Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[Cl:12][C:13]1[C:14]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:14]2[C:13]([Cl:12])=[CH:18][C:17]([Cl:19])=[CH:16][N:15]=2)=[N:22]1)=[O:11])[CH3:8]
Reactant: Cc1cc(Oc2ncc(Cl)cc2Cl)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ncc(Cl)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
Potassium carbonate (0.30 g, 2.2 mmol) and ethyl isocyanate (0.14 g, 2.0 mmol) were added to a solution of 3-(3,5-dichloropyridin-2-yloxy)-5-methylpyrazole (0.49 g, 2.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-ethyl-3-(3,5-dichloropyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.44 g, yield: 69.8%). mp: 74-76° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.23 (t, J=7.2 Hz, 3H), 2.64 (s, 3H), 3.39 (dq, J=5.8 and 7.2 Hz, 2H), 6.00 (s, 1H), 6.90-7.15 (m, 1H), 7.80 (d, J=2.3 Hz, 1H), 8.05 (d, 2.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17](O)[CH3:18].S(Cl)([Cl:22])=O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH:17]([Cl:22])[CH3:18])=[CH:5][CH:6]=[CH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: O=S(Cl)Cl
Reactant: COc1c(Sc2ccccc2F)cccc1C(C)O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1c(Sc2ccccc2F)cccc1C(C)Cl
Yield: 79.7 %

Procedure:
A mixture of 1-[2-methoxy-3-(2-fluorophenylthio)phenyl]ethanol (1 g), thionyl chloride (500 mg) and pyridine (2 drops) in benzene (30 ml) was refluxed under heating for 30 minutes. The reaction mixture was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with diethyl ether. The extract was washed with dil. hydrochloric acid, saturated aqueous sodium bicarbonate and water in turn, dried and then evaporated under reduced pressure to give oily 2-fluorophenyl 2-methoxy-3-(1-chloroethyl)phenyl thioether (850 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30]Cl.[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:30][CH2:29][CH2:28][O:27][C:26]4[CH:32]=[CH:33][CH:34]=[CH:35][C:25]=4[O:24][CH3:23])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: COc1ccccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C

Procedure:
A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2-benzisoxazole (2.45 g; 11.1 mmol), K2CO3 (2.0 g), and 3-(2-methoxyphenoxy)propyl chloride (3.5 g, 17.4 mmol) in acetonitrile (40 ml) was heated at 90° C. for 4 hours. At the end of the reaction, the solvent was removed, and the solids were dissolved into dichloromethane (100 ml). The solution was washed with water and brine, then dried over MgSO4. The crude material from the solution was combined with 1.2 g of crude prepared in the same fashion (using 0.5 g of starting material). The combined material was purified by flash chromatography on a silica gel column (49 g, eluted with 0.5% diethylamine: 1% methanol:98.5% dichloromethane, 1 L). The fractions containing the pure product were pooled and concentrated down to a light oil (3.68 g). This oil was treated with fumaric acid (1.14 g, 9.8 mmol) in ethanol (13 ml). The 6-fluoro-3-[1-[3-(2-methoxyphenoxy)-propyl]-4-piperidinyl]-1,2-benzisoxazole fumarate crystals obtained weighed 4.01 g (60%), m.p.=169-170° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O-:17].[Na+]>CO>[CH2:1]([C:8]1[N:9]=[C:10]([C:14](=[NH:15])[O:17][CH3:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: N#Cc1cccc(Cc2ccccc2)n1
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cccc(Cc2ccccc2)n1
Temperature: 20 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
2-Benzyl-6-cyanopyridine (0.84 g, 0.0043 moles) was added to a solution of sodium methoxide in methanol [prepared by dissolving sodium metal (0.11 g, 0.0047 gram atoms) in methanol (10 ml)] and the mixture stirred at 20° C. for 5 hours. The methanol was evaporated, the residue taken up in chloroform and the precipitate filtered off through a silica bed. Removal of the solvent from the filtrate gave methyl 6-benzyl-2-picoline imidate (0.81 g, 84%) which was used in the next stage without further purification.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:12]([CH:13]2OCC[O:14]2)=[C:11]([F:18])[C:10]([O:19][CH2:20][CH3:21])=[CH:9][CH:8]=1.[B:22](OC)([O:25]C)[O:23]C>C1COCC1>[CH2:20]([O:19][C:10]1[CH:9]=[CH:8][C:7]([B:22]([OH:25])[OH:23])=[C:12]([CH:13]=[O:14])[C:11]=1[F:18])[CH3:21]
Reactant: COB(OC)OC
Reactant: CCOc1ccc(Br)c(C2OCCO2)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(B(O)O)c(C=O)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
Under a nitrogen atmosphere, n-BuLi (43.3 mL, 71.42 mmol) was slowly added dropwise, at −70° C. or lower, to a THF (200 mL) solution of compound (54) (19.8 g, 68.02 mmol). The reaction mixture was agitated at −70° C. or lower for 1 hour, and then trimethyl borate (10.6 g, 102.0 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 200 mL of 2N hydrochloric acid aqueous solution, and extracted with 100 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was washed with heptane, and thus (4-ethoxy-3-fluoro-2-formylphenyl)boronic acid (55) (9.85 g, yield 68.3%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]C(O)=O)([CH3:4])([CH3:3])[CH3:2].C1C=CC(OP(OC2C=CC=CC=2)([N:36]=[N+]=[N-])=O)=CC=1>C(#N)C>[C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)O
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCN
Reaction time: 16 h
Yield: 31.5 %

