Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:20]2[C:19](=[O:21])[C:18]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]3[C:16]2=[O:26])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccc(Cc2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of 4-benzoylbenzoic acid (2.00 g) in trifluoroacetic acid (30 mL) was added dropwise triethylsilane (3.53 mL), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then n-hexane was added to the residue. The precipitate was collected by filtration, washed with n-hexane and dried under reduced pressure at 60° C. to give 4-benzylbenzoic acid (1.66 g). To an ice-cold suspension of lithium aluminium hydride (0.315 g) in tetrahydrofuran (45 mL) was added dropwise a solution of 4-benzylbenzoic acid (1.60 g) in tetrahydrofuran (30 mL), and the resulting mixture was stirred at room temperature for 4.5 hours. The reaction was quenched by sequential addition of water (0.320 mL), 15% aqueous sodium hydroxide (0.320 mL) and water (0.320 mL). The insoluble material was filtered out and the filtrate was concentrated under reduced pressure to give 4-benzylbenzyl alcohol (1.56 g). 4-Benzylbenzylalcohol (1.56 g) was dissolved in tetrahydrofuran (39 mL). After addition of phthalimide (1.39 g) and triphenylphosphine (2.68 g), diisopropylazodicarboxylate (40% toluene solution, 5.17 g) was added dropwise, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give the title compound (1.87 g).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[C:17]2C=O)=[CH:12][CH:11]=1.[C:23](=O)([O-])[O-:24].[K+].[K+]>ClC(Cl)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH:17]=[CH:18][C:19]([CH:23]=[O:24])=[CH:20]2)=[CH:14][CH:15]=1
Reactant: O=Cc1cccn1-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CC(Cl)Cl
Product: O=Cc1ccn(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trifluoromethanesulfonic acid (127 ml) was added dropwise to a dichloroethane solution (680 ml) containing 1-(4-fluorophenyl)-2-formylpyrrole (68 g) at room temperature, and the mixture was stirred at a refluxing temperature for 5 h. After cooling to room temperature, the reaction mixture was poured into aqueous potassium carbonate solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (mobile phase:methylene chloride) to give 1-(4-fluorophenyl)-3-formylpyrrole (13 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH:7]=[CH:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]=[O:17])=[C:11]([CH3:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[Pd]>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]=[O:17])=[C:11]([CH3:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C=CC(=O)OC(C)(C)C)cc(C)c1C=O
Agent: [Pd]
Solvent: ClCCl
Product: Cc1cc(CCC(=O)OC(C)(C)C)cc(C)c1C=O

Procedure:
A solution of 3-(4-formyl-3,5-dimethylphenyl)-acrylic acid tert-butyl ester (210 mg) in CH2Cl2 (8 mL) was hydrogenated at 1 atm over 10% Pd/C (21 mg) for 4 h. The catalyst was filtered and the filtrate concentrated to give 3-(4-formyl-3,5-dimethylphenyl)-propionic acid tert-butyl ester as a yellow solid. MS (ESI)m/z 286 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 52.7 %

Procedure:
The title compound (48 mg) was prepared as in Example 177, Steps C and D, using 129 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 173 mg of 4-chlorophenylboronic acid. MS (ESI): exact mass calculated for C19H24ClN3, 329.17; found, m/z 330.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.60-7.53 (m, 2H), 7.36-7.27 (m, 2H), 3.94-3.83 (m, 1H), 3.43-3.36 (m, 2H), 3.34-3.26 (m, 2H), 3.2-3.12 (m, 2H), 2.80-2.72 (m, 2H), 1.98-1.76 (m, 6H), 1.67 (br s, 1H), 1.32-1.17 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:23].F[P-](F)(F)(F)(F)F.CNC.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13](=[O:14])[N:22]([CH3:23])[CH3:21])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (100 mg, 0.3 mmol), HATU (188 mg, 0.5 mmol), dimethylamine (0.2 mL, 2M in THF) and DIPEA (0.23 mL, 1.3 mmol) in DMF (2 mL) was stirred for 16 h at ambient temperature. The crude product was purified without aqueous workup by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 ml/min) to give the title compound. MS (LC-MS): 275.0 [M−55]+; tR (HPLC conditions c): 4.68 min.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10](Cl)(Cl)=[O:11]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]=[C:10]=[O:11]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1N=C=O
Yield: 76 %

