Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(OCC)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([O:37][CH3:38])=[O:36])[CH:7]=1
Reactant: COC(=O)c1cccc(-n2ncc3c(N)cc(C)cc32)c1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
2-{2-[5-Fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 96 mg, 0.33 mmol), methyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate (85 mg, 0.3 mmol) and ytterbium trifluoromethanesulfonate (28 mg, 0.045 mmol) were stirred in acetonitrile (0.4 mL) with some molecular sieves. The resulting mixture was then heated to reflux (80° C.) overnight and then allowed to cool to room temperature. The mixture was poured into ethyl acetate (5 mL) and washed successively with saturated aqueous sodium bicarbonate and aqueous brine. The organic phase was separated, dried over anhydrous sodium sulphate and then concentrated and the residue purified by silica gel column chromatography (10% ethyl acetate in cyclohexane) to give the title compound as a white solid (75 mg).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:28])[NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([F:26])[CH:17]=2)=[CH:9][C:8]=1[CH3:27])[CH2:2][CH3:3].C=O.[C:31]([BH3-])#N.[Na+].O>CO>[CH2:1]([O:4][C:5](=[O:28])[NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[C:18]([F:26])[CH:17]=2)[CH3:31])=[CH:9][C:8]=1[CH3:27])[CH2:2][CH3:3]
Reactant: CCCOC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)c(F)c2)cc1C
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCOC(=O)Nc1c(C)cc(N(C)Cc2ccc(C(F)(F)F)c(F)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
[4-(3-Fluoro-4-trifluoromethyl-benzylamino)-2,6-dimethyl-phenyl]-carbamic acid propyl ester (4f, 22 mg) and formaldehyde (0.1 mL) were refluxed in methanol (1 mL) for 3 hours. Sodium cyanoborohydride (35 mg) was added and the reaction mixture was stirred for 16 hours at 25° C., followed by addition of water (3 mL). The product was extracted with ethyl acetate (3×3 mL) and the combined organic phases were washed with brine (5 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was subjected to preparative LC-MS purification to furnish 9.7 mg (43% yield) of the title compound as a solid. LC-MS (m/z) 413 (MH+); tR=3.68, (UV, ELSD) 88%, 96%.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[S:21][C:22](Br)=[CH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].C(N(CC)CC)C.O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CCOCC>[Si:1]([O:18][CH2:19][C:20]1[S:21][C:22]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])=[CH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1ccc(Br)s1)(c1ccccc1)c1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)s1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottom flask was flame-dried under high vacuum. The vacuum was broken by the addition of dry argon, and the flask was allowed to cool to room temperature. The flask was charged with 2.16 g (5.0 μmmol) of (5-bromothiophen-2-yl)methyl tert-butyldiphenylsilyl ether (Compound 12), 2.12 mL (15 mmol) of (trimethylsilyl)acetylene, and 17.5 mL of triethylamine. The solution was purged with argon for 15 min and bis(triphenylphosphine)palladium (II) chloride (88 mg, 0.125 mmol) and copper (I) iodide (24 mg, 0.125 mmol) were added and the solution stirred at ambient temperature for 3 days. The solution was poured into a separatory funnel containing water and ether. The layers were separated and the aqueous layer was extracted 3 times with ether. The combined ether layers were washed once with brine, and dried over magnesium sulfate, and the solvents were removed under reduced pressure. The residue was purified by silica gel chromatography (hexane) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][C:11]([OH:13])=O)[CH:3]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][C:11]([Cl:17])=[O:13])[CH:3]=1
Reactant: Cc1ccc(Cl)cc1OCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1OCC(=O)Cl
Temperature: 45 °C

Procedure:
To a cold suspension of 4-chloro-o-tolyloxyacetic acid (17.4 mmol) in 40 mL of dry dichloromethane was added oxalyl chloride (39.15 mmol) followed by one drop of N,N-dimethylformamide. Bubbling began immediately. After 30 minutes the reaction mixture was warmed in a 45° C. oil bath for 1.5 hours. The solution was cooled to room temperature and all volatiles were removed by evaporation. Dry nitrogen gas was introduced into the evaporator and more dry dichloromethane was added. This was again evaporated in vacuo. Finally, dry toluene was added to the residue and this was evaporated at reduced pressure. The crude acid chloride was used without further purification in the following step.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][OH:15]>C(#N)C>[Cl-:12].[OH:15][CH2:14][CH2:13][N+:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1
Reactant: Cc1ccnc2ccccc12
Reactant: OCCCl
Solvent: CC#N
Product: Cc1cc[n+](CCO)c2ccccc12
Product: [Cl-]
Temperature: 120 °C
Yield: 63.1 %

