Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13].[C:43]([O:47][C:48]([N:50]1[CH2:55][C@@H:54]([CH3:56])[N:53]([C:57]2[CH:62]=[CH:61][C:60]([C:63](=[O:78])[NH:64][C:65]3[CH:70]=[C:69]([O:71][C:72]([F:75])([F:74])[F:73])[C:68](Br)=[CH:67][C:66]=3[F:77])=[CH:59][N:58]=2)[CH2:52][C@@H:51]1[CH3:79])=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1(C)C=CC=CC=1.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>[C:43]([O:47][C:48]([N:50]1[CH2:55][C@@H:54]([CH3:56])[N:53]([C:57]2[CH:62]=[CH:61][C:60]([C:63](=[O:78])[NH:64][C:65]3[C:66]([F:77])=[CH:67][C:68]([C:30]4[CH:31]=[CH:32][C:27]([C:25]5[N:26]=[C:22]([C@@H:18]6[CH2:19][CH2:20][CH2:21][N:17]6[C:15](=[O:16])[C@@H:11]([NH:10][C:9]([O:8][CH3:7])=[O:42])[CH:12]([CH3:14])[CH3:13])[NH:23][CH:24]=5)=[CH:28][CH:29]=4)=[C:69]([O:71][C:72]([F:75])([F:74])[F:73])[CH:70]=3)=[CH:59][N:58]=2)[CH2:52][C@@H:51]1[CH3:79])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2F)cn1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
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: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(F)c(NC(=O)c4ccc(N5C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
Potassium carbonate (470 mg, 3.4 mmol) was added to a solution of [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (340 mg, 0.68 mmol) and (2S,5R)-4-[5-(4-bromo-2-fluoro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (400 mg, 0.68 mmol; Preparation 49) dissolved in toluene (2.5 mL) and water (0.73 mL). The reaction mixture was sparged under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (94 mg, 0.081 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100° C. for 4 h. The reaction mixture was diluted in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce (2S,5R)-4-[5-(5-fluoro-4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a red solid.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=O.P(Br)(Br)[Br:15].O>C(OCC)C>[Br:15][CH2:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[F:1]
Reactant: BrP(Br)Br
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1F
Solvent: O
Solvent: CCOCC
Product: Cn1nc(C(F)(F)F)c(CBr)c1F
Temperature: -30 °C
Reaction time: 12 h
Yield: 67.3 %

Procedure:
A solution of 35.4 g (178.7 mmoles) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 500 ml of diethyl ether was cooled to −30° C. Thereto was added 54.0 g (199.5 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water and extraction with diethyl ether was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 31.4 g (yield: 80.8%) of 4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: C[O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[CH:4]=1
Reactant: COC(=O)c1cc(OC)c2ncsc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc(O)c2ncsc2c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a stirred solution of methyl 4-methoxy-1,3-benzothiazole-6-carboxylate (20.0 g, 0.0897 mol) in anhydrous CH2Cl2 (300 mL) was added drop wise BBr3 (112.5 g, 0.448 mol) at -78° C. Then the resulting mixture was stirred at −78° C. for 3 hours and allowed to warm to room temperature overnight. TLC (EtOAc/Petroleum ether 1:4) showed the reaction was complete. The reaction mixture was concentrated in vacuum and methanol (100 mL) was added drop wise to the residue. Then the mixture was concentrated again in vacuum. The residue was washed with water and recrystallized from methanol to afford the desired product (12 g, 64%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 10.671 (s, 1H), 9.437 (s, 1H), 8.252-8.248 (s, 1H), 7.488-7.484 (s, 1H), 3.898 (s, 3H).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3]C1.[Mg].Br[C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1>C1COCC1>[O:18]1[C:17]2[CH:22]=[CH:23][C:14]([C:7]3([OH:10])[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]3)=[CH:15][C:16]=2[O:21][CH2:20][CH2:19]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc2c(c1)OCCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccc3c(c2)OCCO3)CC1
Reaction time: 16 h

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (7.8 g, 50 mmole) in 50 ml dry THF was added to a of the Grignard reagent prepared from magnesium metal (1.34 g, 55 mmole) and 6-bromo-1,4-benzodioxane (10.75 g, 50 mmole). The mixture was stirred for 16 hr, quenched with saturated NH4Cl and extracted with ether. The ether extracts were dried with Na2SO4 and the solvent removed in vacuo. Acetone (75 ml) and 1N HCl (75 ml) were added and the solution was stirred 18 hr to give a tan precipitate which was filtered and air dried (6.38 g, 