Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]1([N:31]2[C:35](Cl)=[N:34][N:33]=[N:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([C:35]4[N:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:32]=[N:33][N:34]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(-c2nnnn2-c2ccccc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 80 °C
Yield: 10 %

Procedure:
To a stirred solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, in 0.7 mL of DMF was added N-phenyl-5-chlorotetrazole (25 mg, 0.14 mmol) and 19 mg of K2CO3. The resulting red solution was heated at 80° C. for 4 days and, upon cooling to room temp, the mixture was diluted with 50 mL of ethyl acetate and 50 mL of 1N HCl. The layers were extracted, and the organic layer was washed with 50 mL of saturated aqueous NaCl. The organic layer was dried over MgSO4, filtered and evaporated to an orange solid. The material was purified via silica gel column chromatography followed by reverse phase HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(1-phenyl-1H-tetrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (7 mg, 10%) yield as a yellow solid. LCMS Anal. Calc'd for C24H14Cl2N8O, 500.07, [M+H] 501 observed; 1H NMR (400 MHz, CD3CN) δ 8.30 (s, 1H), 7.69-7.55 (m, 5H), 7.39 (dt, 2H, J=2.1, 6.6 Hz), 7.28 (dt, 2H, J=1.9, 8.6 Hz), 7.23 (dt, 2H, J=2.2, 8.6 Hz), 7.06 (dt, 2H, J=2.1, 8.7 Hz).
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][N:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]2[CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH2:6][CH2:5][CH2:4][CH2:3]1>C(O)(C)C>[O:17]1[CH2:16][CH2:15][CH:14]([C:12]2[N:11]=[C:10]([CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[N:9]([CH2:8][CH2:7][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:13]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCN2CCCC2)CC1
Agent: Cl
Solvent: CC(C)O
Product: c1c(C2CCOCC2)nc(C2CCNCC2)n1CCN1CCCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 107.2 %

Procedure:
Add aqueous 35% hydrochloric acid (23.20 mL, 4.7 eq) to a solution of tert-butyl 4-[1-(2-pyrrolidin-1-ylethyl)-4-tetrahydropyran-4-yl-imidazol-2-yl]piperidine-1-carboxylate (29.0 g, 60.33 mmol) in isopropyl alcohol (120 mL). Stir at 50° C. for six hours. Concentrate in vacuo. Add water (1 L) and 2 M aqueous sodium hydroxide to adjust the pH to 12. Extract with ethyl acetate (3×200 mL) and dichloromethane (3×200 mL). Dry the organics over anhydrous magnesium sulfate and concentrate in vacuo to give 4-(4-(tetrahydro-2H-pyran-4-yl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine (21.5 g, 100%). MS (ES) m/z=333 [M]+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1C=CC=C[CH:4]=1.C([C:15]1[CH:19]=[C:18]([CH:20]=[CH2:21])[S:17][C:16]=1C=C)CCCCC>ClC1C=CC=CC=1>[CH2:20]([C:18]1[S:17][CH:16]=[CH:15][CH:19]=1)[CH2:21][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1ccccc1
Reactant: C=Cc1cc(CCCCCC)c(C=C)s1
Solvent: Clc1ccccc1
Product: CCCCCCc1cccs1
Temperature: 124 °C
Reaction time: 16 h

Procedure:
A mixture of the polymeric macroinitiator, 6 (2.0 g, 0.30 mmol, Mw) 7200, PDI) 1.09), styrene (0.258 g, 2.48 mmol), and 5 (0.916 g, 4.15 mmol) was dissolved in chlorobenzene (2.9 mL), degassed by four freeze/pump/thaw cycles, and sealed under argon. The polymerization mixture was then stirred at 124° C. for 16 h and allowed to cool, and the star polymer, 16, was obtained after precipitation into methanol (3.1 g, 90%, Mw) 49400, PDI) 1.58). 1H NMR (CDCl3): δ (ppm) 6.32-7.2 (br m), 0.81-2.12 (br m).
Reaction SMILES: [C:1]([O:7][C:8]1([CH3:17])[CH2:13][CH2:12][CH:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]>CO>[OH:4][C@@H:3]([CH3:5])[CH2:2][C:1]([O:7][C:8]1([CH3:17])[CH2:9][CH2:10][CH:11]([CH:14]([CH3:15])[CH3:16])[CH2:12][CH2:13]1)=[O:6]
Reactant: CC(=O)CC(=O)OC1(C)CCC(C(C)C)CC1
Solvent: CO
Product: CC(C)C1CCC(C)(OC(=O)C[C@H](C)O)CC1
Yield: 98.4 %