Procedure:
7 g (0.05 mole) of 2,6-dimethyl aniline dissolved in 20 ml of toluene are added dropwise to a 20% solution of phosgene in toluene (1.5 equivalents) maintained at 0° in an ice bath. The mixture is then heated at reflux for 3 h. The mixture is concentrated and the residue is distilled under vacuum. B.p.=100°/13 mm Hg. Yield: 76%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.CC(=CC)C.[O-:20]Cl=O.[Na+]>C(O)(C)(C)C.O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]([OH:20])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ccc(-c2ccncc2)cc1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Reaction time: 0.33 h
Yield: 78.3 %

Procedure:
To a suspension of 4-[pyridin-4-yl]-benzaldehyde (approx. 2.8 g, 15 mmol) (reference example 12a) in t-butanol (100 mL) is added 2-methy-but-2-ene (15 mL) followed by a solution comprised of NaClO2 (14.7 g, tech.grade) and NaH2PO4.H2O (14.7 g, 105 mmol) in H2O (100 mL). This mixture is stirred for 20 minutes then the precipitated solid filtered off. This solid is washed with water then set aside. The organic phase of the mother liquor is separated, then washed with brine, dried over MgSO4 and concentrated to give a solid. This material is combined with the solid obtained by filtration and dried under vacuum to give 2.34 g of the title compound. 1H NMR (DMSO) d 7.77 (d, J=6 Hz, 2H), 7.93 (d, J=8 Hz, 2H), 8.06 (d, J=8 Hz, 2H), 8.70 (d, J=6 Hz, 2H). MS (EI) m/z 199 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][CH:9]1[CH2:17][C:18]#[N:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1.Cl>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[C:17]([C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1)[C:18]#[N:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2NC1CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C(=C(C#N)c2nccc(C(F)(F)F)n2)Nc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A solution of 2-[1-(tert-butoxycarbonyl)benzimidazol-2(3H)-yl]acetonitrile (6 g, 23 mmol) in THF (50 mL) was added to a suspension of 60% sodium hydride in mineral oil (1.38 g, 35 mmol) in tetrahydrofuran (85 mL) at 0° C. over 10 min. The suspension was stirred at 0° C. for 15 min, and 2-chloro-4-trifluoromethylpyrimidin (2.79 mL, 23 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight, and water (300 mL) and then 1N hydrochloric acid (40 mL) were added. The crude product was extracted into chloroform and washed twice with water (100 mL each). The organic phase was dried over magnesium sulfate, and the solvent was removed under vacuum to give 2-[1-(tert-butoxycarbonyl)benzimidazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (8.17 g) as a brown oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Cl.Cl[CH2:35][C:36]#[C:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:35][C:36]#[C:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: ClCC#Cc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#Cc2cccnc2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 29.8 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]piperazine (0.67 g), 1-chloro-3-(3-pyridyl)-2-propyne hydrochloride (0.3 g) and potassium carbonate (0.52 g) in N,N-dimethylformamide (5 ml) was stirred for 5 hours at 50° C. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(1H-indol-3-yl)methyl]-4-[3-(3-pyridyl)-2-propynyl]piperazine (0.25 g) as a syrup.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH:17]([OH:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][CH:17]([OH:19])[CH3:18])[CH:10]=2)[O:3]1
Reactant: CC(O)CBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Yield: 79.9 %

Procedure:
A mixture of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.58 mmoles, 1.0 equiv.), 1-bromopropan-2-ol (358 mg, 2.58 mmoles, 1.0 equiv.), and cesium carbonate (1010 mg, 3.09 mmoles, 1.20 equiv.) in DMF (10 mL) was heated in an oil bath at 80° C. for 16 hours. LCMS indicated the reaction complete. The reaction was filtered and concentrated to dryness under high vacuum to give the desired product (520 mg).
Reaction SMILES: [CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([C:14](=[O:25])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[Cl:24])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:26])[CH:2]=[CH2:3].[CH3:27]I>C(O)C>[CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([C:14](=[O:25])[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[Cl:24])[CH3:27])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:26])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCN1C(=O)COc2ccc(C(=O)Cc3ccc(OC)cc3Cl)cc21
Solvent: CCO
Product: C=CCN1C(=O)COc2ccc(C(=O)C(C)c3ccc(OC)cc3Cl)cc21