59.1%). This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[C:11]([NH2:32])=[N:12][CH:13]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:20]=3)[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][C:35]=1[C:43]([F:46])([F:45])[F:44]>O1CCCC1.C(OCC)(=O)C>[NH2:32][C:11]1[C:10]([C:9]#[C:8][C:4]2[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[C:35]([C:43]([F:45])([F:44])[F:46])[CH:36]=3)=[O:42])[CH:7]=[CH:6][CH:5]=2)=[CH:15][C:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[N:20]=2)=[CH:13][N:12]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cnc(N)c(C#Cc3cccc(N)c3)c2)n1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cnc(N)c(C#Cc3cccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-((3-aminophenyl)ethynyl)-5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)pyridin-2-amine (135 mg, 0.3 mmol, 1 eq) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (67 mg, 1 eq) in anhydrous tetrahydrofuran (3 mL) was stirred at room temperature and under nitrogen atmosphere for 3 hours. The mixture was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The clear solution was decanted, concentrated under reduced pressure, and the resulting clear oil was dried in vacuo for 5 minutes. It was then treated with a small amount of EtoAc-Hex (1:9), followed by stirring at room temperature for 30 minutes. The white solid that appeared during the process was filtered giving 1-(3-((2-amino-5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)pyridin-3-yl)ethynyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea in the amount of 201 mg.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[CH2:44][O:45][CH3:46]>C1COCC1>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:44][O:45][CH3:46])[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COCCl
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCn1cc2cc(C)c(NC(=O)c3cc(OC)nn3-c3ncccc3Cl)c(C(=O)NC(C)C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (500 mg, 1.07 mmol) and diisopropylethylamine (225 μL, 1.2 mmol) in THF (10 mL) was treated dropwise with chloro-methoxy-methane (90 μL, 1.2 mmol). The resulting reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated in vacuo. Purification of the residue by flash-chromatography (SiO2, CH2Cl2/acetone 7:3) afforded the title compound as a colorless crystalline solid. M.p. 148° C., LC/MS:512/514 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:4]=1[OH:12].O.C(=O)(O)[O-].[Na+].[Br:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[C:21](Cl)=[O:22]>C(OCC)(=O)C>[Br:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[C:21]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:10])[CH3:11])[C:4]=1[OH:12])=[O:22]
Reactant: CC(C)c1cccc(N)c1O
Reactant: CC(C)[C@@H](Br)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1cccc(NC(=O)[C@H](Br)C(C)C)c1O
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a stirred, ice-cooled mixture of 2-amino-6-isopropylphenol hydrochloride (15.0 g), ethyl acetate (200 ml), water (100 ml), and sodium bicarbonate (20.0 g), was added dropwise a solution of (R)-2-bromo-3methylbutyryl chloride (16.0 g) in ethyl acetate (30 ml). The whole was stirred for 30 minutes, and the ethyl acetate layer was separated, washed with water and dried over MgSO4. Removal of the solvent gave (R)-2-(2-bromo-3-methylbutyryl)amino-6-isopropylphenol as crystals (19.1 g, 76.1%). Recrystallization from isopropyl ether afforded colorless needles, mp 108°-109° C. [α]D23 +44.8° (c=0.82, MeOH).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]3[O:20][C:21]([C:24]4[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=4)=[CH:22][N:23]=3)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[S:37]1[CH2:38][CH2:39][N:34]([CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]4[O:20][C:21]([C:24]5[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=5)=[CH:22][N:23]=4)=[O:18])=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)[CH2:35][CH2:36]1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(C=O)cc4)cc3)o2)n1
Reactant: C1CSCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCSCC5)cc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 60.5 %

Procedure:
Methyl 6-(2-(3-(4′-formylbiphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (124 mg, 0.282 mmol) and thiomorpholine (0.040 mL, 0.42 mmol) were dissolved in dichloroethane (12 mL) and NaBH(OAc)3 (179 mg, 0.845 mmol) was added. The reaction solution was stirred under an atmosphere of Ar at ambient temperature for 3.5 h and then quenched with saturated aqueous NaHCO3. The crude product was extracted with EtOAc and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 50-90% EtOAc/hexanes) to furnish methyl 6-(2-(3-(4′-(thiomorpholinomethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate as a pale tan solid (90 mg, 61%): 1H NMR (CDCl3, 600 MHz) δ 8.12 (d, 1H, J=7.7 Hz), 8.04-8.02 (m, 2H), 7.97 (t, 1H, J=7.8 Hz), 7.52 (dd, 4H, J=8.2, 1.8 Hz), 7.35 (t, 4H, J=8.6 Hz), 4.03 (s, 3H), 3.55 (s, 2H), 3.51 (t, 2H, J=7.6 Hz), 3.16 (t, 2H, J=7.6 Hz), 2.74-2.73 (m, 4H), 2.70-2.68 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 165.1, 157.4, 152.4, 148.5, 146.5, 139.7, 139.3, 139.0, 138.3, 137.0, 129.4, 128.9, 128.0, 127.1, 126.8, 125.2, 123.3, 63.3, 54.9, 53.0, 40.6, 29.3, 28.0; HR ESI-TOF m/z 528.1950 (M+H+, C30H29N3O4S, requires 528.1951).
