Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].[CH3:17][S:18]([NH:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[N:27]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]2=[O:41])(=[O:20])=[O:19]>CN(C=O)C>[O:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:21]([CH2:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[N:27]([CH2:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[C:26]3=[O:41])[S:18]([CH3:17])(=[O:19])=[O:20])[CH2:6][CH2:7]1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(CNS(C)(=O)=O)cc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(CN(CCN3CCOCC3)S(C)(=O)=O)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of 4-(2-chloroethyl)morpholine hydrochloride (0.195 g, 1.050 mmol), K2CO3 (0.242 g, 1.751 mmol) and tert-butyl 2-(5-(methylsulfonamidomethyl)-1,3-dioxoisoindolin-2-yl)acetate (0.258 g, 0.700 mmol), (prepared in an analogous manner as described in Example 46, Scheme 46, Steps 1, 2, 3, 4), was heated to 80° C. for 5 hours in DMF (10 ml) and then stirred at room temperature overnight. The insoluble inorganic salts were filtered off and then washed with ethyl acetate. The filtrate was concentrated to dryness, and the resulting crude was purified by filtration through a silica gel cartridge (100% DCM to DCM:MeOH=98:2) to afford tert-butyl 2-(5-((N-(2-morpholinoethyl)methylsulfonamido)methyl)-1,3-dioxoisoindolin-2-yl)acetate (0.200 g, 0.415 mmol, 59.3% yield, MS/ESI+ 482.1 [MH]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:14]([C:17]([F:18])([F:20])[F:19])[CH2:15][O:16][C:29]3=[O:31])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OCC(Nc1nc(-c2ccc(Br)cc2)cs1)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OCC(C(F)(F)F)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
2-{[4-(4-Bromophenyl)-1,3-thiazol-2-yl]amino}-3,3,3-trifluoropropan-1-ol (0.61 g, 1.6 mmol), prepared in the previous step, was dissolved in 48 mL methylene chloride. Triethylamine (2.2 mL, 16 mmol) was added and the solution was cooled to 0° C. Triphosgene (1.20 g, 4.15 mmol) was added in two portions and the mixture was stirred at 0° C. for 45 min and then at 25° C. for 2 h. The mixture was poured into 250 mL of saturated aqueous sodium bicarbonate and the layers were separated. The organics were washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (gradient 2% acetone/hexane to 10% acetone/hexane) afforded the title compound (0.47 g, 75%) as a white solid, mp 154-156° C. HRMS: calcd for C13H8BrF3N2O2S+H, 392.95202; found (ESI, [M+H]+), 392.9518. Analytical HPLC: retention time 10.6 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min 1.2 mL/min 5 μL injection.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])O[C:10](C)(C)[O:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:18][C:19]([CH3:31])([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH3:20]>C1(C)C(C)=CC=CC=1>[CH3:13][C:12]1[O:11][CH2:10][N:18]([C:19]([CH3:31])([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH3:20])[C:8](=[O:16])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Reactant: C=NC(C)(C)c1ccc2ccccc2c1
Solvent: Cc1ccccc1C
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccc3ccccc3c2)CO1
Yield: 37.6 %

