Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C@@H:5]([CH:7]2[CH2:9][N@@:8]2[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[O:4][C:3]1=[O:22].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][CH2:33][C:32]1=[O:39]>C1(C)C=CC=CC=1>[F:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[C:25]=1[N:31]1[C:32](=[O:39])[CH2:33][N:34]([CH2:9][C@H:7]([NH:8][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C@@H:5]2[CH2:6][C@@H:2]([CH3:1])[C:3](=[O:22])[O:4]2)[C:35]([CH3:38])([CH3:37])[CH2:36]1
Reactant: C[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: CC1(C)CN(c2c(F)cccc2F)C(=O)CN1
Agent: C[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3c(F)cccc3F)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 98.8 %

Procedure:
A solution of 600 mg of (3R,5S)-3-methyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (76g) (1.84 mmol) and 574 mg of 1-(2,6-difluorophenyl)-5,5-dimethylpiperazin-2-one obtained in Example (60d) (2.40 mmol) in toluene (18 ml) was stirred at 110° C. for two hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=5/1) to obtain 1.03 g of the title compound (yield: 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:10]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH:20]2[CH2:22][O:21]2)=[C:15]([F:23])[CH:14]=1)(=[O:12])=[O:11].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:10]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH:20]([OH:21])[CH2:22][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:15]([F:23])[CH:14]=1)(=[O:12])=[O:11]
Reactant: C1COCCN1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cc(F)c(C3CO3)c(F)c2)c(C)c1
Solvent: CCO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cc(F)c(C(O)CN3CCOCC3)c(F)c2)c(C)c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of N-(2,4-dimethylphenyl)-3,5-difluoro-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (150 mg, 0.379 mmol) in ethanol (1.5 mL) at 25° C. was added morpholine (0.033 ml, 0.379 mmol) and the reaction mixture stirred at 50° C. for 6 hours. The mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The appropriate fractions were combined and evaporated in vacuo to give the required product, 9 mg, as a colourless oil. LCMS [LCMS2] Rt 1.33 min, m/z (ES+) 483 (M+H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:28]5[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: OC1CCNCC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCC(O)CC3)cc1OCC2
Yield: 42 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 4-hydroxypiperidine, the crude product was recrystallised from methanol to give 340 as a white solid (106 mg, 42%). LCMS: RT=2.48 min, [M+H]+=396. 1H NMR 400 MHz (DMSO-d6) δ: 9.09 (1H, s), 7.88 (1H, d, J=0.64 Hz), 7.83 (1H, s), 6.33 (1H, s), 5.97-5.88 (1H, m), 4.69 (1H, d, J=4.26 Hz), 4.49-4.48 (4H, m), 4.03-3.99 (2H, m), 3.75-3.67 (1H, m), 3.14-3.13 (2H, m), 1.80-1.71 (2H, m), 1.47 (6H, d, J=6.60 Hz), 1.34-1.33 (2H, m)
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[N:21]=[CH:22][N:23]([CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[C:24]=1[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=1.[NH4+].[OH-]>O.CC(O)=O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[N:21]=[CH:22][N:23]([CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[C:24]=1[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([S:31]([CH3:32])=[O:2])[N:26]=1
Reactant: CSc1nccc(-c2c(-c3ccccc3F)ncn2C2CCN(C)CC2)n1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCC(n2cnc(-c3ccccc3F)c2-c2ccnc(S(C)=O)n2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Potassium persulfate (3.2 g, 7.0 mmol) in water (75 mL) was added to a solution of 4-(fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methylthio-4-pyrimidinyl)imidazole (2.7 g, 7.0 mmol) in glacial AcOH (150 mL). After stirring at ambient temperature for 72 h, the reaction mixture was neutralized by the portion-wise addition of concentrated aqueous NH4OH and extracted with CH2Cl2. The organic extract was washed with brine, dried (MgSO4) and concentrated. The residue was triturated with ethyl ether to afford the title compound as an off-white solid; yield 2.3 g (83%).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[NH2:10][CH2:11][C:12]1([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CS(C)=O>[F:8][C:7]1[C:2]([NH:19][CH2:18][C:12]2([C:11]#[N:10])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:3][C:4]([F:9])=[CH:5][CH:6]=1
Reactant: Fc1ccc(F)c(F)n1
Reactant: N#CC1(CN)CCOCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#CC1(CNc2nc(F)ccc2F)CCOCC1
Temperature: 105 °C
Yield: 48.3 %