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17]/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([O:26]CC3C=CC=CC=3)=[C:22]([C@@H:34]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:35][CH2:36][N:37]([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH:21]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:50])[NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C@@H:34]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:35][CH2:36][N:37]([CH:38]([CH3:39])[CH3:40])[CH:41]([CH3:43])[CH3:42])[CH:21]=2)=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(/C=C/COc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1O)C(C)C
Temperature: 25 °C

Procedure:
tert-Butyl[2-(4-{[(2E)-3-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}prop-2-en-1-yl]oxy}phenyl)ethyl]carbamate (Preparation 6, 475 mg, 0.70 mmol) was dissolved in ethanol (20 ml) and 10% palladium on carbon (50 mg) added. The reaction was heated to 40° C. under 50 psi of hydrogen for 4 hours. The reaction was cooled to room temperature and filtered through Arbocel™, the filtrate was collected and the solvent removed in vacuo to furnish the title compound as a glass, 400 mg.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:16])[CH2:14]Cl)[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([CH2:14][N:28]2[CH2:27][CH2:26][N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][CH3:17])[CH2:30][CH2:29]2)=[O:16])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)CCl)c(OC)nc1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCc1cc(NC(=O)CN2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
After N-(5-ethyl-2-methoxy-6-metylpyridine-3-yl)chloroacetamide(0.10 g, 0.43 mmol) and 1-(2-methoxyphenyl)piperazine(0.0091 g, 0.47 mmol) were dissolved into tetrahydrofuran(5 ml) and was added DBU(0.060 g, 0.43 mmol), the reaction mixtures were stirred at room temperature for 2 hours. After the product of reaction were concentrated, separated by column chromatography to obtain 0.12 g of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C@H:11]([CH2:19][C:20]#[CH:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([O:33][CH2:34][CH2:35][N:36]=[N+:37]=[N-:38])(=[O:32])=[O:31].C(N(CC)C(C)C)(C)C>O1CCCC1.[Cu]I>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C@H:11]([CH2:19][C:20]1[N:38]=[N:37][N:36]([CH2:35][CH2:34][O:33][S:30]([CH3:29])(=[O:32])=[O:31])[CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1cn(CCOS(C)(=O)=O)nn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
Di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-prop-2-yn-1-yl-L-glutamate (60 mg, 151 μmol) and 2-azidoethyl methanesulfonate (37.4 mg, 226 μmol) were dissolved in tetrahydrofuran (4 ml). To the solution, copper(I) iodide (2.9 mg, 15 μmol) and N,N-diisopropylethylamine (32 μl, 181 μmol) were added and the mixture was stirred for 18 h at room temperature. The mixture was then concentrated in vacuo and the residue was purified by preparative reversed phase HPLC. The product fractions were collected, lyophilized, and purified again by silicagel chromatography to yield 50 mg (47%) of the product.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]=O>>[C:1]1([C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][O:9]1)=[O:8]
Reactant: C=O
Reactant: O=C(O)c1ccccc1
Product: O=C1OCc2ccccc21

Procedure:
A benzoic acid derivative of formula 1 is reacted with formaldehyde under acidic conditions to yield a phthalide derivative of formula 2. ##STR4## The phthalide derivative is then brominated with any suitable brominating agent, e.g. N-bromosuccinimide to yield an unstable bromophthalide derivative, 3, which is readily reacted with water to a phthalaldehydic acid derivative, 4. ##STR5## The phthalaldehydic acid derivative may then be oxidized to the desired phthalic anhydride derivative, 5, in good yield using a suitable oxidizing agent such as manganese dioxide. ##STR6##
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14](Cl)Cl>S(Cl)(Cl)=O>[Cl:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:14])=[O:10])=[CH:12][CH:13]=1)(=[O:4])=[O:3]
Reactant: ClCCl
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
