4]2[C:3]([C:31]3[CH2:36][CH2:35][N:34]([C:37](=[O:39])[CH3:38])[CH2:33][CH:32]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)=[CH:11][CH:12]=1
Reactant: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: CC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CC(=O)[O-]
Agent: CC(N)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CC=C(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 90 °C

Procedure:
N-(4-(3-bromopyridin-2-yloxy)phenyl)pyridin-2-amine hydrochloride (0.388 g, 1.14 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.30 g, 1.2 mmol), potassium acetate (0.60 g, 10.2 mmol), and Amphos (0.063 g, 0.090 mmol) were taken up in 12 mL of 3:1 mixture of acetonitrile and water. The mixture was purged with nitrogen and heated to 90° C. for 15 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organics was washed with 30 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (10 to 100% EtOAc/hexane, then 5% MeOH in EtOAc) afforded 1-(4-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as tan solid. MS (ESI, pos. ion) m/z: 387.0 (M+1). IC50 (uM) 0.002698.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:22][C:23](OC(C)=O)=[O:24].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([CH2:7][O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:23](=[O:24])[CH3:22])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(OCc2ccccc2)nc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OCc2ccccc2)nc1
Yield: 94.5 %

Procedure:
To a solution of 6-[(phenylmethyl)oxy]-3-pyridinamine (0.213 g, 1.07 mmol; step B above) in CH2Cl2 (5 mL) at rt was added pyridine (0.17 mL, 2.14 mmol), DMAP (0.0065 g, 0.050 mmol) and Ac2O (0.12 mL, 1.28 mmol). After 5 min the mixture was poured into water and extracted with CH2Cl2 (×3). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.245 g of the title compound as a colorless solid: MS (ESI) m/z 243 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.[CH3:24]I>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([N:19]([CH3:24])[C:20](=[O:23])[CH2:21][CH3:22])=[CH:15][C:13]=3[N:14]=2)=[CH:8][CH:9]=1
Reactant: CCC(=O)Nc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)N(C)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
To sodium hydride (15 mg, 0.37 mmol) under nitrogen at 0° C. was slowly added a solution of N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)propionamide (100 mg, 0.33 mmol) in dimethylformamide (10 mL). After 10 min at 0° C., methyl iodide (56 μL, 0.37 mmol) was added, and the solution was left warming up to room temperature for 16 h. The mixture was then diluted with ethyl acetate, and then washed three times with water. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 36.4 mg (35%) of the title compound (LCMS RT=7.00 min, MH+ 315.0)
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][O:7][C:6]2[C:9]([C:13](O)=O)=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[CH:30][CH:31]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OC(=O)C)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:4]2[C@@H:3]([CH2:2][OH:1])[CH2:8][O:7][C:6]3[C:9]([C:13]4[NH:33][C:28]5[CH:27]=[C:26]([C:25]([F:24])([F:34])[F:35])[CH:31]=[CH:30][C:29]=5[N:32]=4)=[CH:10][CH:11]=[CH:12][C:5]2=3)=[N:17][CH:18]=1
Reactant: COc1ccc(N2c3cccc(C(=O)O)c3OC[C@@H]2CO)nc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(N2c3cccc(-c4nc5ccc(C(F)(F)F)cc5[nH]4)c3OC[C@@H]2CO)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a solution of (S)-3-(hydroxymethyl)-4-(5-methoxypyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid 3.2 g (10 mmol) of step 7 in dimethylformamide 50 mL were 4-(trifluoromethyl)benzen-1,2-diamine 1.9 g (11 mmol), diisopropylethylamine 3.5 mL (20 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate 5.7 g (15 mmol), followed by stirring at room temperature for 3 hrs. The reaction mixture was diluted with ethylacetate, washed with a saturated sodium bicarbonate solution and a saturated NaCl solution, dried over magnesium sulfate and concentrated in a vacuum. The concentrate was dissolved in acetic acid/toluene (90 mL/10 mL), heated at 75° C. for 4 hrs with stirring, cooled to room temperature and concentrated in a vacuum. The concentrate was dissolved in ethylacetate, washed with a saturated sodium bicarbonate solution and a saturated NaCl solution, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by column chromatography (developing solvent: ethylacetate/hexane=2/3) afforded 4.1 g of the title compound (yield 82%).