Procedure:
In analogy to Example 56, step 2, 4-allyl-6-[2-(2-chloro-4-methoxy-phenyl)-acetyl]-4H-benzo[1,4]oxazin-3-one (8.9 g) was reacted with methyl iodide at r.t. for 2 h. The crude product was treated with ethanol (25 ml), filtered and dried under high vacuum to give the title compound (7.2 g) as a light yellow solid. MS (m/e)=386.2 [M+H+].
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1>C(#N)C>[N:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:16][CH:15]=3)=[CH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=c1cc(-c2ccc(O)cc2)oc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1cc(-c2ccc(OCc3ccc4ccccc4n3)cc2)oc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
2-Morpholinyl-6-(4-hydoxyphenyl)-4-pyrone, as prepared in Example 5, (273 mg, 1.0 mmole) was suspended in 8 ml acetonitrile in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated successively with potassium carbonate (829 mg, 6.0 mmole) and 2-chloromethyl-quinoline (533 mg, 3.0 mmole). The reaction mixture was stirred at 70° C. overnight. The acetonitrile was removed in vacuo and the residue was washed with 1×25 ml dichloromethane. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo to a yellow solid. The crude material was washed with diethyl ether and was recrystallized from ethyl acetate to give 377 mg (91%) of Compound 8 as an orange solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[N:7][CH:8]=1.Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:24]=3[N:25]2[S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[CH:21][CH:20]=1>>[O:15]=[C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][N:7]=2)[CH:14]=[CH:13][N:12]1[C:19]1[CH:27]=[C:26]2[C:22]([C:23]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:24]=3[N:25]2[S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=2)(=[O:30])=[O:29])=[CH:21][CH:20]=1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CCN(C(=O)OC(C)(C)C)C3)cc1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(-c6ccc(C(F)(F)F)cn6)cc5=O)cc42)CCN(C(=O)OC(C)(C)C)C3)cc1
Yield: 40.2 %