4-Chlorosulphonylbenzoic acid (15 g, 68 mmol, 1 eq) was suspended in thionyl chloride (60 ml) and DCM (60 ml) and the reaction mixture heated at reflux for 2 hours. The solvent was evaporated in vacuo and ice cold MeOH (120 ml) was added to the residue. The reaction was stirred for 10 minutes in an ice bath before the addition of ice cold water (100 ml). The resulting precipitate was collected by filtration to yield the title compound as a white solid (15.3 g, 0.065 mmol, 96%).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:20]3[N:21]([S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[CH:22]=[C:23]([CH2:25][C:26]([CH3:33])([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH2:28])[N:24]=3)=[O:19])=[CH:13][CH:12]=2)=[N:9][CH:10]=1>O1CCCC1>[F:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:20]3[N:21]([S:34]([N:37]([CH3:38])[CH3:39])(=[O:35])=[O:36])[CH:22]=[C:23]([CH2:25][C:26]([CH3:33])([C:29]([F:30])([F:32])[F:31])[CH:27]=[CH2:28])[N:24]=3)([OH:19])[CH3:1])=[CH:13][CH:12]=2)=[N:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(-c3ccc(F)cn3)cc2)n1)C(F)(F)F
Solvent: C1CCOC1
Product: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (0.50 mL, 1.49 mmol) was added to a 0° C. solution of 2-{[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole-1-sulfonamide (780 mg, 1.49 mmol) in tetrahydrofuran (10 mL). After stirring at 0° C. for 30 min, the reaction mixture was quenched with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-80% ethyl acetate/hexane afforded 2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole-1-sulfonamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cnccc1NCc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 90 parts of 4-chloro-3-nitropyridine, 71 parts of 4-fluorobenzenemethanamine, 63 parts of sodium carbonate and 900 parts of N,N-dimethylacetamide (DMA) was stirred for 1 hour at 50° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 106 parts (75%) of N-[(4-fluorophenyl)methyl]-3-nitro-4-pyridinamine; mp. 136.8° C. (5).
Reaction SMILES: [CH3:1][NH2:2].Cl.O[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=2)[CH:6]=1.[OH-].[Na+]>O>[C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([NH:2][CH3:1])[CH:14]=[CH:13]2)(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CN
Reactant: CCCCCCCCCCCC(=O)c1ccc2cc(O)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCC(=O)c1ccc2cc(NC)ccc2c1
Temperature: 140 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
MeNH2.HCl (11.0 g, 0.13 mol) was added to a mixture of 2-hydroxy-6-dodecanoylnaphthalene (8.0 g, 25 mmol), Na2S2O5 (12 g, 61 mmol), NaOH (5.2 g, 0.13 mol) and water (100 ml) in a high-pressure tube. The resulting mixture was stirred at 140° C. for 48 hours, followed by filtration to collect a solid. The solid was sufficiently washed with water and recrystallized from CH2Cl2-EtOH to give the title compound (5.6 g, yield: 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[C:9]([NH2:21])[CH:8]=2)=[C:4]([F:24])[CH:3]=1.COC1C=C2C(=CC=1OC)N=C(SC)C=C2OC1C=CC(N[C:49]([C:51]2([C:54]([NH:56][C:57]3[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=3)=[O:55])[CH2:53][CH2:52]2)=[O:50])=CC=1F>>[NH2:21][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:49]([C:51]3([C:54]([NH:56][C:57]4[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=4)=[O:55])[CH2:53][CH2:52]3)=[O:50])=[CH:3][C:4]=2[F:24])[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=1
Reactant: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Reactant: COc1cc2nc(N)cc(Oc3ccc(N)cc3F)c2cc1OC
Product: COc1cc2nc(N)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC

Procedure:
N-(4-{[2-amino-6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide was synthesized from 4-(4-amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-ylamine in a similar manner as N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. It was purified by preparatory HPLC using ammonium acetate and isolated as a white solid (4.0% yield). 1H NMR (DMSO-d6) δ 10.34 (s, 1H), 9.95 (s, 1H), 7.82 (d, 1H), 7.58 (m, 2H), 7.44 (d, 1H), 7.33 (t, 1H), 7.25 (s, 1H), 7.09 (t, 2H), 7.07 (s, 1H), 6.17 (br s, 2H), 5.66 (s, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 1.40 (d, 4H). LCMS: m/z 535 (M+H)+.