Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([I:9])[C:6]([CH:10]([O:12]COC)[CH3:11])=[CH:5][N:4]=1.C(Cl)(Cl)Cl>CO.C(=O)([O-])[O-].[Na+].[Na+]>[F:2][C:3]1[N:4]=[CH:5][C:6]([CH:10]([OH:12])[CH3:11])=[C:7]([I:9])[CH:8]=1
Reactant: COCOC(C)c1cnc(F)cc1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(O)c1cnc(F)cc1I
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Add 1 N HCl (5 mL) to a solution of 2-fluoro-4-iodo-5-(1-methoxymethoxy-ethyl)-pyridine (1 g, 3.2 mmol) in methanol (10 mL). Stir the mixture overnight. Dilute the reaction mixture with 2 N sodium carbonate. Abstract the product into chloroform. Dry the organic phase over sodium sulfate. Concentrate the solution in vacuo to a give the crude. Purify the crude by column chromatography (10% methanol in dichloromethane) to afford the product as a white solid (0.75 g, 87%). MS (ES) m/z 268 [M+1]+.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].S(=O)(=O)(O)O.[F:19][C:20](I)([F:22])[F:21].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:19][C:20]([F:22])([F:21])[C:8]1[N:9]([CH3:10])[C:11]2[C:12](=[O:13])[NH:1][C:2](=[O:3])[N:4]([CH3:5])[C:6]=2[N:7]=1
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 12 %

Procedure:
0.18 g (1.0 mmol) of theobromine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 17 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 8-trifluoromethyltheobromine (19F-NMR yield: 12%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 8-Trifluoromethyltheobromine was obtained as a white solid (0.024 g, yield: 10%) by column chromatography.
Reaction SMILES: [CH2:1]([N:4]1[CH:13]2[C:8]([C:9]3[N:16]=[C:15]([NH:17]C(=O)C(C)C)[S:14][C:10]=3[CH2:11][CH2:12]2)=[CH:7][CH2:6][CH2:5]1)CC.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:1][N:4]1[CH:13]2[C:8]([C:9]3[N:16]=[C:15]([NH2:17])[S:14][C:10]=3[CH2:11][CH2:12]2)=[CH:7][CH2:6][CH2:5]1
Reactant: CCCN1CCC=C2c3nc(NC(=O)C(C)C)sc3CCC21
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN1CCC=C2c3nc(N)sc3CCC21

Procedure:
In a process analogous to Example 16 by substituting (±) N-(4,5,5a,6,7,8-hexahydro-6-methylthiazolo[4,5-f]quinolin-2-yl)-2-methylpropanamide (Example 15) for (±) N-(4,5,5a,6,7,8-hexahydro-6-propylthiazolo[4,5-f]quinolin-2-yl)-2-methylpropanamide (Example 15c), the title compound can be prepared as its dihydrochloride salt, hydrate; mp 265°-267° C. (dec.). [α]D =+164.4° (C=1.17, H2O).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.O[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:32][CH:31]([CH2:33][O:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)[CH2:30][C:29]2=[O:45])=[CH:24][CH:23]=1>C(Cl)Cl>[C:1]([O:5][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:32][CH:31]([CH2:33][O:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=3)[CH2:30][C:29]2=[O:45])=[CH:26][CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(O)cc3)C2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OC(C)(C)C)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.5 %

Procedure:
tert-Butanol (1.58 g), dicyclohexylcarbodiimide (4.04 g) and cuprous chloride (35 mg) are suspended in methylene chloride (5 ml) and the mixture is stirred at room temperature under shading for 4 days. Thereto is added a suspension of methyl 4-[1-(4-hydroxyphenyl)-2-pyrrolidon-4-yl]methoxybenzoate (1.52 g) in methylene chloride (30 ml) and the mixture is further stirred for 14 hours. The reaction mixture is concentrated under reduced pressure and thereto is added chloroform. The insoluble material is removed by filtration and the filtrate is subjected to silica gel column chromatography and eluted with chloroform to give the desired product (0.93 g), m.p. 126°-127.5° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:26]([CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:25]=[CH:24][C:7]=3[C:8](=[O:23])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH3:22])[C:10]=2[CH:11]=1.Br[C:34]1[C:39]([CH3:40])=[CH:38][C:37](C2CCOCC=2)=[CH:36][C:35]=1[CH3:47].CC1C=CC=C(C)C=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)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.O>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:10]2[CH:11]=[C:2]([C:34]3[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:47])[CH:3]=[CH:4][C:5]=2[C:6]2[N:26]([CH:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:25]=[CH:24][C:7]=2[C:8]1=[O:23]
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(Cl)cc32)c(OC)c1
Reactant: Cc1cc(C2=CCOCC2)cc(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cccc(C)c1B(O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(-c4c(C)cccc4C)cc32)c(OC)c1