Reaction SMILES: [NH:1]=[C:2]1[C:15]([NH:16][C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])=[S:18])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+].[CH2:33](Br)[CH:34]=[CH2:35].C(N=C(SCC=C)NC1C=CC(C(C2C=CC=CC=2)=O)=CC=1)(OC)=O>CC(C)=O.O>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:19][C:20]([O:22][CH3:23])=[O:21])[S:18][CH2:35][CH:34]=[CH2:33])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)NC(=S)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2)C1=N
Reactant: C=CCBr
Agent: C=CCSC(=NC(=O)OC)Nc1ccc(C(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C=CCSC(=NC(=O)OC)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2)C1=N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-iminophenylmethyl-4-(3-carbomethoxythioureido)benzophenone (2.09 g.; 0.005 mole) in acetone (40 ml.) and water (6.0 ml.) is added an aqueous sodium hydroxide solution (50% aqueous; 0.4 g.). The suspension is stirred at room temperature for one hour and then allyl bromide (0.6 g.; 0.005 mole) is added and the solution is stirred at room temperature over the weekend. The precipitate which forms is collected by filtration and then dried to afford 1.3 g. of 3-iminophenylmethyl)-4-(3-carbomethoxy-S-allylisothioureido)benzophenone, m.p. 125°-127° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O.[CH2:63]([O:67][C:68]1([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH2:71][NH:70][CH2:69]1)[CH2:64][CH2:65][CH3:66]>ClCCl.CN(C)C=O>[CH2:63]([O:67][C:68]1([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH2:71][N:70]([C:12](=[O:14])[CH:11]([NH:10][C:9]([NH:8][CH2:7][CH2:6][C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:24])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:69]1)[CH2:64][CH2:65][CH3:66]
Reactant: CCCCOC1(c2ccccc2)CNC1
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC1(c2ccccc2)CN(C(=O)C(Cc2ccc(OC)cc2)NC(=O)NCCc2c[nH]cn2)C1
Reaction time: 3 h
Yield: 3.4 %

Procedure:
To 57 mg (0.17 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)-propanoic acid (cf. preparation 2-3) dissolved in 4 mL of dichloromethane and 1.5 mL of dimethylformamide are added 0.12 mL (0.68 mmol) of diisopropylethylamine, 61 mg (0.19 mmol) of TBTU and 55 mg (0.17 mmol) of 3-butoxy-3-phenylazetidine trifluoroacetate. After 3 hours, the solution is washed with 1N sodium hydroxide solution and the organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product obtained is purified by preparative TLC (eluent: 9/1 dichloromethane/methanol). 3 mg of 1-[2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-[2-(1H-imidazol-4-yl)ethyl]urea are obtained in a yield of 3%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12](Cl)=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1.C1COCC1.[CH2:24]([NH2:26])[CH3:25]>O>[CH2:24]([NH:26][C:12]([C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:5]=2)=[CH:8][CH:9]=1)=[O:13])[CH3:25]
Reactant: CCN
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(C(=O)Cl)s1
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1ccc(-c2cc(C(F)(F)F)nn2C)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(1-Methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonyl chloride (150 mg) and THF (2 ml) were added to a mixture of 70% ethylamine aqueous solution (1 ml) and THF (2 ml), followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give N-ethyl-5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxamide (96 mg) as colorless powder crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[C:21]([S:25]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([NH2:38])(=[O:37])=[O:36])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.[Cl-].[Na+].O.C(Cl)Cl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:19]2[CH:20]=[C:21]([S:25]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:36])(=[O:37])[NH2:38])(=[O:26])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2cccc(S(=O)(=O)Nc3ccccc3S(N)(=O)=O)c2)n1
Temperature: 120 °C
Yield: 18.8 %

Procedure:
1,1′-Bis(diphenylphosphino)ferrocene palladium dichloride methylene chloride adduct (14 mg, 0.02 mmol) was added to a solution of 6-methoxy pyridine-2-boronic acid pinacol ester (135 mg, 0.57 mmol), 2-[(3-bromophenyl)sulfonylamino]benzenesulfonamide (150 mg, 0.38 mmol) (see Example 113a) and Na2CO3 (0.18 mg, 1.72 mmol) in THF:water, 10:1 (4 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 20 min. Some DCM was added followed by brine and the aqueous layer was extracted twice with DCM. The combined organic layers were dried with Na2SO4 and after filtration and evaporation the crude was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (30 mg, 19%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:15][CH:16]=C)[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1)=[O:4].C(OCC)(=[O:20])C>CC(O)C.O.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:15][CH:16]=[O:20])[CH2:6][CH2:7][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: CCOC(C)=O