Procedure:
To 2,3,6-Trifluoropyridine (0.6 g, 4.5 mmol) in DMSO (5 ml) at room temperature was added 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate R, 1.01 g, 7.23 mmol) and triethylamine (1.57 ml, 11.24 mmol) sequentially. The light brown mixture was heated at 105° C. in a sealed glass bomb for 18 hours. After cooled to room temperature the reaction mixture was extracted with EtOAc (40 ml), washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to give a light brown liquid. This crude material was purified by silica gel chromatography using a 12 g column, eluting with 5%-20% ethyl acetate in hexane to afford 550 mg (48.2% yield) of the desired product. LCMS (m/z): 254.1 [M+H]+; retention time=0.743 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.69-1.95 (m, 4 H) 3.60-3.82 (m, 4 H) 4.00 (ddd, J=12.13, 4.30, 1.96 Hz, 2 H) 5.02 (br. S., 1 H) 6.12 (td, J=5.58, 2.54 Hz, 1 H) 7.19-7.33 (m, 1 H).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH3:16])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5].CN(C=O)C.[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[NH2:1][CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH3:16])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5]
Reactant: BrCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)CCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
The Fmoc-β-Ala-Ile-Ala-Leu (SEQ ID NO:37), (24.34 g, 0.04 mol) is added into a round bottom flask with DMF (350 mL) and a magnetic stirrer. After the tetrapeptide is dissolved, benzyl bromide (4.76 mL, 0.04 mol), followed by cesium carbonate (13.04 g, 0.04 mol), is added to the solution with stirring. The reaction mixture is stirred at room temperature for 1.5 hrs. Then, the reaction mixture is slowly poured into a flask with 450 mL of iced water. A large amount of white solid precipitates out which is collected by suction filtration. The product is washed with water (2×200 mL) and placed in a vacuum desiccator.
Reaction SMILES: [OH-].[K+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=O)[CH:9]=[CH:10][C:11]([OH:13])=[O:12].[NH2:15][NH2:16]>CO>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH2:9][CH:10]([C:11]([OH:13])=[O:12])[NH:16][N:15]=1
Reactant: O=C(O)C=CC(=O)c1ccco1
Reactant: NN
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC(c2ccco2)=NN1
Yield: 66.7 %

Procedure:
Potassium hydroxide (660 mg) is dissolved in 25 cc of methanol and 1.66 g of 4-(2-furanyl)-4-oxo-2-butenoic acid is added. Hydrazine (320 mg) is then added and the solution is refluxed for 2 hours. The methanol is removed and the viscous residue is dissolved in 50 cc of water. The solution is made strongly acid with 20% HCl and a precipitate forms. The solid is filtered quickly to yield 1.2 g of the title compound, melting point 185°-190° C., dec.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH3:14])[C:6]=2[CH:15]=1.[CH3:16][C:17]1[C:18]([O:20][C:21](=O)[C:22]=1[CH3:23])=[O:19].O>C(O)(=O)C>[CH2:12]([N:7]1[C:6]2[CH:15]=[C:2]([N:1]3[C:18](=[O:19])[C:17]([CH3:16])=[C:22]([CH3:23])[C:21]3=[O:20])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[CH2:13][CH3:14]
Reactant: CCCN1C(=O)COc2ccc(N)cc21
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: CC(=O)O
Solvent: O
Product: CCCN1C(=O)COc2ccc(N3C(=O)C(C)=C(C)C3=O)cc21
Yield: 49.1 %

Procedure:
2.27 g of 6-amino-4-propyl-2H-1,4-benzoxazin-3(4H)-one and 1.7 g of 2,3-dimethylmaleic anhydride were refluxed for 2 hours in acetic acid. After the reaction mixture was allowed to cool, 50 ml of water was added, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 1.7 g of 1-[4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-3,4-dimethyl-2,5-dioxo-2,5-dihydropyrrole. m.p. 147°-149° C.
Reaction SMILES: N[C:2]1[C:11](C)=[C:10]2[C:5]([C:6](C)=[CH:7][C:8](C)(C)[NH:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(=O)CC(OCC)=[O:21]>>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:21]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC1=CC(C)(C)Nc2c1ccc(N)c2C
Product: O=c1ccc2ccccc2[nH]1
Yield: 105.4 %

