Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:26][CH:25]=2)=[N:6][N:7]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:19][C:18](F)([F:20])[C:17](F)([F:22])[CH2:16]3)=[CH:13][CH:14]=2)[CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.O>C(OCC)(=O)C>[F:20][C:18]1[C:17]([F:22])=[CH:16][N:15]([C:12]2[N:11]=[CH:10][C:9]([N:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:35])[C:5]([C:24]4[N:28]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:27]=[CH:26][CH:25]=4)=[N:6]3)=[CH:14][CH:13]=2)[CH:19]=1
Reactant: COc1cn(-c2ccc(N3CC(F)(F)C(F)(F)C3)nc2)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)nc2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
A mixture of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-3-yl]pyridazin-4(1H)-one (367 mg), cesium carbonate (1.23 g) and DMF (4 ml) was stirred at 100° C. for 4 hr. To the reaction mixture were added water and ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized from DMSO-ethanol to give the title compound (146 mg) as whitish yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[N:10]=[C:9]2I.C([Mg]Cl)(C)C.[CH2:25]([Sn:29]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:31][CH2:32][CH2:33][CH3:34])Cl)[CH2:26][CH2:27][CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[N:10]=[C:9]2[Sn:29]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2cc(Oc3cccc(Cl)c3)ccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(Oc3cccc(Cl)c3)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
5-(3-Chlorophenoxy)-3-iodo-1-methyl-1H-indazole (0.154 g, 400 μmol) was dissolved in THF (3.00 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath) then isopropylmagnesium chloride (2M in THF, 224 μL, 448 μmol) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min then tributylchlorostannane (150 mg, 125 μL, 460 μmol) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the combined organics dried over MgSO4 and concentrated to a yellow oil. The residue was dried under high vacuum to give 5-(3-chlorophenoxy)-1-methyl-3-(tributylstannyl)-1H-indazole. The mass of this material was greater than the theoretical yield of the desired product. The yield was assumed to be quantitative, and the material was used directly in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]1[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])[CH:10]=2)=[O:5])C.[OH-].[Na+]>CO>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:27]=[CH:26][C:25]([C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)=[CH:13][CH:12]=3)=[O:18])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a solution of 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester (50 g, 114.5 mmol, 1 equiv) and methanol (750 mL, 15 volumes) was slowly added 1 N sodium hydroxide (220 mL, 4.4 volumes). After stirring at room temperature for 2 hours, the reaction was concentrated in vacuo. Water (750 mL) was added to the residue and the pH was adjusted to 5.0 using 1 N hydrochloric acid (250 mL). The resulting slurry was stirred for 30 minutes and the precipitated solids were collected by filtration and dried in vacuo and then dissolved in methanol (75 mL) and ethyl acetate (675 mL). The solution was dried over sodium sulfate and filtered, and concentrated in vacuo. The residue was slurried in ethyl acetate (250 mL). The solids were collected by filtration to give 7-[(4′-trifluoromethyl-biphenyl -2-carbonyl)-amino]-quinoline-3-carboxylic acid (28.1 g, 60%).
Reaction SMILES: CC1C=C(C)C=C(C)C=1[Mg]Br.C1([Mg]Br)C=CC=CC=1.[C:20]1([CH3:32])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[C:28](O)([CH3:30])[CH3:29]>COC1CCCC1.C1COCC1>[CH3:30][C:28]([C:21]1[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=1[CH3:32])=[CH2:29]
Reactant: Cc1cc(C)c(C(C)(C)O)c(C)c1
Agent: Br[Mg]c1ccccc1
Agent: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: COC1CCCC1
Solvent: C1CCOC1
Product: C=C(C)c1c(C)cc(C)cc1C
Yield: 81.9 %

Procedure:
The same experiment as in Example 2 was carried out, except for using 45 ml (0.045 mol) of a 1 M 2,4,6-trimethylphenylmagnesium bromide solution in CPME instead of 45 ml of the 1 M phenylmagnesium bromide solution in THF. The resulting reaction mixture was analyzed by gas chromatography to confirm that 2-mesityl-2-propanol and α-methyl-2,4,6-trimethylstyrene were obtained in a yield of 81.9% and 1.6%, respectively.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](OCC)=[O:37])[CH2:20][C:19]2[C:14](=[C:15]([O:27][CH3:28])[C:16]([O:25][CH3:26])=[C:17]([O:23][CH3:24])[C:18]=2[O:21][CH3:22])[CH2:13]1)=O)C.Cl>C(OCC)C>[OH:9][CH2:10][C:12]1([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[CH2:13][C:14]2[C:19](=[C:18]([O:21][CH3:22])[C:17]([O:23][CH3:24])=[C:16]([O:25][CH3:26])[C:15]=2[O:27][CH3:28])[CH2:20]1