Procedure:
4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (200 mg, 0.830 mmol) and tert-butyl 7-bromo-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (419 mg, 0.830 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (222 mg, 40%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.02 (s, 1H), 8.26 (s, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.80 (br s, 2H), 7.57 (d, J=7.2 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.27 (3H, under solvent peak), 7.07 (d, J=6.8 Hz, 1H), 4.91 (br m, 2H), 3.71 (br m, 2H), 2.71 (br m, 2H), 2.36 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[CH3:9][O:8][C:6]1[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:3]=[C:2]([C:26]2[CH:25]=[N:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=2)[N:7]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: COc1ccc(CCNc2cc(Cl)nc(OC)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CCNc2cc(-c3ccc(OC)nc3)nc(OC)n2)cc1
Temperature: 85 °C
Yield: 100 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine (600 mg, 2.04 mmol), 2-methoxy-5-pyridyl-boronic acid (469 mg, 3.06 mmol, prepared according to the procedure described in J. Org. Chem., 2002, 67, 7541), and Cs2CO3 (1.66 g, 5.11 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL), at room temperature, is degassed with argon gas for 5 minutes and treated with tetrakis(triphenylphosphine)palladium (0) (118 mg, 0.1 mmol). The mixture is heated at 85° C. for 5 hours, diluted with water (50 mL), and extracted twice with EtOAc (50 mL). The combined extracts are dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with a mixture of EtOAc and heptane (1:1, v/v) affording [2-methoxy-6-(6-methoxy-pyridin-3-yl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [0.75 g, 100%, Example 35(o)] as an oil. LCMS: RT=2.74 minutes, MS: 367 (M+H). 1H NMR (300 MHz, CDCl3): □08.78 (1H, d, J=2.1 Hz), 8.21 (1H, dd, J=8.7, 2.4 Hz), 7.16 (2H, d, J=8.4 Hz), 6.88 (1H, dd, J=8.7, 2.4 Hz), 6.82 (2H, d, J=8.4 Hz), 6.3 (1H, s), 4.95 (1H, brs), 4.03 (3H, s), 4.02 (3H, s), 3.82 (3H, s), 3.72-3.63 (2H, m), 2.92 (2H, t, J=6.9 Hz). IC50=1.7 nM
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[O:24][C:23]([CH3:26])([CH3:25])[CH:22]=[CH:21][C:5]2=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[C:8](=[CH:9][CH:10]=[C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]3=1)[NH:7]2.[H-].[Na+].[CH3:29]OS(OC)(=O)=O>CN(C)C=O>[CH3:29][O:1][C:2]1[CH:3]=[C:4]2[O:24][C:23]([CH3:26])([CH3:25])[CH:22]=[CH:21][C:5]2=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[C:8](=[CH:9][CH:10]=[C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]3=1)[NH:7]2
Reactant: COS(=O)(=O)OC
Reactant: CC1(C)C=Cc2c(cc(O)c3c(=O)c4c(ccc5ccccc54)[nH]c23)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(c3[nH]c4ccc5ccccc5c4c(=O)c13)C=CC(C)(C)O2
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A solution of 300 mg of compound of Example 1 in 15 ml of anhydrous dimethylformamide is added dropwise to a suspension of 125 mg of sodium hydride in 10 ml of anhydrous dimethylformamide previously cooled to 0° C. The reaction mixture is maintained at 0° C. for 15 minutes, at room temperature for 30 minutes and then 0.57 ml of dimethylsulfate are added. After 17 hours, the reaction mixture is poured into 150 ml of ice-cold water and extracted with dichloromethane (3×50 ml). The combined organic phases are dried over anhydrous sodium sulphate and then filtered and evaporated to dryness under reduced pressure. Chromatography over silica gel (cyclohexane and then a gradient of acetone 5 to 20%) allowing the expected product to be obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][CH:20]=1)(=[NH:14])=[O:13].Cl.CN(C)CCCN=C=NCC.CCOC(C)=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:14]=[S:12]([C:15]2[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][CH:20]=2)([CH3:11])=[O:13])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: COC(=O)Cc1cccc(S(C)(=N)=O)c1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 5-bromonicotinic acid (648 mg, 3.21 mmol), methyl [3-(S-methylsulfonimidoyl)phenyl]acetate (802 mg, 3.53 mmol), and catalytic DMAP in 15.0 ml DMF at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (738 mg, 3.85 mmol). The reaction was stirred 1 hour at room temperature then added to EtOAc. The EtOAc solution was washed with dilute brine, NaHCO3 solution, brine, dilute HCl/brine mixture, brine/NaHCO3 solution, dried with anhydrous Na2SO4 and rotary evaporated. The oil was chromatographed eluting with CHCl3/EtOAc to give viscous clear oil (994 mg, 75%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([S:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)=[C:8]([CH3:24])[C:6]=2[N:7]=1.[NH:31]1[C:39]2[C:34](=[CH:35][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:38]=2)[CH:33]=[CH:32]1>>[CH3:24][C:8]1[C:6]2[N:7]=[C:2]([C:36]3[CH:35]=[C:34]4[CH:33]=[CH:32][NH:31][C:39]4=[N:38][CH:37]=3)[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]=2[S:10][C:9]=1[C:11]1[CH:12]=[C:13]([S:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Cc1c(-c2cccc(S(=O)(=O)C[C@H](C)O)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(-c2cccc(S(=O)(=O)C[C@H](C)O)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
(S)-1-(3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylsulfonyl)propan-2-ol (10 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 38 mg of 415. MS (Q1) 550.0 (M)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([O:12]CC3C=CC=CC=3)=[O:11])[CH2:9][CH2:8]2)[CH:6]=1>CO>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=1
Reactant: O=C(OCc1ccccc1)C1(n2cc(F)cn2)CC1
Solvent: CO
Product: O=C(O)C1(n2cc(F)cn2)CC1
Yield: 93.1 %

Procedure:
A solution of benzyl 1-(4-fluoro-1H-pyrazol-1-yl)cyclopropanecarboxylate (115 mg, 0.442 mmol) in methanol (20 mL) was hydrogenated using the H-Cube (full H2, room temperature). The solvent was removed under reduced pressure to afford the title compound as a solid (70 mg). MS (AP+) (M+H) 171.4; LCMS retention time 1.06 minutes (Method M).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][CH3:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CNC1CCN(C(C)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N1CCC(NCCc2ccccc2)CC1
Yield: 65 %

Procedure:
A mixture containing 0.5 mol of the compound obtained in Stage A of Example 19, 0.5 M benzyl chloride and 1 M sodium carbonate in 650 ml of ethanol is refluxed for one night. The precipitate formed is filtered off, the solvent is evaporated, the evaporation residue is taken up in 1N hydrochloric acid and extracted with diethyl ether, and the ethereal extract is rendered basic with sodium hydroxide solution and extracted with ethyl acetate to obtain the desired compound.