Procedure:
7-chloro-5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one obtained in Preparation Example 2 (100 mg) was dissolved in DMF (3.3 mL). 2,6-dimethylphenylboronic acid (33 mg), Pd(PPh3)4 (13 mg), potassium carbonate (91 mg) and water (0.7 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 150° C. for two hours. The reaction mixture was returned to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 30% to 50% to 80%) to give 5-(2,4-dimethoxybenzyl)-7-(2,6-dimethylphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (80 mg). The 5-(2,4-dimethoxybenzyl)-7-(2,6-dimethylphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (75 mg) was dissolved in TFA. (1 mL), and the mixture was stirred at 65° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was neutralized by adding a saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 70% to 80%) to give the title compound (10 mg).
Reaction SMILES: [C:1]([O:4][CH:5]([C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)[CH2:6][CH2:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:15][CH:14]=2)[C@@H:9]1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]2([O:43][C:44](=[O:46])[CH3:45])[CH2:40][O:39]C(C)(C)[O:37][CH2:36]2)=[CH:29][CH:28]=1)(=[O:3])[CH3:2].[C:54](O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C1COCC1.O>[C:44]([O:43][C:35]([CH2:40][OH:39])([CH2:36][OH:37])[CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C@@H:9]2[C@@H:8]([CH2:7][CH2:6][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C:47]3[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=3)[C:11](=[O:12])[N:10]2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH2:26][CH3:54])(=[O:24])=[O:25])=[CH:15][CH:14]=2)=[CH:28][CH:29]=1)(=[O:46])[CH3:45]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)OC(CC[C@H]1C(=O)N(c2ccc(CCCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(CCC2(OC(C)=O)COC(C)(C)OC2)cc1)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)NCCCc1ccc(N2C(=O)[C@H](CC[C@H](OC(C)=O)c3ccc(F)cc3)[C@H]2c2ccc(CCC(CO)(CO)OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the intermediate of step E (1.5 g, 2 mmol) in THF/water (16 mL/4 mL) was added TFA (1 mL). The reaction mixture was stirred at RT for 16 hr. To the reaction mixture was added 100 mL toluene and the water was removed under vacuum with water bath temperature of 40° C. The residue was treated twice with 100 mL toluene followed by azeotropic removal of water. The solvent was completely removed under vacuum. The crude product was purified by MPLC (silica column) with stepwise gradient elution (50-100% EtOAc/hexanes as eluent). Mixed fractions were also isolated and were further purified by prep TLC eluting with CH2Cl2/MeOH (95/5). The purified fractions were combined to afford the title compound. m/z (ES) 653 (M-OAc)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.Cl.Cl[CH2:29][C:30]1[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCCCCC.C(OCC)(=O)C.O>[CH3:35][N:31]1[CH:32]=[CH:33][N:34]=[C:30]1[CH2:29][O:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: Cn1ccnc1CCl
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCc3nccn3C)c2[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
A mixture of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (100 mg), 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (50 mg), potassium carbonate (83 mg) and N,N-dimethylformamide (20 mL) was stirred at 50° C. for 3 hr. Water was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column to chromatography (ethyl acetate:hexane=60:40 to 100:0, volume ratio) to give the title compound (72 mg, yield 57%) as a white solid. The white solid was recrystallized from ethyl acetate-hexane to give colorless crystals. melting point 91-92° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1[C:28](=[O:43])[C:29]2C(C=1C1C=CC=CC=1)=C[CH:32]=[C:31](O)[CH:30]=2.O1CCCC1CO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:32][CH:31]4[CH2:30][CH2:29][CH2:28][O:43]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: OCC1CCCO1
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCC3CCCO3)cc21
Reaction time: 17 h
Yield: 7 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, (tetrahydrofuran-2-yl)methanol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 17 h, and being purified by prep. HPLC (20% H2O/CH3CN and 30% H2O/CH3CN) to provide the title compound (7%).
Reaction SMILES: FC(F)(F)C(O)=O.[Si]([O:15][CH2:16][CH2:17][N:18]1[C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]2[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=2[C:20](=[N:33]O)[C:19]1=[O:35])(C(C)(C)C)(C)C>ClCCl.CO.[Zn]>[NH2:33][C@H:20]1[C:21]2[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[N:25][C:24]=2[N:18]([CH2:17][CH2:16][OH:15])[C:19]1=[O:35]
Reactant: CC(C)(C)[Si](C)(C)OCCn1c(=O)c(=NO)c2ccccc2c2cccnc21
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: N[C@@H]1C(=O)N(CCO)c2ncccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.5 %