Procedure:
A solution mixture of lepidine (0.8 g, 5.6 mmol) and 2-chloroethanol (2.25 g, 28 mmol) in acetonitrile (15 mL) was heated to 120° C. in a sealed tube overnight. After cooling to room temperature, the solvent was removed. The resulting mixture was precipitate from methanol and ethyl acetate to give the desired product 5 (0.79 g) in 63% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J=6 Hz, 1H), 8.61 (d, J=7.2 Hz, 1H), 8.55 (d, J=7.2 Hz, 1H), 8.25 (m, 1H), 8.06 (m, 2H), 5.15 (br, 1H), 5.08 (t, J=4.8 Hz, 2H), 3.91 (t, J=4.8 Hz, 2H), 3.01 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 158.8, 149.2, 137.1, 135.1, 129.7, 129.1, 127.2, 122.4, 119.5, 59.4, 59.0, 19.9. MS (FAB) m/z Calcd for C12H14NO+ 188.2 Found 188.2 [M]+.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][CH2:12][C:13]2([OH:16])[CH2:15][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([S:7]([O:10][CH2:11][CH2:12][C:13]2([O:16][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)[CH2:14][CH2:15]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: C1=COCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2(O)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCC2(OC3CCCCO3)CC2)cc1
Reaction time: 5 h

Procedure:
To a solution of 1-(2-p-toluenesulphonyloxyethyl)cyclopropanol (an intermediate in Preparation 2) (1.30 g) in dichloromethane (15 ml) at room temperature was added dihydropyran (0.88 g, 95%) and pyridinium p-toluenesulfonate (0.1 g). After 5 hours, the reaction solution was diluted with ether (70 ml) and extracted consecutively with water, 5% sodium hydrogen carbonate solution, and brine. After drying and removal of the solvent in vacuo, the product was purified by chromatography (50 g silica gel; 30% ether in petroleum ether as solvent) followed by recrystallisation from hexane to give the title compound as plates, m.p. 56°-57° C. (Found C, 59.99; H, 7.13; S 9.37. C17H24O5S requires C, 59.98; H, 7.11; S 9.42%), δ (100 MHz) 0.5 (2H, m), 0.85 (2H, m), 1.2-2.4 (8H, m), 3.1-3.9 (4H, m), 4.55 (1H, m), 7.6 (3H, m), 7.9 (2H, m).
Reaction SMILES: [CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]([C:8]1[C:12]([Cl:13])=[CH:11][NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].F[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=1[C:30]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1)=[O:31]>>[Cl:13][C:12]1[C:8]([C:6](=[O:7])[N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:10]([C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=2[C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[CH:11]=1
Reactant: CCCCN(CCCC)C(=O)c1n[nH]cc1Cl
Reactant: CCOC(=O)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)cc1Cl
Yield: 70.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, N,N-dibutyl-4-chloro-1H-pyrazole-3-carboxamide (100 mg, 0.39 mmol) and ethyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 1D, 140 mg, 0.43 mmol) were converted to the title compound (156 mg, 71%). 1H NMR (CDCl3, mixture of amide rotamers) δ 8.23-8.16 (m, 1H), 8.12-8.06 (m, 1H), 7.98-7.85 (m, 1H), 7.71-7.58 (m, 1H), 7.26-7.04 (m, 3.5H), 6.78 (d, J=7.5 Hz, 0.5H), 4.99-4.70 (m, 1H), 4.45-4.24 (m, 2.5H), 4.17-4.01 (m, 1H), 3.79-3.73 (m, 0.5H), 3.57-3.15 (m, 5H), 3.11-2.87 (m, 1H), 2.74 (t, J=5.8 Hz, 1H), 1.67-1.06 (m, 10.5H), 1.00-0.86 (m, 3.5H), 0.86-0.73 (m, 3H); MS(ESI+) m/z 565.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]([O:12][CH2:13][CH2:14]Cl)=[O:11].[F:16][C:17]([F:21])=[C:18]([F:20])[F:19]>COCCOCCOC.O>[O:9]([C:18]([F:20])([F:19])[C:17]([F:21])([F:16])[CH:10]1[O:12][CH2:13][CH2:14][O:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: FC(F)=C(F)F
Reactant: O=COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: FC(F)(Oc1ccccc1)C(F)(F)C1OCCO1
Reaction time: 8 h
Yield: 56.9 %