Procedure:
Acetonitrile (10 mL) was added to octadecanedioic acid mono-tert-butyl ester (500 mg, 1.3 mmol) and TEA (0.226 mL, 1.6 mmol) was added. Diphenylphosphonic azide (0.37 g, 1.3 mmol) was added in a solution of acetonitrile (1 mL). The mixture was stirred at reflux for 2 h, and at RT for 16 h. The reaction was concentrated under vacuum, and suspended/dissolved in 1:2, AcOEt:heptane (2 mL) and applied to a dry bed of silica (2×4 cm dia). It was eluated with 1:2 AcOEt:heptane (2 mL) and 1:1 AcOEt:heptane (60 mL). The eluate was concentrated to dryness. The residue was partly suspended in THF (2 mL) and 1 N NaOH (2 mL) was added. The turbid solution/suspension was stirred for 1 h at RT. Water (15 mL) was added and this was extracted with AcOEt (2×25 mL), adding some brine to aid separation. The organic phase was washed with sat. NaCl, dried, filtered and conc. to dryness. To the residue was added 20% acetonitrile/water (15 mL), TFA (15-20 ul) and DMSO (1 mL). A filtration of the mixture failed, so the filter and the solution were extracted with DCM (2×60 mL). The organic extracts were concentrated to yield the crude product (0.14 g),
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1ccc(-c2cc([N+](=O)[O-])ccc2F)cc1

Procedure:
4-Bromobenzonitrile and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane were coupled using the procedure described in Example 7 part c) to afford 2′-fluoro-5′-nitrobiphenyl-4-carbonitrile as a brown solid: δH(400 MHz, CDCl3) 7.37 (1H, dd, J 9 and 9), 7.70 (2H, dd, J 8 and 1), 7.80 (1H, dd, J 8 and 1), 8.29-8.33 (1H, m), 8.37-8.40 (1H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[S:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH3:25])(=[O:28])=[O:27]
Reactant: CCCCCCCC(=O)NCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NCCCCCCOS(C)(=O)=O
Yield: 107.2 %