Procedure:
A mixture of 5-phenyl-2,2,6-trimethyl-2H,4H-1,3-dioxin-4-one (0.65 g), N-methylene-1-methyl-1-(2-naphthyl)ethylamine (0.60 g) and xylene (3 ml) was heated at reflux for 20 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.40 g).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Br[C:7]1[S:8][C:9]([C:13]2[C:14]([CH3:28])=[N:15][N:16]3[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:20][C:19]([CH3:27])=[N:18][C:17]=23)=[C:10]([Br:12])[N:11]=1.ICCCC.[Cl-].N>C1COCC1>[Br:12][C:10]1[N:11]=[C:7]([CH2:1][CH2:2][CH2:3][CH3:4])[S:8][C:9]=1[C:13]1[C:14]([CH3:28])=[N:15][N:16]2[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:20][C:19]([CH3:27])=[N:18][C:17]=12
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)nc3Br)c(C)nn12
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Solvent: CCCCI
Solvent: C1CCOC1
Product: CCCCc1nc(Br)c(-c2c(C)nn3c(C(CC)CC)cc(C)nc23)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
Under a nitrogen atmosphere, add n-butyl lithium (2.5 M in hexane, 0.2 mL, 0.5 mmol) to a solution of 3-(2,4-dibromo-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (230 mg, 0.5 mmol) in THF (3 mL) at −78° C. After 30 min, add 1-iodobutane (138 mg, 0.75 mmol) and continue stirring for 1 hour. Warm up to room temperature and stir for one hour. Quench the reaction by adding saturated ammonia chloride solution and extract with ethyl acetate. Dry the organic portion over sodium sulfate, filter, and concentrate to a residue. Purify the crude material by flash chromatography, eluting with hexanes/ethyl acetate (10/1.5) to give the title compound as orange foam (78 mg). ES/MS m/z (81Br) 437.4 (M+1)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:13]([CH2:25][CH3:26])[N:12]=1.[OH-].[NH4+]>>[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[C:22]([N+:1]([O-:4])=[O:2])[CH:23]=2)=[C:13]([CH2:25][CH3:26])[N:12]=1
Reactant: O=[N+]([O-])O
Reactant: CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCc1nc(N)nc(N)c1-c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A stirred solution of 75 mL of 70% nitric acid and 75 mL of concentrated sulfuric acid warmed to about 50° C. from the heat of solution. To this was added 25 grams (0.10 mole) of 2,4-diamino-5-(4-chloro-phenyl)-6-ethylpyrimidine (commercially available) during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at 50° C. for about 1 hour. After this time, the reaction mixture was allowed to cool to ambient temperature where it was stirred for about 18 hours. The reaction mixture was then poured into 1000 mL of ice containing 110 mL of concentrated ammonium hydroxide. The resultant solid was collected by filtration and recrystallized from aqueous ethanol, yielding 29.2 grams of 2,4-diamino-5-(4-chloro-3-nitrophenyl)-6-ethylpyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](F)=[CH:13][C:12](Br)=[CH:11][C:10]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li:22])CCC.CCCCCC.COB(OC)OC>CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Li:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Fc1cc(Br)cc(F)c1OCc1ccccc1
Agent: COB(OC)OC
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]c1ccccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A stirred solution of 4-benzyloxy-3,5-difluoro-bromobenzene (9.87 g, 0.033 mole) in ether (100 ml) under an atmosphere of argon was cooled to less than 31 70° C. in a dry ice-acetone bath. To this solution was slowly added a solution of butyllithium in hexane (1.5M, 22 ml, 0.033 moles). Stirring was continued for 30 minutes after the addition was complete. In a separate apparatus, a stirred solution of trimethylborate (3.1 g, 0.033 mole) in ether (50 ml) under an atmosphere of argon was cooled to less than -70° C. The freshly prepared benzyloxyphenyllithium formed in the first reaction solution was slowly transferred to the trimethylborate/ether solution by way of a double-tipped stainless steel needle. The addition was at such a rate that the reaction temperature was maintained at less than -66° C. After the addition was complete, the temperature was allowed to rise to room temperature. At this point, 10 percent hydrochloric acid (25 ml) was carefully added. After stirring an additional 15 minutes, the aqueous phase was separated and discarded. The organic phase was treated with 10 percent hydrogen peroxide (20 ml) and the resulting mixture stirred and heated at reflux for 24 hours. After cooling, the aqueous phase was separated and discarded. The organic layer was washed with 10 percent ferrous ammonium sulfate (25 ml), then with water (50 ml). After drying (MgSO4), the ether was evaporated to yield a brown oil (7.1 g, 91 percent) which solidified upon standing. G.C. showed that this material was approximately 92 percent pure. The proton and fluorine NMR spectra were consistent with the desired structure. Recrystallization of this material from hexane/ether gave a partially purified sample: m.p.=42°-44° C. It was used without additional purification.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=2)[N:4]([CH3:13])[N:3]=1.[C:14]([O:18][C:19](=[O:37])[NH:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:22]=1[F:36])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19](=[O:37])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[C:5](=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=3)[N:4]([CH3:13])[N:3]=2)=[CH:23][C:22]=1[F:36])([CH3:17])([CH3:15])[CH3:16]
Reactant: CSc1ncc2c(Br)nn(C)c2n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: CSc1ncc2c(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)nn(C)c2n1

Procedure:
Following the procedure of Example 15, 3-Bromo-1-methyl-6-methylsulfanyl-1H -pyrazolo[3,4-d]pyrimidine and [2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert-butyl ester gave the title compound as an off white solid; LC/MS(m/e) at 390.2 (MH+), Rt=2.56 min.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])#[C:9][C:10]([O-])=[O:11]>C(O)C>[CH2:16]([O:15][C:13]([C:8]1[CH:9]=[C:10]([OH:11])[N:6]2[C:5]([CH3:7])=[N:4][N:3]=[C:2]2[N:1]=1)=[O:14])[CH3:17]
Reactant: Cc1nc(N)n[nH]1
Reactant: CCOC(=O)C#CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)c1cc(O)n2c(C)nnc2n1
Reaction time: 1 h
Yield: 32.4 %

