Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2(OCC[O:35]2)[CH2:28][S:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[CH:23][CH:22]=1.Cl>ClCCl.O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH2:28][S:29][CH2:30][C:31]([F:34])([F:32])[F:33])=[O:35])=[CH:23][CH:22]=1
Reactant: O=C(N1CCc2ccc(Cl)c(NCc3ccc(C4(CSCC(F)(F)F)OCCO4)cc3)c2CC1)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(CSCC(F)(F)F)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 42.9 %

Procedure:
To a solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-{4-[2-(2,2,2-trifluoroethylthio)-1,1-(ethylenedioxy)ethyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (97 mg, 0.16 mmol) in anhydrous dichloromethane (0.5 mL), add a solution of 4M hydrogen chloride in dioxane (1.2 mL) and reflux overnight. Dilute with dichloromethane and wash with saturated aqueous NaHCO3. Dry the organics extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain 7-chloro-3-(2,2,2-trifluoroacetyl)-6-[4-(2,2,2-trifluoroethylthio-methylcarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (37 mg, 41%). MS (ES+) m/z: 539 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccccn3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M42) (245 mg, 0.476 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (162 mg).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19].C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCCC1.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.O.C(O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:18]#[N:19])[CH:25]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)s1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) and 3-cyanophenylboronic acid, using tetrakis(triphenylphosphine)palladium(0), and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The hydrochloride salt was prepared by evaporation of the product-containing fractions, dissolution of the residue in methanol, addition of excess hydrogen chloride solution (1M in diethyl ether) and evaporation. Recrystallisation from methanol/diethyl ether gave the hydrochloride salt of the title compound as a colourless solid; MS (ES+) 338 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([NH2:21])(=[O:20])[CH2:16][C:17]([CH3:19])=O.C([O-])(O)=O.[Na+]>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[N:21]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)CC(N)=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)nc2c1CN(Cc1ccccc1)CC2
Temperature: 110 °C

Procedure:
A mixture of 1-benzyl-4-piperidone (19.6 mL, 106 mmol), acetoacetamide (11.7 g, 116 mmol) in Eaton's reagent (40 mL) was allowed to stir at 110° C. After stirring for 18 h, the reaction mixture was cooled to rt, and then slowly poured into stirred aq NaHCO3 (150 g of NaHCO3 in 1000 mL of water. The mixture was diluted with DCM (1000 mL) and H2O (50 mL), and the two phases were separated. The products were extracted once with DCM (500 mL) from the aqueous layer. The combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The brown residue was triturated with acetone (200 mL). The precipitated solid was collected on a funnel, washed with acetone (100 mL), and dried under reduced pressure to give 6-benzyl-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ol. 1H NMR (400 MHz, CDCl3) δ ppm 12.71 (br s, 1 H), 7.26-7.35 (m, 5 H), 6.22 (s, 1 H), 3.71 (s, 2 H), 3.34 (s, 2 H), 2.70-2.73 (m, 2 H), 2.77-2.79 (m, 2 H), 2.03 (s, 3 H); MS (ESI+) m/z 255.42 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:13][C:14]([S@:17](/[N:19]=[CH:5]/[C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:12])([F:11])[F:1])=[O:18])([CH3:16])[CH3:15]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC(C)(C)[S@](N)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
To a 100-mL round-bottom flask purged and maintained with an inert atmosphere of argon, was added CH2Cl2 (50 mL), 2-(trifluoromethyl)benzaldehyde (2.01 g, 11.54 mmol, 1.00 equiv), (R)-(+)-2-methylpropane-2-sulfinamide (1.68 g, 13.86 mmol, 1.20 equiv), pyridinium p-toluenesulfonate (0.145 g, 0.05 equiv) and magnesium sulfate (6.93 g, 5.00 equiv). The resulting solution was stirred for 48 h at 40° C. The mixture was cooled to room temperature and the solid was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography (silica gel, eluting with EtOAc/petroleum ether (1:20)). This resulted in 0.96 g (30%) the title compound as a light yellow solid. LC/MS: m/z (ES+) 278 (M+H)+. 1H-NMR (300 MHz, DMSO-d6): δ ppm 8.82-8.80 (m, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.95-7.80 (m, 3H), 1.22 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([P:9]([Cl:12])([Cl:11])=O)[CH:5]=[CH:6][C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:11][P:9]([Cl:12])[C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc(P(=O)(Cl)Cl)cc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(P(Cl)Cl)cc1C
Yield: 92 %