Procedure:
To a solution of 2.00 g (7.37 mmol) of N- (6-hydroxyhexyl)caprylamide and 1.23 ml of triethylamine in 50 ml of methylene chloride was added 0.68 ml (8.84 mmol) of methanesulfonyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 2.54 g of the desired compound (98.6%, colorless powder), mp: 62.0°-63.0° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:19].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][CH3:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: N#Cc1ccc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a magnetically stirred solution of 4-benzyloxy-2-hydroxybenzonitrile (1-A, WO 00/69841) (7.95 g, 35.3 mmol) and iodomethane (5.43 mL, 87.2 mmol) in DMF (90 mL) cooled to −5° was added all at once sodium hydride (60% dispersion, 2.17 g, 54.2 mmol). The mixture was stirred for 30 min, warmed to room temperature and stirred for an additional 2 h. Most of the DMF was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated brine and dried (MgSO4). The residue after removal of the solvent in vacuo was triturated with hexane and chromatographed on silica gel with hexanes —CH2Cl2 (2:3) to give 4-benzyloxy-2-methoxybenzonitrile (1-B). MS: m/z 240 (M+1); 1H NMR (500 MHz, CDCl3): δ 7.47 (d, 1H, J=8.4 Hz), 7.36-7.45 (m, 5H), 6.58 (dd, 1H, J=2.3, 8.4 Hz), 6.57 (d, 1H, J=2.3 Hz), 5.10 (s, 2H), 3.88 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:24][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: CC(c1ccc(-c2ccccc2Cl)cc1)S(=O)CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 19.9 gm (0.059 mol) of [1-(2'-chloro-4-biphenylyl)-ethylsulfinyl]-acetic acid and 12.5 gm (0.088 mol) of methyl iodide in 120 ml of dry dimethyl sulfoxide was admixed with 12.2 gm (0.088 mol) of dry potassium carbonate, and the mixture was stirred at room temperature for 19 hours. The crude reaction product was precipitated with water and extracted with ethyl acetate (yield: 23.1. gm). For purification, the obtained crude product was purified by chromatography on 1200 gm of silicagel with cyclohexane ethyl acetate = 1/1. The combined fractions with an Rf -value of 0.23 (on carrier 2) were combined and evaporated, leaving 6.2 gm (31.2% of theory) of the title compound; oil, Rf -value: 0.23 on carrier 1 with cyclohexane/ethyl acetate = 1/1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12]([C:14]2[N:18]([CH2:19][CH3:20])[C:17]3[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:16]=3[N:15]=2)=[O:13])=[C:4]([N:26]2[C:30](=[O:31])[C:29]3=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]3[C:27]2=[O:36])[CH:3]=1.[NH2:37][NH2:38]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:16]2[N:15]=[C:14]([S:12]([CH2:11][C:5]3[C:6]([CH3:10])=[C:7]([O:8][CH3:9])[C:2]([CH3:1])=[CH:3][C:4]=3[NH:26][C:27]([C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[C:30]([NH:37][NH2:38])=[O:31])=[O:36])=[O:13])[N:18]([CH2:19][CH3:20])[C:17]=2[CH:21]=1
Reactant: NN
Reactant: CCn1c(S(=O)Cc2c(N3C(=O)c4ccccc4C3=O)cc(C)c(OC)c2C)nc2ccc(Cl)cc21
Product: CCn1c(S(=O)Cc2c(NC(=O)c3ccccc3C(=O)NN)cc(C)c(OC)c2C)nc2ccc(Cl)cc21

Procedure:
The title compound of Example 122 (65 mg, 0.12 mmol) was treated with hydrazine according to the general procedure of Example 39 to give 48 mg (100%) of the partially deprotected amine title compound. 1H NMR (CDCl3) δ1.31 (t, 3H), 2.28 (s, 3H), 2.32 (s, 3H), 3.65 (s, 3H), 4.16 (s, 1H), 4.32 (m, 2H), 4.48 (q, 2H), 7.19 (s, 1H), 7.31 (m, 1H), 7.49 (s, 1H), 7.59 (m, 2H), 7.70 (m, 1H), 7.80 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][S:5][C:6]1[CH:11]=[N:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[Cl:23])(=[O:15])=[O:14])=[C:8]([O:24][CH3:25])[N:7]=1.[OH-].[Li+]>CO.O>[Cl:23][C:17]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[N:10]=[CH:11][C:6]([S:5][CH2:4][C:3]([OH:26])=[O:2])=[N:7][C:8]=1[O:24][CH3:25])(=[O:15])=[O:14]
Reactant: COC(=O)CSc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nc(SCC(=O)O)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]acetic acid methyl ester (Example 82) (0.1 g) and lithium hydroxide (0.04 g) in methanol (5 mL) and water (1 mL) was stirred at room temperature. After 2 h, the mixture was evaporated and saturated aqueous citric acid (5 mL) added. The white solid was collected, washed with water and dried. Yield 0.07 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[K+].[C:25]([C:27]1[N:28]=[C:29]([C:40]([O-])=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26]>CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:40]([C:29]3[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=3)=[O:41])=[C:13]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)[CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: COC(=O)C1(c2ccc(N)c(C3=CCCCC3)c2)CCOCC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CCOCC1
Yield: 78 %

Procedure:
The title compound was prepared by the coupling procedure of Example 1, step (f) using 4-(4-amino-3-cyclohex-1-enyl-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 250 mg, 0.793 mmol), and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 266 mg, 0.872 mmol). Silica gel chromatography (20% EtOAc-hexane) afforded the title compound (348 mg, 78%) as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C30H40N4O5Si, 565.3 (M+H). found 565.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: FC(F)(F)c1onc(-c2ccc(Cl)cc2)c1-c1c[nH]cn1
Product: N#Cc1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)cc1
Yield: 53 %