Procedure:
A suspension of 14.7 g of 3-amino-5-methyl-s-triazole and 26.8 g of ethyl acetylenedicarboxylate in 120 ml of ethanol was refluxed for three hours, the reaction mixture was allowed to stand at room temperature for one hour, and the formed crystals were collected by filtration. The filtrate was concentrated and the residue was recrystallized from dichloromethane, and the crystals were joined with those obtained above. Purification by silica gel chromatography gave 10.8 g of the objective compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:17]([O:19]CC)=O)=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.O.[NH2:23][NH2:24]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:17]([NH:23][NH2:24])=[O:19])=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cc(O)ccc1-c1cc(OC)ccc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(F)c(-c2ccc(O)cc2C(=O)NN)c1
Temperature: 95 °C
Reaction time: 46 h

Procedure:
To a solution of ethyl 2′-fluoro-4-hydroxy-5′-methoxy-[1,1′-biphenyl]-2-carboxylate (1.37 g) in ethanol (15 mL) was added hydrazine monohydrate (4.47 mL), and the mixture was stirred at 95° C. for 46 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane and then methanol/ethyl acetate) to give the title compound (1.05 g) as a white amorphous solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(CCNS(C)(=O)=O)CC1
Reaction time: 12 h
Yield: 39.3 %

Procedure:
Methanesulfonyl chloride (0.7 mL, 9.0 mmol) was added to a cooled solution of 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.33 g, 5.8 mmol) in pyridine (25.0 mL). The reaction was stirred for 12 h and partitioned between partitioned between aqueous sodium bicarbonate and methylene chloride. The organic phase was washed with 1 M hydrochloric acid, aqueous sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by chromatography over silica gel using 0-5% methanol in methylene chloride gave 4-(2-methanesulfonylamino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.70 g, 70%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:9][S:10][CH:11]=1)(=O)=O.[F:19][C:20]1[C:25]([F:26])=[C:24](O)[CH:23]=[CH:22][C:21]=1[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:7]([CH2:6][O:5][C:24]3[CH:23]=[CH:22][C:21]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:20]([F:19])[C:25]=3[F:26])=[CH:11][S:10][N:9]=2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Cl)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Product: O=C(O)CCc1ccc(OCc2csnc2-c2ccc(Cl)cc2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(4-chlorophenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 2H), 7.66 (d, J=7.0 Hz, 2H), 7.43 (d, J=7.5 Hz, 2H), 6.84 (m, J=8.1 Hz, 1H), 6.64 (m, J=7.2 Hz, 1H), 2.95 (m, 2H), 2.68 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C@H:3]([OH:6])[CH2:4][OH:5].N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[OH:6][C@@H:3]([C:2]([CH3:8])([CH3:7])[CH3:1])[CH2:4][O:5][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CC(C)(C)[C@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a solution of (2S)-3,3-dimethyl-butane-1,2-diol (3.1 g, 26.3 mmol) in dichloromethane (25 ml) is added pyridine (4.3 ml, 52.6 mmol). To the mixture is then added dropwise a solution of 4-toluenesulfonyl chloride (5.0 g, 26.3 mmol) in dichloromethane (25 ml) at 0° C. The reaction mixture is warmed to room temperature and stirred for additional 16 h. The reaction mixture is diluted with dichloromethane (50 ml) and washed with 10% copper(II) sulfate solution (2×30 ml). The organic layer is dried over sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 5% ethyl acetate/hexane) affording 4-methyl-benzenesulfonic acid [(2S)-2-hydroxy-3,3-dimethyl-butyl]ester (4.2 g, 14.4 mmol, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCN(C(C)C)C(C)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(C(F)(F)F)cc1Br