Procedure:
144.2 g (0.60 mol) of 1-menthyl acetoacetate, 98.8 mg (12.0 μmol) of a catalyst [{RuCl((S)-SEGPHOS)}2(μ-Cl)3][NH2Me2] and 75 ml of methanol were put into a 500 ml capacity autoclave and allowed to undergo the reaction at 70° C. for 5.5 hours under a hydrogen pressure of 4 MPa. The thus obtained reaction solution was subjected to evaporation of the solvent and then distilled under a reduced pressure (121° C./170 Pa) to obtain 143.1 g (yield 98.4%) of the (3S)-1-menthyl 3-hydroxybutyrate of interest as a colorless oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[Cl:12][C:13]1[C:14]([O:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=2)=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH3:11][N:5]1[C:6](=[O:7])[CH:8]([C:28](=[O:29])[NH:27][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:14]3[C:13]([Cl:12])=[CH:18][C:17]([Cl:19])=[CH:16][N:15]=3)=[CH:26][CH:25]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: O=C=Nc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3ncc(Cl)cc3Cl)cc2)C(=O)N(C)C1=O
Reaction time: 18 h

Procedure:
7.8 g (0.05 mol) of 1,3-dimethylbarbituric acid and 14 g (0.05 mol) of 4-(3,5-dichloropyrid-2-yloxy)phenylisocyanate are suspended in 50 ml of xylene. 1 g of triethylamine is added dropwise to the suspension and the temperature rises to 45°-50° C. After further addition of 50 ml of xylene the mixture is stirred for 18 hours at this temperature. Then 1/3 of the xylene is distilled off. After cooling, the precipitate is isolated by filtration, washed with xylene, suspended several times in HCl and the suspension is thoroughly washed with water and dried, affording 1,3-dimethyl-5-[4-(3,5-dichloropyrid-2-yloxy)phenylcarbamoyl]barbituric acid of the formula ##STR25## with a melting point of 234°-235° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[C:22]3[C:17]([CH:18]=[C:19]([C:27]([O:29]CC)=[O:28])[N:20]=[CH:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([CH:24]3[CH2:25][CH2:26]3)=[C:22]3[C:17]([CH:18]=[C:19]([C:27]([OH:29])=[O:28])[N:20]=[CH:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C3CC3)c2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C(=O)O)ncc3c2C2CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a solution of compound ethyl 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-8-cyclopropyl-isoquinoline-3-carboxylate (425 mg, 1 mmol) in EtOH/THF (5 mL) was added NaOH (5 ml, 2 N) followed by stirring for 2 hrs at r.t. After extraction by EA, the residue was concentrated in vacuo to give 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-8-cyclopropylisoquinoline-3-carboxylic acid as a yellow solid (400 mg, yield: 95%).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=[O:2].[Br:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][N+:17]([CH3:26])=[CH:18]2.C([O-])([O-])=O.[Na+].[Na+].OO>C(Cl)Cl>[Br:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]([CH3:26])[C:18]2=[O:2]
Reactant: C[n+]1ccc2c(Br)ccc([N+](=O)[O-])c2c1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: Cn1ccc2c(Br)ccc([N+](=O)[O-])c2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a solution of 5-bromo-2-methyl-8-nitroisoquinolinium tosylate (20.0 g) in CH2Cl2 (400 mL) was added aq. Na2CO3 (5%, 400 mL) and hydrogen peroxide (30%, 20 mL). The resulting mixture was stirred at room temperature for 16 h, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (5×100 mL). The combined organic layer was washed with water (100 mL), dried over sodium sulfate and evaporated to give the crude product, which was purified by column chromatography on silica gel (EtOAc/CH2Cl2 (1:9)) to give 2.2 g of the desired product (yield: 8%). 1H NMR (CDCl3, 300 MHz): δ=3.60 (s, 3 H), 6.90 (d, J=7.8 Hz, 1 H), 7.28 (d, J=7.2 Hz, 1 H), 7.30 (d, J=7.2 Hz, 1 H), 7.92 (d, J=7.8 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11]C(C)(C)C)=[O:10])[C:6](=O)[CH2:5][CH:4]([CH3:8])[O:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:26][O:27][C:28]([CH2:30]P(OC)(OC)=O)=[O:29]>CO>[CH3:1][C:2]1([C:9]([OH:11])=[O:10])[CH:6]([CH2:30][C:28]([O:27][CH3:26])=[O:29])[CH2:5][CH:4]([CH3:8])[O:3]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC1CC(=O)C(C)(C(=O)OC(C)(C)C)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CO
Product: COC(=O)CC1CC(C)OC1(C)C(=O)O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
2,5-Dimethyl-3-oxo-2-tetrahydrofuroic acid, t-butyl ester (64 mg, from Reference Example 23, Step D) was dissolved in anhydrous methanol (1 mL) and cooled to −78° C. Potassium bis(trimethylsilyl)amide 0.66 mL) was added dropwise over 10 minutes. After being stirred at 78° C. for 15 minutes, trimethyl phosphonoacetate (65 mg, dissolved in 1.5 mL tetrahydrofuran) was added dropwise over 25 minutes. Upon completion of addition, the cold bath was removed and the mixture was allowed to stir at room temperature for 3 h when TLC (4/1 hexane/ethyl acetate) showed formation of a new spot. At 0° C., the reaction was quenched by addition of 1.5 mL of saturated aqueous ammonium chloride and the product was extracted with ethyl acetate twice, washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. The crude product obtained after filtration and removal of volatiles was flash chromatographed over silica get, using gradient elution (50-10/1 hexane/ethyl acetate) to give 31 mg of the desired compound, homogeneous by TLC (Rf=0.5 in 4/1 hexane/ethyl acetate). The NMR showed that all the diastereomers are present in this sample.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH2:15][CH2:16][CH2:17]Br.O>CO>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][C:7]=1[O:14][CH2:15][CH2:16][CH2:17][O:2][CH3:1]
Reactant: COc1ccc(C=O)cc1OCCCBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCOc1cc(CO)ccc1OC
Temperature: 25 °C