Reactant: CCOC(=O)CCCCCCCC1(C(=O)OCC)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CO)(CCCCCCCCO)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Lithium aluminium hydride (72.1 mg, 1.90 mmols) was added to a diethyl ether (6.0 ml) solution of ethyl 8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoate (315 mg, 0.634 mmols), with cooling with ice. The reaction mixture was warmed to room temperature, and then stirred for 1 hour. 1N hydrochloric acid was added to the reaction mixture with cooling with ice, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:1) to obtain the entitled compound (239 mg) as an oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[CH3:15][CH:16](O)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH-].[Na+]>O1CCCC1>[CH:16]([O:12][C:5]1[CH:4]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([CH3:17])[CH3:15]
Reactant: CC(C)O
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
To a solution of p-(trifluoromethyl)salicylic acid (CAS 345-28-8) (500 mg, 2.271 mmol), 2-propanol (0.209 ml, 2.725 mmol) and triphenylphosphine (706.2 mg, 2.612 mmol) in 6.5 ml tetrahydrofurane under nitrogen at 0° C., was added dropwise a solution of di-tert-butyl azodicarboxylate (575.2 mg, 2.498 mmol) in 1 ml tetrahydrofurane. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. 8 ml 2N NaOH (15.9 mmol) was added and the reaction mixture was heated in an 80° C. oil bath for 5 hours. The reaction mixture was allowed to cool to room temperature and extracted twice with 5 ml ether. The aqueous layer was acidified under ice bath cooling with a 5N HCl solution to pH 1. The resulting precipitate was filtered and dried in vacuo to provide 444 mg (79%) of the title compound as a white solid. MS (m/e): 247.0 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: O=C(O)[C@](O)(c1ccc(F)cc1)[C@@H]1CCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Product: O=C(O[C@H]1CCNC1)[C@](O)(c1ccc(F)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)acetic acid and t-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.C(N(CC)CC)C.[CH3:59][O:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[N:67]=[C:68]=[O:69]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:68]([NH:67][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=3[O:60][CH3:59])=[O:69])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: COc1ccccc1N=C=O
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution of 100 mg (0.142 mmol) of 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]-propanamide, trifluoroacetate (Example 36, Step A) in 2 mL of dry methylene chloride under nitrogen atmosphere was added 0.040 mL (0.28 mmol) of triethylamine followed by 0.021 mL (0.16 mmol) of 2-methoxyphenyl isocyanate. The reaction mixture was stirred at room temperature for 30 minutes, diluted with 100 mL of ethyl acetate, washed with 25 mL of saturated aqueous ammonium chloride, 25 mL of saturated aqueous sodium bicarbonate and 25 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum to afford 102 mg (97%) of the product as a white foam. 1H NMR (200 MHz, CD3OD): δ 1.38 (s, 6H), 1.80 (m, 1H), 2.15-2.50 (m, 3H), 3.80 (s, 3H), 4.19 (s, 2H), 4.27 (m, 1H), 4.68 (d, 16 Hz, 1H), 5.00 (s, 2H), 5.30 (d, 16 Hz, 1H), 6.90 (m, 3H), 7.10-7.45 (m, 17H), 7.92 (m, 1H). FAB-MS: calculated for C44H45N5O6 739; found 740 (M+H, 60%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([CH3:12])[C:7]([O:9]CC)=[O:8])[N:3]=[CH:2]1.[OH-].[Na+].O>CO>[S:1]1[CH:5]=[C:4]([CH:6]([CH3:12])[C:7]([OH:9])=[O:8])[N:3]=[CH:2]1
Reactant: CCOC(=O)C(C)c1cscn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1cscn1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 5.0 g (27 mmol) of ethyl 2-(1,3-thiazol-4-yl)propanoate from step A above in 25 mL of methanol was added dropwise to a mixture of 6.6 mL (33 mmol) of a 5 N aqueous NaOH solution, water (16 ml) and methanol (30 ml). After addition was complete the mixture was stirred for 2 h. The methanol was removed by evaporation and the pH of the remaining aqueous was adjusted to ˜2.5 with a concentrated hydrogen chloride solution. The mixture was saturated with solid sodium chloride and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and treated with activated charcoal overnight. The mixture was filtered and evaporated to afford the title compound as an off-white solid 4.0 g (95%). 1H NMR (500 MHz, CDCl3) δ: 1.63 (d, J=7.3, 3H), 4.11 (q, J=7.3), 7.25 (d, J=1.8, 1H), 8.88 (d, J=1.8, 1H), 10.25 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].CCCCCC.C([Li])CCC.[CH3:19][C:20]1[CH:21]=[C:22]([O:25][C:26]=1[CH3:27])[CH:23]=[O:24]>O1CCCC1.O>[CH3:19][C:20]1[CH:21]=[C:22]([CH:23]([C:4]2[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=2)[OH:24])[O:25][C:26]=1[CH3:27]