Procedure:
Add trifluoroacetic acid (124.0 mL, 1.64 mol) in several portions to a solution of 5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7-hydroxyimino-pyrido[2,3-d][3]benzazepin-6-one (155.0 g, 389.9 mmol) in a mixture of dichloromethane (620 mL) and methanol (310 mL) in an ambient temperature water bath. Add zinc (76.5 g, 1.2 mol) in several portions so that internal temperature was maintained at 33-38° C. Stir for 15 hours at ambient temperature. Filter mixture through Celite®, wash with 10% methanol/dichloromethane (100 mL) and concentrate the filtrate. Add dichloromethane (0.5 L) and ice (500 g), stir and basify with a 50% aqueous solution of NaOH. Filter out solids, separate filtrate layers. Extract from aqueous with dichloromethane (2×100 mL), and concentrate combined organics. Slurry solids in hexane, and then filter and dry under high vacuum to obtain the racemate of the title compound as a light yellow solid (74.0 g, 274.8 mmol, 71%). Purify the material on a Chiralpak® AD column eluting with ethanol (0.2% dimethethylamine): acetonitrile (0:100 to 100:0) to obtain the title compound (35.0 g, 130 mmol, 33.3%) as a white solid. MS (m/z): 270 (M+1); [α]Na25=+187.83° (c=6.9, methanol).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:32])[CH:10]2[NH:14][C:15](=[O:31])[CH:16]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][CH2:28][CH2:27][C:26]=3[CH:30]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]=1[C:33]([OH:35])=[O:34])(=[O:3])[CH3:2].[Na].[C:37]([O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45]O)=[CH:43][CH:42]=1)(=[O:39])[CH3:38].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:37]([O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][O:34][C:33]([C:7]2[N:8]3[CH:11]([S:12][CH2:13][C:6]=2[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:10]([NH:14][C:15](=[O:31])[CH:16]([C:22]2[CH:23]=[CH:24][C:25]4[O:29][CH2:28][CH2:27][C:26]=4[CH:30]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]3=[O:32])=[O:35])=[CH:43][CH:42]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Oc1ccc(CO)cc1
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CSC12)c1ccc2c(c1)CCO2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC(C)=O)cc3)=C(COC(C)=O)CSC12)c1ccc2c(c1)CCO2

Procedure:
To a suspension of 6 mmole of 3-[(acetyloxy)methyl]-7-[[3-ethoxy-1,3-dioxo-2-(2,3-dihydro-5-benzofuranyl)-propyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt in 40 ml of dimethylformamide (DMF) is added 2 equivalents of p-(acetyloxy)-benzyl alcohol. The mixture is cooled to 0° C. after which 6.8 mM of dicyclohexylcarbodiimide in 10 ml of DMF is added dropwise with stirring. The mixture is stirred at 0° C. for 1 hour and an addition 4 hours at room temperature. Dicyclohexylurea is removed by filtration. The filtrate is diluted with chloroform, washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo to give the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=3)[CH:13]=2)[CH:8]=1)(=O)=O.CN(C=O)C.[CH3:32][C:33]#[CH:34].Cl>C(N(CC)CC)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.[Cu](I)I>[F:24][C:19]1[CH:18]=[C:17]([C:12]2[CH:11]=[CH:10][C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:32]#[C:33][CH3:34])[CH:8]=3)[CH:13]=2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: C#CC
Reactant: O=S(=O)(Oc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1)C(F)(F)F
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC#Cc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1
Reaction time: 2 h