Procedure:
A 30% solution of sodium methanolate in methanol (0.86 liter, 4.64 mol) is added dropwise at 61°-64° C. to a solution of 4-methoxy-3-(3-bromopropoxy)-benzaldehyde (844 g) in methanol (4.15 liters). The batch is stirred under reflux for a further 1.5 hours, then allowed to cool to room temperature, and water (150 ml) is added. The methanol is removed in a rotary evaporator (30° C. bath temperature) and the residue is then partitioned between diethyl ether (3×3 liters) and ice-cold 4N hydrochloric acid. The combined organic phases are washed with water and saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. The residue is purified by FC on silica gel (ethyl acetate/hexane 1:3) and the title compound is obtained in the form of an oil (498 g): Rf (ethyl acetate/hexane 1:2)=0.18.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]#[N:17]>O.C(O)(=O)C>[C:16]([CH2:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([NH:5][C:2]([NH2:3])=[O:1])[CH:7]=2)[NH:11][CH:10]=1)#[N:17]
Reactant: N#C[O-]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CCc1c[nH]c2ccc(NC(N)=O)cc12
Yield: 16 %

Procedure:
A solution of sodium cyanate (1.2 g) in water (10 ml) was added to a stirred solution of 5-amino-1H-indole-3-aceto-nitrile (1.5 g) in glacial acetic acid (5 ml) and water (10 ml). Stirring was continued until a brown gum precipitated (10 min). The aqueous layer was then decanted off, and extracted with ethyl acetate (2×100 ml). The combined extracts were washed with sodium carbonate soln. (2N, 2×100 ml), dried (Na2SO4) and evaporated in vacuo to yield the crude urea as an off-white solid (0,3 g). The brown gum was purified by column chromatography (Kieselgel 60, 25 g) using ethyl acetate as eluant to yield more of the crude urea (0.1 g). The crude urea was then crystallised from isopropanol to yield the title compound as a fawn solid (0.3 g) m.p. 200°-204°.
Reaction SMILES: OS(O)(=O)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[N:7]1.[CH3:18]O>>[CH3:18][O:16][C:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][N:7]=1)=[O:17]
Reactant: CO
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ccccc12
Yield: 61 %