Procedure:
121 g (0.52 mole) of 3,4-dimethylphenylphosphonic acid dichloride and 283 g (1.08 moles) of triphenylphosphane were stirred for 11 hours at 200° C. under an atmosphere of nitrogen. Distillation was then carried out until an internal temperature of 170° C. at 0.067 kPa was reached. This gave 120 g, containing 45% of dichloro-3,4dimethylphenylphosphane and 48% of 3,4-dimethylphenylphosphonic acid dichloride. This corresponds to a yield of approx. 92% of theory at a conversion of 52.2%. Fractional distillation of the crude distillate gave pure dichloro-3,4-dimethylphenylphosphane, boiling point: 107° C./0.44 kPa.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[C:28]1[CH:29]=[CH:30][C:31](=[O:34])[NH:32][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[CH3:19][C:11]1([CH3:20])[O:10][C:9](=[O:21])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([N:32]3[CH:33]=[C:28]([C:23]4[N:22]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:29]=[CH:30][C:31]3=[O:34])=[CH:3][CH:4]=2)[C@H:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1ccc(-c2ncccn2)c[nH]1
Reactant: CC1(C)OC(=O)N(c2ccc(I)cc2)[C@H]1c1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-n3cc(-c4ncccn4)ccc3=O)cc2)[C@H]1c1ccccc1
Temperature: 140 °C
Yield: 70.1 %

Procedure:
A microwave vial was charged with (S)-3-(4-iodophenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (Intermediate C)(0.100 g, 0.254 mmol), 5-(pyrimidin-2-yl)pyridin-2(1H)-one (0.048 g, 0.280 mmol), tribasic potassium phosphate (0.270 g, 1.272 mmol) and dioxane (2.5 mL). The mixture was purged with argon and then copper (I) iodide (0.048 g, 0.254 mmol) and N,N′-dimethylethylenediamine (0.055 mL, 0.509 mmol) were added. The system was purged with argon, the tube was sealed, and the reaction mixture was heated at 140° C. for 4 hours in the microwave. The reaction mixture was then filtered through Celite® brand filter aid and the filtrate was concentrated to afford a green solid. The resulting green solid was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 50-100% EtOAc-hexane) to afford (S)-5,5-dimethyl-3-(4-(2-oxo-5-(pyrimidin-2-yl)pyridin-1 (2H)-yl)phenyl)-4-phenyloxazolidin-2-one (0.078 g, 0.178 mmol, 70% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 3H), 1.66 (s, 3H), 5.52 (s, 1H), 6.60 (dd, J=9.59, 0.59 Hz, 1H), 7.21-7.53 (m, 8H), 7.59-7.71 (m, 2H), 8.36 (dd, J=9.63, 2.59 Hz, 1H), 8.43-8.53 (m, 1H), 8.79 (d, J=4.89 Hz, 2H). m/z (ESI) 439 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:19][C:20]([O:22]CC)=[O:21])[C:7]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:18])C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH2:16]([O:15][C:13]([C:11]1[CH:10]=[CH:9][C:8]([CH3:18])=[C:7]([N:6]([CH2:5][C:4]([OH:25])=[O:3])[CH2:19][C:20]([OH:22])=[O:21])[CH:12]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(C(=O)OCC)ccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C)c(N(CC(=O)O)CC(=O)O)c1
Yield: 100.1 %

Procedure:
The compound (0.62 g, 1.76 mmol) obtained in step A was dissolved in a ethanol (10 ml)-tetrahydrofuran (5 ml) mixed solvent, 1N sodium hydroxide (3.53 ml, 3.53 mmol) was added at room temperature with stirring, and the mixture was stirred at the same temperature for 90 min. To the reaction mixture was added 1N hydrochloric acid (5 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (0.52 g) as a crude colorless oil.
Reaction SMILES: C([Li])CCC.[CH:6]([C:9]1[C:14]2[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7].[B:22](OC)([O:25]C)[O:23]C.[NH4+].[OH-]>C1COCC1>[CH:6]([C:9]1[C:14]2[O:15][C:16]3[C:21]([B:22]([OH:25])[OH:23])=[CH:20][CH:19]=[CH:18][C:17]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7]
Reactant: COB(OC)OC
Reactant: CC(C)c1cccc2c1oc1ccccc12
Agent: [Li]CCCC
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1cccc2c1oc1c(B(O)O)cccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.7 %