Procedure:
This compound was prepared in a manner similar to that described for Compound 102 (EXAMPLE 2) with 7-amino-1,2-dihydro-2,2,4,8-tetramethylquinoline (100 mg, 0.49 mmol) and ethyl 4,4,4-trifluoroacetoacetate (107 mL, 0.73 mmol, 1.5 equiv), affording 75 mg (47%) of the desired 2-quinolone as a fluorescent-yellow solid. Data for 1,2-dihydro-2,2,4,10-tetramethyl-6-trifluoromethyl-8-pyridono[5,6-f]quinoline: 1H NMR (400 MHz, CDCl3) 9.23 (br s, 1H, CONH), 7.37 (s, 1H, 5-H), 6.67 (s, 1H, 7-H), 5.45 (s, 1H, 3-H), 4.14 [br s, 1H, (CH3)2CNH], 2.12 (s, 3H, 10-CH3), 2.04 (d, 3H, J=1.1 Hz, 4-CH3), 1.37 [s, 6H, 2-(CH3)2].
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[Cl:19][CH:20](O)[CH3:21]>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:21][CH2:20][Cl:19])[CH:16]=[CH2:17]
Reactant: CC(O)Cl
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Product: C=CCOC(=O)NC1CC(=O)OC1OCCCl
Yield: 34.9 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester (5.2 g, 20 mmol) as described for 40 using chloroethanol (4.05 mL, 60 mmol) to afford 1.84 g (35% yield) of the title compound as a mixture of epimers. For the anti-diastereomer: 1H-NMR (500 MHz, CDCl3) δ 2.42 (dd, J=18.1 Hz, 1H), 3.00 (dd, J=18.1, 7.8 Hz, 1H), 3.63 (m, 2H), 3.85 (m, 1H), 4.02 (m, 1H), 4.23 (m, 1H), 4.57 (br s, 2H), 5.17 (br s, 1H), 5.22 (d, H=11.5 Hz, 1H), 5.29 (d, J=16.8 Hz, 1H), 5.44 (s, 1H), 5.89 (m, 1H) ppm; LC-MS (ES+) m/e=264 (M+H). For the syn-diastereomer: 1H-NMR (500 MHz, CDCl3) δ 2.47 (dd, J=17.3, 10.7 Hz, 1H), 2.83 (dd, J=17.3, 8.4 Hz, 1H), 3.65 (m, 2H), 3.83 (m, 1H), 4.11 (m, 1H), 4.57 (m, 3H), 5.22 (d, H=10.4 Hz, 1H), 5.30 (d, J=17.2 Hz, 1H), 5.33, (m, 1H), 5.47 (d, J=5.2 Hz, 1H), 5.89 (ddt, J=17.1, 11.0, 5.4 Hz, 1H) ppm; LC-MS (ES+) m/e=264 (M+H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(/[CH:20]=[CH:21]/[CH2:22][O:23][CH3:24])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[CH3:24][O:23][CH2:22]/[CH:21]=[CH:20]/[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC/C=C/c1ccc2c(c1)C(=O)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromoindan-1-one (1 eq.) and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.3 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was stirred at 100° C. for 1 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a beige solid.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=2)=[CH:8][CH:7]=1.Cl.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][NH2:35].Cl>C(O)C>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=3)=[CH:8][CH:7]=2)[CH2:4][C:3]([C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])=[N:35]1
Reactant: CSc1cccc(-c2ccc(C=CC(=O)C(F)(F)C(F)(F)F)cc2)c1
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CCO
Product: CSc1cccc(-c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 57.4 %

Procedure:
4,4,5,5,5-Pentafluoro-1-(3′-methylsulfanyl-biphenyl-4-yl)-pent-1-en-3-one (200.0 mg, 0.54 mmol) prepared in Step 2 of Preparation 2, 2-chlorophenylhydrazine hydrochloride (115.0 mg, 0.64 mmol) and conc. hydrochloric acid (200.0 uL) were added to ethanol (5.0 mL). The reaction mixture was stirred at 100° C. for 18 hours, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 154.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[I:34]C1C=CC(OC2C=CC(S(Cl)(=O)=O)=CC=2)=CC=1>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([I:34])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(I)cc2)cc1
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccc(I)cc2)cc1

Procedure:
Compound 4e was prepared following the procedure described for 4a with reagent quantities adapted to the amount of starting material 3e (0.71 g, 1.81 mmol). Yield: 1.04 g, 1.64 mmol, 99% (white solid). 1H-NMR (DMSO-d6): δ 7.96 (d, 3J=8.5 Hz, 2H, ArH), 7.59 (d, 3J=8.5 Hz, 2H, ArH), 4.07 (s, 4H, 2×CH2CO2H), 1.40 (s, 18H, 2×CO2tBu).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH2:4][CH2:3]1.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[NH:34]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>ClCCl>[C:39]([O:38][C:36](=[O:37])[CH2:35][N:34]([C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2=[O:1])=[O:13])[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C(O)c1cccc2c1CCC2=O
Reactant: CC(C)(C)OC(=O)CNCC(=O)OC(C)(C)C
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)c1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Example 5 (500 mg, 2.84 mmol) in dichloromethane (10 mL) was added 1,3-diisopropylcarbodiimide (0.44 mL, 2.84 mmol), 1-hydroxybenzotriazole hydrate (115 mg, 0.85 mmol), and di-t-butyl iminodiacetate (1.04 g, 4.26 mmol). The mixture was stirred at room temperature for about 24 hours, quenched with water, and extracted with diethyl ether. The combined organic extracts were washed with brine and saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (1:1) as the mobile phase to provide the desired product. MS (ESI): m/z 402 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][N:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: FC(F)(F)c1ccc(Br)nc1
Product: COc1cc(-c2ccc(C(F)(F)F)cn2)ccn1
Yield: 73.2 %