Procedure:
Concentrated H2SO4 (1 mL) was added to a solution of indazole-3-carboxylic acid (2.0 g, 12 mmol) in MeOH (40 mL). The reaction mixture was heated at reflux for 3 h, the MeOH was removed under reduced pressure and the residue was partitioned between diethyl ether (100 mL) and H2O (100 mL). Saturated sodium hydrogen carbonate solution was added (100 mL) and the diethyl ether layer was separated. The aqueous layer was further extracted with 2×200 mL of diethyl ether. The combined extracts were dried (MgSO4) and solvent removed under reduced pressure and the solid was recrystallised from cyclohexane/ethyl acetate to afford the title compound (1.29 g, 61%). Mp 158-159° C., lit 168-169° C. v.Auwers, Dereser Chem. Ber. 1919, 52, 1343. 1H-NMR (300 MHz, CDCl3) ppm 4.09 (s, 3H), 7.33-7.38 (m, 1H), 7.46-7.52 (m, 1H), 7.71-7.74 (m, 1H), 8.23-8.26 (m, 1H), 12.03 (s, 1H). MS(EI) m/z 176 [M+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:21]=[N:22][C:23]([C:26]3[C:27](C)=[N:28][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:30]=3)=[CH:24][CH:25]=2)=[CH:9][N:10](C)[CH:11](C2C=CC=CC=2)C)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:11][NH:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C(=CN(C)C(C)c2ccccc2)c2ccc(Cl)cc2)cn1
Agent: [Pd]
Solvent: CCO
Product: CNCC(c1ccccc1)c1ccc(-c2cn[nH]c2)nc1

Procedure:
To a solution of {2-(4-Chloro-phenyl)-2-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-vinyl}-methyl-(1-phenyl-ethyl)-amine in ethanol was added palladium, 10 wt. % on activated carbon and the reaction mixture was subjected to a hydrogen atmosphere for 17 hours. The mixture was filtered through Celite®, the mother liquor was concentrated, the residue was purified by column chromatography (SiO2), eluting with dichloromethane:methanol:acetic acid:water (240:20:3:2) to dichloromethane:methanol:acetic acid:water (90:18:3:2) to afford the title compound. LC/MS: (PS-A2) Rt 1.59 [M+H]+ 293.18. 1H NMR (Me-d3-OD) δ 2.35 (3H, s), 2.40 (3H, s), 3.25 (2H, s), 4.15-4.20 (1H, t), 7.10-7.18 (1H, m), 7.25 (4H, m), 7.45 (1H, d), 7.67 (1H, dd), 7.80 (1H, s), 8.38 (1H, s).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][O:11][C:10]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:15]>CO>[Si:1]([O:8][C@@H:9]([CH2:13][CH2:12][OH:11])[C:10]([NH2:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)[Si](C)(C)OC1CCOC1=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCO)C(N)=O
Reaction time: 48 h