Reactant: Cc1cc(C=O)oc1C
Reactant: Cc1ncsc1C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)c2nc(C)c(C)s2)oc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
4,5-Dimethylthiazole (1.0 g) was dissolved in tetrahydrofuran (40 ml) under an argon atmosphere to prepare a solution. A 1.6M hexane solution (5.6 ml) of n-butyllithium was added dropwise at −78° C., and the mixture was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (1 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and the temperature of the mixture was raised to room temperature with stirring. Water was added to the reaction solution to stop the reaction. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give (4,5-dimethylfuran-2-yl)-(4,5-dimethylthiazol-2-yl)methanol (945 mg, yield 50%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]4[CH2:25][O:24][C:23](=[O:26])[C:12]=4[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:27]N1C(=O)CCC1=O.OS(O)(=O)=O>C1COCC1.C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]4[CH2:25][O:24][C:23](=[O:26])[C:12]=4[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[C:15]4[Cl:27])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1OCc2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C1OCc2c1cc1c(Cl)cc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Yield: 48.8 %

Procedure:
A stirred solution of 2 (104 mg, 0.3 mmol), N-chlorosuccinimide (80 mg, 0.6 mmol) and concentrated H2SO4 (10 μL) in THF (5 mL) was heated to reflux for 24 h, and then diluted with CHCl3 (50 mL). The reaction mixture was washed with 10% aqueous Na2S2O3 solution (50 mL) and water (2×50 mL), dried over MgSO4, and concentrated in vacuo. The product was purified by column chromatography on silica gel eluting with CHCl3 to afford 37 (56 mg, 49%) as a brown solid. mp 267° C. (decomp.); 1H NMR (CDCl3) δ 8.91 (s, 1H, H4), 7.47 (s, 1H, H6), 6.76-6.91 (m, 3H, H2′+H5′+H6′), 6.08 (AB, 2H, 3′,4′-OCH2O—, Δδ=8.7 Hz, J=1.5 Hz), 5.97 (AB, 2H, 7,8-OCH2O—, Δδ=8.7 Hz, J=1.5 Hz), 5.22 (q, 2H, lactone-CH2—, J=8.7 Hz); MS (EI) m/z 384 [M+2]+, 382 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12]C.Br>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[OH:12]
Reactant: COc1cc(CC(=O)O)ccc1Cl
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(Cl)c(O)c1
Yield: 93.4 %

Procedure:
The product from step (ii) (12.2 g), HBr (48% aq.) and acetic acid (10 ml) were charged to a flask and heated at reflux for 24 h, cooled then evaporated under reduced pressure. The residue was triturated with ether/isohexane, and then filtered to give the subtitle compound (10.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](CC#N)=[C:4]([F:11])[C:3]=1[F:12].OS(O)(=O)=O.[CH3:18][C:19](=[O:23])[O:20]CC>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:18][C:19]([OH:20])=[O:23])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: CCOC(C)=O
Reactant: N#CCc1ccc(Br)c(F)c1F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc(Br)c(F)c1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
Compound 2-(4-bromo-2,3-difluorophenyl)acetonitrile (200 mg, 0.690 mmol) was dissolved in H2O (1 mL) and H2SO4 (1 mL) at 20° C. in one charge. The reaction mixture was stirred at 100° C. for 1 h. Then the solution was distributed between EA and H2O. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(4-bromo-2,3-difluorophenyl)acetic acid (180 mg, 0.287 mmol, 41.6% yield) was used in the next step without further purification. TLC (PE/EtOAc=2:1, Rf 0.6): 1H NMR (400 MHz, CDCl3) δ 7.27-7.20 (m, 1H), 6.92-6.85 (m, 1H), 3.65 (s, 2H); ES-LCMS m/z 250.0 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1.O1C2C=CC=CC=2C=C1C(Cl)=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C(Cl)c1cc2ccccc2o1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cc4ccccc4o3)cc2)c2ccc3ccccc3c2N1
Yield: 101.5 %

Procedure:
Benzofuran-2-carboxylic acid (31 mg, 0.189 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (40 mg, 0.126 mmol) obtained in Example 1, and benzofuran-2-carboxylic acid chloride mentioned above, the title compound (59 mg, yield 100%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[I:16])([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:19][O:20][CH2:21]Cl>C(N(CC)C(C)C)(C)C>[F:18][C:2]([F:1])([F:17])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[I:16])([O:8][CH2:19][O:20][CH3:21])[C:4]([F:7])([F:6])[F:5]
Reactant: Cc1ccc(I)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(c1cc(C)ccc1I)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Compound 2 (4 g, 10.42 mmol) was dissolved in N,N-diisopropylethylamine (DIPEA, 20 mL) freshly distilled over calcium hydride. The solution was cooled in an ice-bath and the chloromethyl methyl ether (4.75 mL, 62.5 mmol) was added. A white precipitate appeared instantaneously. The reaction mixture was stirred overnight at room temperature. After removal of DIPEA under vacuum, the residue was chromatographied over silica gel using heptane/acetone (97/3) to give 4.23 g (9.89 mmol, 95% yield) of a slightly yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH:5]1[CH3:19])(=[O:3])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:36][C:37]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH3:49])[C:38]=1[C:39]([NH2:41])=[O:40]>CC(N(C)C)=O.O>[C:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:18]=[CH:17][C:14]([C:15]3[NH:41][C:39](=[O:40])[C:38]4[C:37](=[CH:45][C:44]([O:46][CH3:47])=[CH:43][C:42]=4[O:48][CH3:49])[N:36]=3)=[CH:13][CH:12]=2)[CH2:6][C@H:5]1[CH3:19])(=[O:3])[CH3:2]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4C[C@@H](C)N(C(C)=O)[C@@H](C)C4)cc3)nc2c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 41.7 %

Procedure:
A mixture of 4-(4-acetyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (0.580 g, 2.20 mmol), NaHSO3 (0.260 g, 2.40 mmol), and p-TsOH (0.039 g, 0.20 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.400 g, 2.20 mmol) in DMA (15 mL). The reaction was stirred at 120° C. for 4 hours and then cooled to room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH/CH2Cl2, afforded the title compound (0.400 g, 46%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 11.78 (br s, 1H), 8.10 (d, J=8.9 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 4.01-4.64 (m, 2H), 3.71-3.95 (m, 8H), 2.87-3.07 (m, 2H), 2.06 (s, 3H), 1.25 (d, J=6.2 Hz, 6H). ESI MS m/z 437 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C@H:11]1[CH2:15][CH2:14][C@H:13]([OH:16])[C@@H:12]1[OH:17].[CH3:18][C:19]1([CH3:44])[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[C:25]2[CH:24]=[C:23]([C:31]3[N:36]=[C:35]([N:37]4[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]4)[CH:34]=[CH:33][CH:32]=3)[CH:22]=[CH:21][C:20]1=2.Cl>>[CH3:18][C:19]1([CH3:44])[CH2:28][CH2:27][C:26]([CH3:29])([CH3:30])[C:25]2[CH:24]=[C:23]([C:31]3[N:36]=[C:35]([N:37]4[CH2:42][CH2:41][CH:40]([NH:10][C@H:11]5[CH2:15][CH2:14][C@H:13]([OH:16])[C@@H:12]5[OH:17])[CH2:39][CH2:38]4)[CH:34]=[CH:33][CH:32]=3)[CH:22]=[CH:21][C:20]1=2
Reactant: N[C@H]1CC[C@H](O)[C@@H]1O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(=O)CC4)n3)ccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(N[C@H]5CC[C@H](O)[C@@H]5O)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS1007 without addition of DIPEA starting from 23 mg (0.199 mmol) of (1S,2R,3S)-3-aminocyclopentane-1,2-diol and 80 mg (0.199 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](CCS(C)(=O)=O)[C:16](=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4](OC)[CH:3]=1.C1(B(O)O)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>COCCOC.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[CH3:16][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CNc1cnccc1-c1ccccc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
To a solution of (4-iodo-pyridin-3-yl)-methyl-amine (225 mg, 0.96 mmol, example 36, intermediate b) in DME (5 mL) were added phenyl boronic acid (234 mg, 1.92 mmol) and 2M aqueous Na2CO3 solution (2 mL) and the reaction mixture was purged with nitrogen for 15 min. Then Pd(OAc)2 (22 mg, 0.1 mmol) and triphenylphosphine (50 mg, 0.19 mmol) were added and the reaction mixture was stirred at 100° C. for 5 hours. The reaction mixture was poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted with 30 mL EtOAc. The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and evaporated. The residue was purified by column chromatography eluting with a gradient of n-hexane:EtOAc (80:20 to 70:30) to yield the desired compound as a yellow solid (160 mg, 90%) MS (ESI): m/z=185.0 [M+H]+.