Procedure:
2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.81 mmol) were reacted according to Example 31 (step a) to provide the title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CS([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=O)=O>>[CH:1]1([S:4]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)=[O:20])[CH2:14][CH2:13]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(S(=O)(=O)C2CC2)CC1
Yield: 68 %

Procedure:
Cyclopropylsulfonyl chloride (68.5 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (65 mg, 0.166 mmol, 68% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.78 (s, 1H), 7.57 (s, 4H), 6.38 (d, J=7.5 Hz, 1H), 4.19 (d, J=Hz, 1H), 3.52 (d, J=12.3 Hz, 2H), 2.99 (t, J=11.4 Hz, 2H), 2.58 (m, 1H), 1.91 (d, J=12.6 Hz, 2H), 1.46 (m, 2H), 0.96 (m, 4H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]=[C:12](SC)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:30]([NH:32][NH2:33])=O)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(O)CCC>[Si:1]([O:8][CH2:9][C@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]2[C:30]([C:27]3([C:24]4[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=4)[CH2:29][CH2:28]3)=[N:32][N:33]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NNC(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Temperature: 140 °C
Reaction time: 6 h
Yield: 86.6 %

Procedure:
The compound (2.09 g, 6.54 mmol) obtained in Example 4-1) and the compound (1.38 g, 6.54 mmol) obtained in Example 1-1) were dissolved in 1-butanol (10 mL), and the mixture was stirred at 140° C. for 6 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=30% to 90%) to obtain the title compound (2.63 g, 87%) in a white solid form.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[C:13]([F:23])=[C:14]([CH:19]=[CH:20][C:21]=3[F:22])[O:15][CH2:16][CH2:17][OH:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.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>[F:23][C:13]1[C:12]([CH2:11][C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:3]=3)[NH:8][CH:9]=2)=[C:21]([F:22])[CH:20]=[CH:19][C:14]=1[O:15][CH2:16][CH2:17][OH:18]
Reactant: OB(O)c1cccnc1
Reactant: OCCOc1ccc(F)c(Cc2c[nH]c3ncc(Br)cc23)c1F
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: [K+]
Solvent: CC#N
Solvent: O
Product: OCCOc1ccc(F)c(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Yield: 31.7 %

Procedure:
To 2-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenoxy]-ethanol (P-1392, 35.0 mg, 0.091 mmol) in acetonitrile (4.0 mL) were added 3-pyridylboronic acid (14.6 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium(0) (3.0 mg, 0.0026 mmol) and 1 M potassium carbonate solution (1.5 mL). The reaction was microwaved (300 watts) at 160° C. for 7 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting 4% methanol in methylene chloride to give the compound as white solid (P-1394, 11.0 mg, 32%). MS (ESI) [M+H+]+=382.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]([NH2:13])=[O:12].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]2[C:3]=1[NH:10][C:11](=[O:12])[NH:13][C:14]12[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(F)c(NC(N)=O)c1
Product: COc1ccc(F)c2c1C1(CCCCC1)NC(=O)N2
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a stirred solution of polyphosphoric acid (20 g) at 100° C. was added N-(2-fluoro-5-methoxyphenyl)urea (900 mg, 4.89 mmol) over 5 minutes followed by cyclohexanone (719 mg, 7.33 mmol) in one portion under N2. The mixture was stirred at 100° C. for 2 hours, cooled to 35° C. and quenched into water (400 mL). The crude product was filtered and washed with water (100 mL). The isolated solid was slurred in a mixture of tert-butylmethylether (8 mL) and ethyl acetate (4 mL) at 50° C. for 10 minutes, filtered, washed with tert-butylmethylether (10 mL) and dried in vacuo at 40° C. to give 8′-fluoro-5′-methoxy-1′H-spiro[cyclohexane-1,4′-quinazolin]-2′(3′H)-one (900 mg, 70%) as a light-brown solid, purity (97.3%).