Procedure:
n-Butyl lithium (81 mL, 130 mmol) was added slowly to 4-isopropyldibenzo[b,d]furan (10.9 g, 51.8 mmol) in 100 mL dry THF at −78° C. This mixture was allowed to stir at room temperature for 5 hours and then cooled back to −78° C. Trimethyl borate (20.23 mL, 181 mmol) was added slowly to the reaction and the reaction allowed to warm up to room temperature overnight. The reaction was poured into 100 mL NH4OH solution with ice. The mixture was extracted with 3×100 mL ethyl acetate, dried over sodium sulfate, evaporated and crystallized from DCM/hexane to yield 10.1 g (77%) of the desired product, which was confirmed by NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH:14]3[NH:16][CH:11]2[CH2:12][CH2:13]3)=[N:6][CH:7]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH:14]3[N:16]([C:24]([C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[C:18]4[S:17][CH:21]=[CH:20][CH:19]=4)=[O:25])[CH:11]2[CH2:12][CH2:13]3)=[N:6][CH:7]=1
Reactant: Fc1ccc(OCC2CC3CCC2N3)nc1
Reactant: O=C(Cl)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1ccccc1-c1cccs1)N1C2CCC1C(COc1ccc(F)cn1)C2
Reaction time: 18 h
Yield: 45.3 %

Procedure:
To (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane (35 mg, 0.2 mmol) in DCM (2.5 mL) was added TEA (25 μL, 0.2 mmol)) followed by 2-(thiophen-2-yl)benzoyl chloride (40 mg, 0.2 mmol) in DCM (2.5 mL). After 18 h, the reaction was diluted with DCM and washed with H2O. The aqueous layer was extracted DCM (1×). The combined organics were dried (Na2SO4). Purification via silica gel chromatography (50-100% EtOAc in hexanes) gave the title compound (37 mg, 57%). MS (ESI) mass calcd. for C23H21FN2O2S, 408.1; m/z found 409.1 [M+H]+.
Reaction SMILES: C(OC([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][CH:23]([O:29][CH2:30][CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>O>[CH2:30]([O:29][CH:23]([CH2:22][C:19]1[CH:20]=[N:21][C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][CH3:8])[CH:11]=2)=[CH:17][CH:18]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:31]
Reactant: CCOC(=O)C(Cc1ccc(-c2cccc(NCC(=O)OC(C)(C)C)c2)nc1)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)C(Cc1ccc(-c2cccc(NC)c2)nc1)OCC
Yield: 81.2 %

Procedure:
0.11 g (0.3 mmol) of ethyl 3-{6-[3-(tert-butoxycarbonylmethylamino)phenyl]pyrid-3-yl}-2-ethoxypropanoate, 5 ml of dichloromethane and 0.15 ml (1.9 mmol) of trifluoroacetic acid are stirred at room temperature for 24 hours. After addition of water, the reaction medium is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. 80 mg (94%) of ethyl 2-ethoxy-3-[6-(3-methylaminophenyl)pyrid-3-yl]propanoate are obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@@H:24]([O:27][C:28]2[CH:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=2)[C@H:23]([F:35])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@@H:24]([O:27][C:28]2[CH:29]=[N:30][C:31]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:32][CH:33]=2)[C@H:23]([F:35])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(Cl)nc2)[C@H](F)C1
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)[C@H](F)C1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)-1H-indole (intermediate-21) and trans(±)-tert-butyl-4-((6-chloropyridin-3-yl)oxy)-3-fluoropiperidine-1-carboxylate (intermediate-63) (0.220 g, 37%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl[C:15]1[N:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1>O1CCCC1.C(OCC)(=O)C>[O:7]([C:15]1[N:16]=[N:17][C:18]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][CH:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccc(Oc2ccccc2)nn1
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(Oc2ccc(Oc3ccccc3)nn2)cc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 83.5 %

Procedure:
Phenol (Aldrich, 1.88 g, 20 mmol) in tetrahydrofuran (50 mL) was treated with potassium tert-butoxide (Aldrich, 2.24 g, 20 mmol) at ambient temperature for 10 minutes. The product of Example 27A (3.0 g, 14.5 mmol) was then added and the reaction mixture was stirred at 60° C. for 10 hours. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2×10 mL). The organic phase was concentrated affording the title compound as a solid (3.2 g, yield, 84%). 1H NMR (MeOH-d4, 300 MHz) δ 7.14–7.28 (m, 6H), 7.38–7.48 (m, 6H) ppm. MS (DCl/NH3) m/z 265(M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:3]2[C:2]([N:23]3[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]3)=[C:7]([CH3:8])[CH:6]=[CH:5][N:4]=2)=[CH:12][CH:13]=1
Reactant: OC1CCNCC1
Reactant: COc1ccc(COc2nccc(C)c2Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(COc2nccc(C)c2N2CCC(O)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-2-(4-methoxybenzyloxy)-4-methylpyridine (6.40 g, 20.77 mmol), 4-hydroxypiperidine (3.15 g, 31.15 mmol), tris(dibenzylideneacetone)dipalladium (761 mg, 0.831 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.03 g, 1.66 mmol), and sodium-t-butoxide (2.79 g, 29.08 mmol) in anhydrous toluene (200 ml) was heated at reflux under nitrogen for 22 hours. Upon cooling to room temperature, the reaction mixture was filtered through celite and the filtrate was diluted with ethyl acetate, washed with sat'd NaCl(aq.), dried (MgSO4), filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 1:1 hexanes: EtOAc) gave the title compound as a black, viscous oil (4.76 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][CH2:30][CH3:31])[N:14]([CH2:15][C:16]([NH:19][C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7]([O:32]CC3C=CC=CC=3)[CH:6]=[CH:5][C:4]=2[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][CH2:30][CH3:31])[N:14]([CH2:15][C:16]([NH:19][C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])([CH3:17])[CH3:18])[C:10]=2[C:9]2[CH:8]=[C:7]([OH:32])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccc(O)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Yield: 54 %