Procedure:
11.4 g of 6-(3,4-difluorophenyl)-2-naphthyl trifluoromethanesulfonate and 60 ml of DMF were dissolved in 20 ml of triethylamine. To the solution were then added 0.4 g of tetrakis(triphenylphosphine)palladium (0) and 0.1 g of copper iodide (I). Methyl acetylene was then introduced into the reaction mixture at ordinary temperature and pressure. The reaction mixture was then stirred for 2 hours. The reaction solution was neutralized with a 10% hydrochloric acid, extracted with 100 ml of toluene, and then washed with water and saturated brine. The solvent was then distilled off. The residue was then purified through silica gel column chromatography (hexane) to obtain 7.4 g of 2-(3,4-difluorophenyl)-6-(1-propinyl)naphthalene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([O:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:10]([C:29]#[N:30])=[N:9]2)=[C:4]([F:31])[CH:3]=1.[ClH:32].O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:32].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([O:15][CH:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[C:10]([C:29]#[N:30])=[N:9]2)=[C:4]([F:31])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Br)cc3F)nc2C#N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: N#Cc1nn(-c2ccc(Br)cc2F)c(=O)cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a stirring solution of tert-butyl 4-(1-(4-bromo-2-fluorophenyl)-3-cyano-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (493 mg, 1.0 mmol) in DCM (5 mL) at room temperature under argon was added 4 M HCl in dioxane (1.25 mL, 5.0 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (2 mL×2). After drying under vacuum for 2 hours, 334 mg (85%) of 1-(4-bromo-2-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt was obtained as an off-white solid. MS (ESI) 393 (M+H).
Reaction SMILES: OO.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([C:24]4[NH:28][C:27]5[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:26]=5[N:25]=4)[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][C:6]=1[NH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([O:41][C:42](=[O:44])[CH3:43])[CH2:37][CH2:36]1)#[N:4].CS(C)=[O:47].[OH-].[Na+]>C(O)C.O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([C:24]4[NH:28][C:27]5[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:26]=5[N:25]=4)[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][C:6]=1[NH:34][C@H:35]1[CH2:36][CH2:37][C@H:38]([O:41][C:42](=[O:44])[CH3:43])[CH2:39][CH2:40]1)(=[O:47])[NH2:4]
Reactant: CS(C)=O
Reactant: CC(=O)O[C@H]1CC[C@H](Nc2cc(-n3c4ccccc4c4c(-c5nc6ccc(F)cc6[nH]5)cccc43)ccc2C#N)CC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)O[C@H]1CC[C@H](Nc2cc(-n3c4ccccc4c4c(-c5nc6ccc(F)cc6[nH]5)cccc43)ccc2C(N)=O)CC1

Procedure:
In a 50 ml three-necked flask, 1.36 ml of 30% aqueous hydrogen peroxide are added to a mixture of 200 mg of acetic acid 4-{2-cyano-5-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]phenylamino}-trans-cyclohexyl ester, obtained in the preceding stage, in 7.5 ml of ethanol and 3 ml of dimethyl sulphoxide and 0.96 ml of 1M sodium hydroxide, and the mixture is stirred for ¼ hour at ambient temperature. 40 ml of distilled water are added and the mixture is extracted with 3 times 40 ml of ethyl acetate. The combined organic phases are washed with twice 40 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of dichloromethane and methanol (96/4 by volume). 170 mg of acetic acid 4-{2-carbamoyl-5-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]phenylamino}-trans-cyclohexyl ester are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]([Si:4]([C:11]#[CH:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Li]CCCC.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21].[NH4+].[Cl-]>C1COCC1>[F:18][C:19]([F:26])([F:25])[C:20](=[O:21])[C:12]#[C:11][Si:4]([CH:5]([CH3:6])[CH3:7])([CH:1]([CH3:3])[CH3:2])[CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C#CC(=O)C(F)(F)F)(C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
To a solution of (triisopropylsilyl)acetylene (6.50 mL, 29.0 mmol) in THF (80 mL) at −78° C. was added n-BuLi (2.5 M in hexane, 12.2 mL, 30.4 mmol) while maintaining the internal temperature below −70° C. After 30 min., ethyl trifluoroacetate (4.14 mL, 34.8 mmol) was added dropwise, keeping the internal temperature below −73° C. After 15 min. at −78° C., the mixture was allowed to reach 0° C. After 2 h, a saturated solution of NH4Cl was added. The aqueous layer was extracted with EtOAc (3×), and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated affording the title compound. 1H NMR (400 MHz, acetone-d6): 1.27 (m, 3H), 1.16 (d, 18H).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH2:27][C:28]#[C:29][Si](C)(C)C)[C:14]=2[CH3:34])=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[C:19]([C:17]1[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH2:27][C:28]#[CH:29])[C:14]([CH3:34])=[C:13]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:35])=[O:2])=[CH:10][CH:9]=2)[CH:18]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(CC#C[Si](C)(C)C)c2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#CCc1c(C)c(C#Cc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1OC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.9 %

Procedure:
A solution of {4-[5-tert-butyl-4-isopropoxy-2-methyl-3-(3-trimethylsilanyl-prop-2-ynyl)-phenylethynyl]-phenyl}-acetic acid methyl ester (Intermediate 149, 0.038 g, 0.078 mmol) in methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was treated with 2M lithium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1.5 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.032 g, 98%). 1H NMR (300 MHz, CDCl3): δ 7.50 (d, 2H, J=8.1 Hz), 7.43 (s, 1H), 7.27 (d, 2H, J=8.1 Hz), 4.82 (heptet, 1H, J=6.4 Hz), 3.67 (s, 2H), 3.48 (d, 2H, J=2.5 Hz), 2.58 (s, 3H), 1.39 (s, 9H), 1.28 (d, 6H, J=6.4 Hz).