Procedure:
As described for Example 44, 3-(4-chloro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.32 mmol), using 4-fluorobenzonitrile instead of 4-fluoroacetophenone, was converted to the title compound (70 mg, 53%) which was obtained as a white solid. MS: m/e=415.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:42]1[CH2:47][CH2:46][CH:45]([C:48](O)=[O:49])[CH2:44][CH2:43]1)=O)(C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:42]1[CH2:47][CH2:46][CH:45]([C:48]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[N:17]=[C:16]([NH:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]5)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:49])[CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)C5CCNCC5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (126 mg, 0.278 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (79 mg, 0.347 mmol), PyBOP® (212 mg, 0.455 mmol) and DIEA (250 μL, 1.43 mmol) in CH2Cl2 (10 mL) was stirred at RT for 72 h. Reaction mixture was diluted with more CH2Cl2 (50 mL) and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacu. Crude product was purified by prep TLC to give the desired product tert-butyl 5-(2-(3-(piperidine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[C:19]([NH2:23])=[N:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]N1C(=O)CCC1=O>CN(C)C=O>[I:24][C:22]1[C:17]2[O:16][N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:18]=2[C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: Nc1nccc2onc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2onc(-c3ccc(Oc4ccccc4)cc3)c12
Yield: 64.7 %

Procedure:
3-(4-Phenoxyphenyl)isoxazolo[4,5-c]pyridin-4-amine (0. 11 g, 0.36 mmol) and N-iodosuccinimide (0.098 g, 0.43 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at ambient temperature for 30 minutes. The mixture was applied to a silica gel column and eluted with dichloromethane/ethyl acetate (8:2) to provide the title compound (100 mg): 1H NMR (DMSO-d6, 400 MHz) δ 8.26 (s, 1H), 7.71 (d, 2H), 7.46 (t, 2H), 7.15-7.25 (m, 5H), 6.45 (bs, 2H);
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[CH:26]2.CCOCC>COCCOCCOC>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:2]3[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=3[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:31][CH:30]=2)[CH:26]=[N:27]1
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: CCOC(=O)c1ccc(F)cc1Oc1ccc2[nH]ncc2c1

Procedure:
Ethyl 2,4-difluorobenzoate (1.14 g), K3PO4 (1.30 g) and 5-hydroxyindazole (0.90 g) were stirred at 110° C. in diglyme (12 mL) for 24 hours. The reaction was cooled and poured into ether. The solution was washed three times with 1M NaOH solution, and brine, and dried. The solution was then concentrated, and the crude product was chromatographed on silica gel with 20% ethyl acetate/hexanes.
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)/[CH:10]=[CH2:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:29][CH2:30][CH3:31])(=[O:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Si:5]([O:8][C:9]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:21]([C:20]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][CH:10]=1)([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:7])[CH3:6]
Reactant: CCOC(=O)/C=C/C(=O)OCC
Reactant: C=C/C(=C/c1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Product: CCOC(=O)C1CC=C(O[Si](C)(C)C(C)(C)C)C(c2ccc(F)cc2)C1C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 37 g (˜80% pure, 133.1 mmol, 1 equiv.) of 1E and 1Z-tert-butyl{[1-(4-fluorobenzylidene)prop-2-en-1-yl]oxy}dimethylsilane (intermediate step C) and 17 mL (18 g, 104.6 mmol) diethyl (2E)-but-2-enedioate in 200 mL xylenes under nitrogen atmosphere was heated at 160° C. for 5 hr then cooled to RT. The solvent was evaporated under vacuum to give an oil which was used without further purification.
Reaction SMILES: [OH:1][C:2]1([CH3:21])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:3]1=2.[OH-].[Na+]>C(O)C>[OH:1][C:2]1([CH3:21])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(C)(O)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(O)c2ccccc2COc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 450 mg. of methyl 11-hydroxy-11-methyl-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate in 20 ml. of ethanol and add 20 ml. of 5% aqueous sodium hydroxide solution. Stir at room temperature for 1 hour. Evaporate the alcohol and dilute the residual sodium salt solution with 40 ml of water. Cool in an ice bath and acidify with 5N hydrochloric acid. Separate the solids by filtration and dry (yield 250 mg). Recrystallize from benzene to obtain the title product (yield 200 mg., m.p. 258°-258° C.).