Procedure:
A suspension of 17.3 g (0.36 mol) of 50% NaH in mineral oil in 100 mL of diglyme was treated with a solution of 33.9 g (0.36 mol) of phenol in 50 mL of diglyme. The resulting mixture was stirred overnight and then charged into a 400 mL metal tube along with 38.6 g (0.36 mol) of 2-chloroethyl formate and 40 g (0.40 mol) of tetrafluoroethylene. The resulting mixture was agitated for 12 h, and then added to 1 L of cold water, thereby causing the formation of layers. The lower layer was washed with water, dried over CaSO4, and distilled to afford 54.5 g (57% yield) of 2-(2-phenoxytetrafluoro-ethyl)-1,3-dioxolane, b.p. 62°-65° at 8 Pa (0.06 mm). The IR (neat) and NMR (CCl4) spectra of the product were consistent with the assigned structure. Anal.: Calcd. for C11H10F4O3 :C, 49.63; H, 3.79l F, 28.55. Found: C, 49 90; H, 3.80; F, 28.91.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:17][N:18]([CH3:29])[C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][CH:20]=1.C(O)(=O)C>CCO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:25][CH:24]=[CH:23][C:22]3[CH:21]=[CH:20][C:19]([N:18]([CH3:29])[CH3:17])=[CH:28][CH:27]=3)[C:12]([CH3:16])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CN(C)c1ccc(C=CC=O)cc1
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=CC=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-(4-Carboxyphenyl)-3-methyl-2-pyrazolin-5-one (2.18 g, 0.010 mol), 4-dimethylamino-cinnamaldehyde (1.75 g, 0.010 mol) and glacial acetic acid (10 ml) were mixed together to form a slurry. It was heated to reflux with stirring, held at reflux for five minutes and then cooled to room temperature. EtOH (20 ml) was added to the reaction mixture, which was heated again to reflux, held there for five minutes, and cooled to room temperature. The product was isolated by filtration, washed in succession with ethanol and ligroin, and dried. The reaction was repeated twice on the same scale and the products obtained were all combined. They were treated further by first slurrying in refluxing EtOH (150 ml), isolating the solid by filtration while hot, and then slurrying in refluxing MeOH (200 ml) and isolating it again, while hot, by filtration. The mp was 282°-284° C. The NMR and IR spectra were consistent for the structure assigned. The C, H, and N elemental analyses were in agreement with those calculated for the empirical formula of the dye.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([CH3:12])=[CH:4][N:3]=1.[OH-].[NH4+:14]>>[NH2:1][C:2]1[C:7]([S:8]([NH2:14])(=[O:10])=[O:9])=[CH:6][C:5]([CH3:12])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Cc1cnc(N)c(S(=O)(=O)Cl)c1
Agent: [OH-]
Product: Cc1cnc(N)c(S(N)(=O)=O)c1

Procedure:
The product of Example 104A was reacted with concentrated ammonium hydroxide at ambient temperature overnight. The reaction mixture was concentrated to give the title compound as a light yellow solid in quantitative yield. MS (DCI/NH3) m/z 188 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 2.17 (m, 3H), 6.28 (s, 2H), 7.43 (s, 2H), 7.70 (d, J=1.84 Hz, 1H), 8.00 (d, J=2.21 Hz, 1H).
Reaction SMILES: [H][H].O=O.[OH:5][C:6]1[C:7](=[O:17])[C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.[CH2:18](Br)[CH:19]=[CH2:20]>>[CH2:20]([O:5][C:6]1[C:7](=[O:17])[C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:19]=[CH2:18]
Reactant: [H][H]
Reactant: C=CCBr
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: O=O
Product: C=CCOC1=CC(=O)c2ccccc2C1=O