Procedure:
A solution of 2.650 g (11.000 mmol) 2-bromo-4-trifluoromethyl-phenol and 1.47 mL 13.20 mmol) ethyl bromo-acetate in 20 mL Hünig base was stirred for 5 h at 120° C. The reaction mixture was diluted with EtOAc and the org. phase was washed with water, saturated aqueous sodium bicarbonate and saturated aqueous NaCl, dried over magnesium sulphate and evaporated down i. vac. Column chromatography (silica gel, gradient dichloromethane/MeOH 100:0→19:1) yielded the product.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC([O-])(C)C.[K+].[C:36]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C@H:46]2[CH2:51][CH2:50][C@H:49]([C@H:52]3[CH2:57][CH2:56][C@H:55]([CH:58]=O)[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)=[CH:40][CH:39]=1)#[N:37]>C(OCC)(=O)C>[F:2][CH2:3][CH2:4][CH:5]=[CH:58][C@H:55]1[CH2:56][CH2:57][C@H:52]([C@H:49]2[CH2:50][CH2:51][C@H:46]([CH2:45][CH2:44][C:41]3[CH:42]=[CH:43][C:38]([C:36]#[N:37])=[CH:39][CH:40]=3)[CH2:47][CH2:48]2)[CH2:53][CH2:54]1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(CC[C@H]2CC[C@H]([C@H]3CC[C@H](C=O)CC3)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(CC[C@H]2CC[C@H]([C@H]3CC[C@H](C=CCCF)CC3)CC2)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (15.1 g, 37.4 millimols) with THF (70 ml) was cooled down to -20° C., followed by adding t-BuOK (4.2 g, 37.4 millimols) to the mixture, stirring for one hour, dropwise adding to the mixture, a THF (100 ml) solution of trans-4-(trans-4-(2-(4-cyanophenyl)ethyl)cyclohexyl)cyclohexanecarbaldehyde (11.0 g, 34.0 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 2, except that the quantity of ethyl acetate was made 500 ml, to obtain raw 4-(2-(trans-4-(trans-4-(4-fluorobutenyl)cyclohexyl)cyclohexyl)ethyl)benzonitrile (11.3 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH:10]=[CH:9]1>>[C:8]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12]
Reactant: O=C1C=CC(=O)O1
Reactant: Oc1ccccc1
Product: O=C(O)/C=C\C(=O)Oc1ccccc1

Procedure:
A thermosetting resin was prepared as in Example 1. Phenyl hydrogen maleate was prepared by reacting excess phenol with maleic anhydride and was added to the above resin.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[C:11]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])=[C:10]([F:25])[CH:9]=[C:8]([Cl:26])[C:6]=2[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33]([SH:35])[CH3:34].O>CN(C)C=O>[Cl:26][C:8]1[C:6]2[CH:7]=[C:3]([CH2:2][S:35][CH2:33][CH3:34])[O:4][C:5]=2[C:11]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:10]([F:25])[CH:9]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(CBr)oc23)c1=O
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
1.5 g (3.3 mmol) of 3-(2-bromomethyl-4-chloro-6-fluorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 0.7 g (5.1 mmol) of potassium carbonate were suspended in 20 ml of N,N-dimethylformamide, and 0.21 g (3.4 mmol) of ethylmercaptan was added thereto at room temperature, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.2 g (yield: 83.4%) of the desired product as a yellowish brown glassy substance. Refractive index: 1.5629 (20° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([OH:12])=[CH:7]2.[H-].[Na+].I[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[NH:22][N:23]=[CH:24][C:17]=12>CN(C=O)C>[NH:22]1[C:18]2=[N:19][CH:20]=[CH:21][C:16]([O:12][C:6]3[CH:7]=[C:8]4[C:3](=[CH:4][CH:5]=3)[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9]4)=[C:17]2[CH:24]=[N:23]1
Reactant: Nc1cccc2cc(O)ccc12
Reactant: Ic1ccnc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc2cc(Oc3ccnc4[nH]ncc34)ccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-Aminonaphthalen-2-ol (356 mg, 2.24 mmol) was dissolved in DMF (2.5 mL) then cooled to 0° C. Sodium hydride (94 mg) was added slowly and the stirring was continued for 15 min at 0° C. 4-Iodo-1H-pyrazolo[3,4-b]pyridine (274 mg, 1.12 mmol) was then added slowly and the reaction was heated at 100° C. for 16 h, followed by 4.5 h at 120° C. The mixture was partitioned between water and EtOAc then washed with water, 1N aqueous NaOH, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 6-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)naphthalen-1-amine as a brown solid MS (ESI, pos. ion) m/z: 277.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[NH:5][CH:6]=[N:7]2.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:25]>C1(C)C=CC=CC=1>[Cl:25][C:4]1[C:3]2[C:8](=[CH:9][C:10]([I:12])=[CH:11][C:2]=2[Cl:1])[N:7]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(I)cc(Cl)c12
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(I)cc2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.4 g (1.27 mmol) 5-chloro-7-iodo-3H-quinazolin-4-one, 0.5 ml (3.18 mmol) DIPEA and toluene, 0.3 ml (2.8 mmol) POCl3 is added dropwise and stirred at RT for 1 h, the heated to 90° C. for 1.5 h. After cooling to RT the solvent is evaporated giving rise to crude 4,5-dichloro-7-iodo-quinazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Cl)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Cl)c1
Yield: 47 %

Procedure:
A solution of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (156.2 mg, 0.43 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 5 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 69.7 mg (47%) of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.45 (m, 2H), 7.3 (m, 3H), 7.2 (s, 1H), 7.1 (d, 1H, J=8 Hz), 6.95 (s, 1H), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). IR (CHCl3, cm−1) 3433, 3202 (br), 1630, 1600, 1580, 1564, 1433, 1330, 1261, and 776. MS (ES) m/e 349, 351, 353.