Procedure:
To a solution of 3-(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (11 g, 49 mmol) in methanol was added 7 N ammonia in methanol (20 mL, 140 mmol). The reaction was stirred in a sealed tube for 2 days. The solvent was removed in vacuo to yield (S)-2-(tert-butyldimethylsilyloxy)-4-hydroxybutanamide (4.85 g, 20.8 mmol) as a white solid. [M+H] calc'd for C10H23NO3Si, 234. found, 234.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH3:12])[CH:5]=[CH:4][C:3]=1[C:13]1[C:14]2[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]=2[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH3:12])[CH:5]=[CH:4][C:3]=2[C:13]2[C:14]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]=3[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[CH:35][CH:34]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CNc1ccc(-c2cn(C)c(=O)c3c2ccn3COCC[Si](C)(C)C)c(F)c1[N+](=O)[O-]
Product: CNc1ccc(-c2cn(C)c(=O)c3c2ccn3COCC[Si](C)(C)C)c(Oc2ccc(Cl)cc2)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 1, Step 1, using 4-[2-fluoro-4-(methylamino)-3-nitrophenyl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one and p-chlorophenol as the starting materials. LCMS calculated for C27H32ClN4O5Si (M+H)+: m/z=555.2. found: 555.1.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:12])[NH:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using the procedure described in Example 103A, 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl]urea from Example 95B (0.45 g, 1 mmol) was reacted with tert-butyl 4-hydroxypiperidine-1-carboxylate (0.242 g, 1.2 mmol) in the presence of Ph3P (0.393 g, 1.5 mmol), and di t-butyl azodicarboxylate (0.345 g, 1.5 mmol) in THF (10 mL) at room temperature overnight, to afford tert-butyl 4-(4-{3-[3-(5-tert-butylisoxazol-3-yl)ureido]phenoxy}-6-methoxyquinazolin-7-yloxy)piperidine-1-carboxylate as a crude product. LC-MS (ESI) m/z 633 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[Cl:11])=[O:3].[CH3:12][C:13]([C:25]([N-:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[NH2:14].C(N(CC)CC)C>C1COCC1>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][C:13]([NH:14][C:2](=[O:3])[O:4][C@@H:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]2[Cl:11])([CH3:12])[C:25](=[O:26])[NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:17]1
Reactant: CC(N)(Cc1c[nH]c2ccccc12)C(=O)[N-]CCc1ccccc1
Reactant: O=C(Cl)O[C@@H]1CCCC[C@H]1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)O[C@@H]1CCCC[C@H]1Cl)C(=O)NCCc1ccccc1
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a stirred solution of trans(-)-2-chlorocyclohexyl chloroformate (0.16 g, 0.75 mmol ) in anhydrous THF (5 mL) at room temperature was added dropwise a solution of α-methyl-DL-tryptophylphenethylamide (0.23 g, 0.7 mmol) in THF (5 mL), followed by a solution of triethylamine (0.07 g, 0.7 mmol) in THF (5 mL). The reaction was complete after 30 minutes by thin layer chromatographic analysis. The solvent was removed in vacuo and the residue taken up in ethyl acetate (30 mL) and washed successively with 1M aqueous citric acid (2×20 mL), saturated NaHCO3 solution (2×20 mL), 1M NaOH solution (20 mL) and water (4×20 mL). The organic phase was dried over MgSO4 and filtered. Removal of the solvent by vacuum distillation gave the title compound (0.273 g, 81%), a white solid crystallized from ether-hexane, mp 69°-78° C. (ether-hexane); IR (film) 1709 and 1656 cm-1 ; NMR (CDCl3) δ1.2-1.4 (3H, m), 1.54 (3H, s), 1.6-1.8 (3H, m), 2.03-2.23 (2H, m), 2.63-2.69 (2H, m), 3.2-3.5 (4H, m), 3.72-3.79 (1H, m), 4.67-4.73 (1H, m), 5.23 (1H, br.s), 6.1-6.2 (1H, m), 7.0-7.6 (10H, m), 8.08 (1H, br.s); Anal. (C27H32N3O3Cl), C, H, Cl, N.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[CH:10]([CH2:14][CH2:15][CH3:16])[C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.[CH3:21]O>>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[CH:10]([CH2:14][CH2:15][CH3:16])[C:11]([O:13][CH3:21])=[O:12]
Reactant: CO
Reactant: CCCC(C(=O)O)c1c(C)[nH]c(=O)[nH]c1=O
Solvent: O=S(Cl)Cl
Product: CCCC(C(=O)OC)c1c(C)[nH]c(=O)[nH]c1=O
Yield: 77 %

Procedure:
To a cold (0° C.) solution of 2-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)pentanoic acid (4.24 g; 18.74 mmol) was added thionyl chloride (27.27 mL; 374.84 mmol) dropwise in methanol (70 mL). The mixture was refluxed for 48 h and then concentrated under reduced pressure to give 3.46 g (77%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11]I>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: CI
Reactant: O=Cc1ccc(O)c(Cl)c1
Product: COc1ccc(C=O)cc1Cl

Procedure:
Following a similar procedure to that described in reference example 3, but starting from 3-chloro-4-hydroxybenzaldehyde instead of 4-hydroxybenzaldehyde and using methyl iodide instead of 2-iodopropane, the title compound of the example was obtained as an oil (97% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]=[O:16].[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([F:18])[C:4]=1[CH:15]=[O:16]
Reactant: COc1cc(C=O)c(OC)c2ccccc12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COc1c(F)c(C=O)c(OC)c2ccccc12

Procedure:
Aldehyde 27 (0.517 g, 2.39 mmol) was added to a flame-dried 50 mL round bottom flask under Argon, followed by Selectfluor (1.25 g, 3.37 mmol) and MeCN (20.0 mL). The reaction was then heated to reflux for 8 hours before being cooled and extracted with EtOAc. The organic layer was washed 3 times with brine, dried over MgSO4, filtered, and condensed to provide the crude aldehyde as a yellow solid. Following flash chromatography (3:1 CH2Cl2:hexanes) aldehyde 51 (0.254 g, 1.08 mmol, 45%) was obtained as a yellow solid.