Procedure:
N-{2-[4-Amino-8-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide (1.25 g, 2.36 mmol) was dissolved in 40 mL of ethanol and 10% palladium on carbon (0.58 g) was added. The mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. An additional 0.21 g of 10% palladium on carbon was added and the reaction was shaken under 50 psi (3.4×105 Pa) of hydrogen for three more hours. The reaction was filtered through CELITE filter agent, and the filter cake was washed with 100 mL of ethanol. The filtrate was concentrated under reduced pressure. The resulting off white solid was purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used eluting with a gradient of 10-30% CMA in chloroform to provide 0.56 g of N-{2-[4-amino-8-hydroxy-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide as a white powder, m.p. 231-232° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([Cl:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=3)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][N:16]3S(C2C=CC=CC=2)(=O)=O)=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:42][C@H:43]1[O:48][C@@H:47]([CH3:49])[CH2:46][NH:45][CH2:44]1.CCN(C(C)C)C(C)C.[I-].[Na+].[OH-].[Na+].Cl>CC#N.CC(O)C>[Cl:32][C:24]1[N:23]=[CH:22][C:21]([C:19]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][NH:16]3)=[C:12]([NH:11][C:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:45]4[CH2:44][C@H:43]([CH3:42])[O:48][C@H:47]([CH3:49])[CH2:46]4)[N:8]=3)=[O:10])[CH:20]=2)=[CH:26][C:25]=1[NH:27][S:28]([CH3:31])(=[O:29])=[O:30]
Reactant: CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3cccc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CC#N
Product: C[C@@H]1CN(Cc2cccc(C(=O)Nc3cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc4[nH]ncc34)n2)C[C@H](C)O1
Temperature: 70 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
6-(Chloromethyl)-N-[6-{6-chloro-5-[(methylsulfonyl)amino]-3-pyridinyl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-2-pyridinecarboxamide (80 mg, 0.127 mmol) was dissolved in MeCN (1 ml). (2R,6S)-2,6-Dimethylmorpholine (16.05 mg, 0.139 mmol) was added followed by DIPEA (0.033 mL, 0.190 mmol) and then sodium iodide (18.99 mg, 0.127 mmol). The mixture was heated at 70° C. for 1 h, then the solvent was removed in vacuo to give an orange oil. IPA (1 ml) was added to the crude residue followed by aqueous NaOH (2M, 1 ml) and the solution was stirred at room temperature for 1 h. The solution was neutralised with 2M aqueous HCl and concentrated in vacuo. The residue was dissolved in DMSO (2 ml) and purified by MDAP (Method E). The resulting pale yellow gum was dissolved in DCM/MeOH (1:1) and added to the top of a 500 mg silica SPE cartridge. This was eluted with cyclohexane and the solvent was removed under a stream of nitrogen to give the title compound (2.2 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17]Br)[N:3]=1.[F-:19].[Cs+]>C1S(=O)(=O)CCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH2:17][F:19])[N:3]=1
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CBr)n1
Reactant: [F-]
Agent: [Cs+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CF)n1
Temperature: 100 °C

Procedure:
To a solution of 2,4-diamino-6-bromomethyl-5-(2,4-dichlorophenyl)pyrimidine (1.04 g) in tetramethylene sulphone (4.5 ml) was added cesium fluoride (1 g). The mixture was stirred and heated at 100° C. for 4 hours, cooled, diluted with water and extracted with chloroform. The combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (silica; 19:1:0.1 dichloromethane/methanol/triethylamine) to give the title compound, which was recrystallised from ethanol. 0.19 g, mp. 210°-211° C.