Reactant: C=CCC1(C(=O)OC)CCC(C(=O)OC)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C1CCC(CC=O)(C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
1-Allyl-cyclohexane-1,4-dicarboxylic acid dimethyl ester (4.5 g, 17.71 mmol) was dissolved in 2-propanol (100 mL) and water (50 mL). To this was added an aqueous solution of NaIO4 (9.5 g, 44.3 mmol) in water (50 mL), followed by addition of OsO4 (0.025 g, crystals, in one portion). The reaction mixture was allowed to stir for 16 hours. Then, the reaction mixture was poured into ice water (50 mL) and ethyl acetate (EtOAc) (60 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic solutions were washed with brine, and concentrated to dryness. The material was then purified over silica gel column eluting with ethyl acetate in heptanes (0-60%) to afford 3.09 g (72%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].I[CH2:28][C:29]([CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:33][CH2:32]1)=[O:30]>CS(C)=O.O1CCCC1.C(OCC)(=O)C>[CH2:40]([O:39][C:37]([N:34]1[CH2:35][CH2:36][CH:31]([C:29](=[O:30])[CH2:28][CH:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:16])[CH2:32][CH2:33]1)=[O:38])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Reactant: O=C(CI)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CC(C(=O)c1ccc(F)cc1)c1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of the product of Step 1 (0.5 g (2.3 mmol)) in 5.0 ml of dry dimethyl sulfoxide was added 2.4 ml (2.4 mmol) of a 1M solution of sodium hexamethyldisilazide in tetrahydrofuran. After 10 minutes, a solution of 0.72 g (2.4 mmol) of the product of 4-(2-iodoacetyl)-1-(benzyloxycarbonyl)piperidine was added in 1 ml dimethyl sulfoxide dropwise. The reaction mixture was stirred for 2 hours, diluted with ethyl acetate (EtOAc, 20 ml) and washed with water (3×10 ml). The combined organic phases were washed with brine and dried over MgSO4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by MPLC over silica gel eluting with 2% MeOH/CH2Cl2 to give the desired product. FAB ms: C28H27N2O4F:474; Observed: 475 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=O)=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:56][CH2:57][CH:58]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[CH:59]([CH3:61])[CH3:60].O.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([NH:56][CH2:57][CH:58]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:66])([CH3:68])[CH3:67])[CH:59]([CH3:61])[CH3:60])=[O:19])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(C)C(CN)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC(NC(=O)OC(C)(C)C)C(C)C)n2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
200 mg (0.60 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid from Example 21A, 203 mg (0.63 mmol) of HATU and 0.20 ml (1.81 mmol) of 4-methylmorpholine were initially charged in DMF (3.8 ml), the mixture was stirred at RT for 20 min, 134 mg (0.66 mmol) of rac-tert-butyl (1-amino-3-methylbutan-2-yl)carbamate were added and the reaction mixture was stirred at RT overnight. Water/TFA were added and the mixture was purified by preparative RP-HPLC (acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were concentrated and the residue was taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate, filtered off and concentrated. This gave 262 mg (84% of theory, purity 100%) of the target compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([Cl:12])[C:6]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)(=O)C.[OH-].[K+].O>O1CCOCC1>[Br:11][C:9]1[CH:8]=[C:7]([Cl:12])[C:6]2[O:13][CH2:14][CH:15]([CH2:17][OH:16])[O:4][C:5]=2[CH:10]=1
Reactant: CC(=O)Oc1cc(Br)cc(Cl)c1OCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: OCC1COc2c(Cl)cc(Br)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
To a solution of 5-bromo-3-chloro-2-(oxiran-2-ylmethoxy)phenyl acetate (4.4 g, 13.7 mmol) in dioxane (20 ml) was added KOH (10%, 40 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. Water was added and the solution was extracted with EtOAc: The combined organic phases were washed with brine, dried (Na2SO4) and evaporated to dryness. Purification on flash column chromatography (isooctane/EtOAc) gave the title compound (0.34 g). MS m/z (rel. intensity, 70 eV) 280 (M+, bp), 278 (78), 224 (68), 222 (54), 57 (37).