Procedure:
The process shown in Scheme 2 can be used for the preparation of compounds in Formula II, III and IV when R7 is not hydrogen and X is oxygen from same starting material 1-1 as shown in Scheme 1. The reaction of 2-hydroxy-1,4-naphthoquinone 1-1 with the appropriate allylbromide gives 2-allyloxy-1,4-naphthoquinone 2-2. Rearrangement of 2-2 in ethanol afford 2-hydroxy-3-allyl-1,4-naphthoquinone 2-3, which can be cyclized by sulfuric acid treatment to form orthonaphthoquinone 2-4. Oxidation of 2-4 with n-bromosuccinimide and lead tetraacetate gives 3-acetoxy-orthonaphthoquinone 2-5. Hydrochloric acid treatment of compound 2-5 gives 2-alkyl (or aryl)-3-alkyl (or aryl)-naphtha[2,3-b]furan-4,9-dione 2-6.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]1C[O:15][CH2:14][CH2:13]1.[CH2:17]([C@@H:24]1[CH2:28][O:27][C:26](=[O:29])[NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)(=O)CC>C(OCC)(=O)C>[CH2:17]([C@@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:14](=[O:15])[CH2:13][CH3:12])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CCOC1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CCC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
1.57M n-butyllithium hexane solution (96 ml, 150 mmol) was slowly added dropwise to a THF (400 ml) solution of (R)-4-benzyl-2-oxazolidinone (25.36 g, 143 mmol) at −78° C. under stirring. Subsequently propionyl chloride (13.7 ml, 157 mmol) was added at once and the reaction solution was stirred at the same temperature for 30 minutes. After the reaction solution was warmed to room temperature for 30 minutes, it was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; heptane:ethyl acetate=5:1) to obtain the title compound (36.58 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[C:29]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:28]=[CH:27][C:26]=2[N+:37]([O-:39])=[O:38])[N:22]=[CH:21][N:20]=1>CN(C=O)C>[N+:37]([C:26]1[CH:27]=[CH:28][C:29]([N:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[CH:30][C:25]=1[C:23]1[CH:24]=[C:19]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:20]=[CH:21][N:22]=1)([O-:39])=[O:38]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Oc2cccc(C(F)(F)F)c2)ncn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 160 mg of 3-(trifluoromethyl)phenol in 2 mL of DMF was added 104 mg of potassium carbonate and 160 mg of intermediate 3.1b. After stirring overnight at 50° C. the reaction mixture was partitioned between water and ethyl acetate. The organic extracts were washed with brine and dried (Na2SO4). The solvent was evaporated to give a yellow syrup that was used directly in the next step.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]12[CH2:14][CH:13]1[C:12](=[O:15])[O:11][C:10]2=[O:16]>ClCCl>[C:1]1([NH:7][NH:8][C:12]([C@H:13]2[CH2:14][C@H:9]2[C:10]([OH:16])=[O:11])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: O=C1OC(=O)C2CC12
Solvent: ClCCl
Product: O=C(NNc1ccccc1)[C@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.2 g (11.1 mmol) of phenylhydrazine was dissolved in 20 ml of dichloromethane and 1.24 g (11.1 mmol) of 3-oxa-bicyclo[3.1.0]hexane-2,4-dione were added. The resulting solution was stirred at room temperature for 16 h. The precipitated product was isolated by filtration and washed with dichloromethane. Yield: 1.85 g.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:25]([F:31])=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>O1CCOCC1.C(#N)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([Cl:23])[C:25]=3[F:31])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OCc1ccccc1
Temperature: 80 °C
Yield: 95.7 %

Procedure:
4.0M HCl in Dioxane (4.0 ml) was added to a stirred suspension of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (60 g, 0.2 mol) [prepared as described in WO98/13354, Example 1] and 3-chloro-2-fluoroaniline (31.96 g, 0.22 mol) in acetonitrile (1200 mL). The reaction mixture was heated at 80° C. for 1 hour then left to stand O/N. Acetonitrile (500 mL) was added and the resulting precipitate filtered, washed with Acetonitrile (3×500 mL) and dried under vacuum to give 7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine hydrochloride 2 as a beige solid (85.45 g, 96%); 1H NMR Spectrum: (DMSO d6) 4.02 (s, 3H), 5.35 (s, 2H), 7.30-7.60 (m, 9H), 7.65 (m, 1H), 8.38 (s, 1H), 8.85 (s, 1H), 11.8 (s, 1H); Mass Spectrum: (M+H)+ 410.27.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:27][NH:28][C:29](=[O:45])[C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([NH:28][CH3:27])=[O:45])=[N:31][CH:32]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCOCC4)c23)cn1
Temperature: 85 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
2-Chloro-5-iodo-4-(tetrahydro-2H-pyran-4-yloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (1 equiv), 1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (0.1 equiv), sodium carbonate (3 equiv) were suspended in a 3:1 mixture of 1,4-dioxane and water (0.09 M) were combined in a sealed reaction vessel. The resulting solution was flushed with nitrogen and stirred at 85° C. for 2 h. After cooling to room temperature the reaction mixture was loaded directly onto a silica-gel column and purified using flash chromatography (0-55% ethyl acetate in hexane). Fractions were combined, concentrated and the residue dried under high vacuum to give the title compound (61% yield) as a brown semi solid. MS (ESI) m/z 519.1 [M+1]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:30]O.Cl>CO.O.C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:30][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](CCc2ccc(F)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CCc1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylate (730 mg, 1.92 mmol) (from example 92, step 1) was dissolved in MeOH (7 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (77 mg, 1.92 mmol) dissolved in water (0.700 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.118 mL, 1.92 mmol) was added. The resulting solution was stirred at −40° C. for 3 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (9.94 mL, 59.64 mmol) and the mixture was stirred at 80° C. for 20 min. DCM and water were added. The phases were separated, the aqueous phase extracted with DCM and the combined organic layers passed through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. DCM:MeOH:HCOOH=50:1:0.1 over 10 CV was used as mobile phase. Trans-methyl 2-(4-fluorophenethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (550 mg, 82%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.01-2.13 (m, 6H), 2.48-2.70 (m, 2H), 2.88-3.08 (m, 2H), 3.70 (s, 3H), 3.98-4.69 (m, 2H), 5.64 (s, 1H), 6.91-7.02 (m, 2H), 7.06-7.21 (m, 2H). MS m/z 349 (M+H)+