Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH:3]([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[CH3:17])([CH3:5])[CH3:4]>O1CCCC1.O>[CH:3]([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH3:17])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(OC(C)C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1OC(C)C
Temperature: 65 °C
Yield: 90.9 %

Procedure:
To methyl 4-hydroxy-3-methyl-benzoate (1.0 g, 59.8 mmol) in dry DMF (62 mL) was added finely ground potassium carbonate (33.1 g, 239.3 mmol) followed by 2-iodopropane (20.3 g, 12.0 mL, 119.6 mmol). The reaction mixture was heated at 60° C. for 2 hours. The reaction mixture was cooled and diluted with ether (350 mL), and filtered over celite. The filtrate was washed with water (3×100 mL) and brine (100 mL) solution. The layers were separated and organics were dried over MgSO4. The solvent was evaporated and resulting residue was purified by silica gel using 0-30% EtOAc/hexanes mixtures as eluent to give methyl 4-isopropoxy-3-methylbenzoate as a colorless oil (11.2 g, 89%). ESI-MS m/z calc. 208.25. Found 209.2 (M+1)+; Retention time: 1.93 minutes (3 min run). Lithium hydroxide (4.4 g, 181.6 mmol) was added to a solution of methyl 4-isopropoxy-3-methylbenzoate (11.2 g, 53.8 mmol) in tetrahydrofuran (31 mL) and water (31 mL). The mixture was rapidly stirred and heated at 65° C. for 6 hours. The reaction mixture was cooled, diluted with water (75 mL) and extracted with ether (2×50 mL). The aqueous layer was acidified to pH 2 with 6N aq. HCl and extracted with ethyl acetate (4×75 mL). The combined organics were washed with water (75 mL) and brine solution (75 mL) and layers were separated. The organics were dried over MgSO4 and concentrated in vacuo to give 4-isopropoxy-3-methyl-benzoic acid (9.5 g, 82%) as colorless crystals. ESI-MS m/z calc. 194.2. Found 195.3 (M+1)+; Retention time: 1.53 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.78-7.71 (m, 2H), 7.02 (d, J=8.6 Hz, 1H), 4.70 (dt, J=12.1, 6.0 Hz, 1H), 2.15 (s, 3H), 1.30 (d, J=6.0 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[C:25]=1[CH3:35])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:33])[C:25]=1[CH3:35])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid (100 mg, 0.19 mmol), DIPEA (45 mg, 1.9 eq.) and morpholine (82 mg, 5 eq.) in DMF (2 mL) was stirred at rt for 30 mins. To the mixture was added HATU (85 mg, 1.2 eq.) was added and stirring was continued for another 3 hours. The reaction was concentrated, diluted with DCM, washed with sat.NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][S:7][N:8]=[C:4]2[C:3]=1[NH:11][C:12]#[N:13].[Na].[CH2:15](Br)[CH:16]=[CH2:17]>C(O)C>[CH2:17]([N:11]([C:12]#[N:13])[C:3]1[C:4]2[C:5](=[N:6][S:7][N:8]=2)[CH:9]=[CH:10][C:2]=1[Cl:1])[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: N#CNc1c(Cl)ccc2nsnc12
Agent: [Na]
Solvent: CCO
Product: C=CCN(C#N)c1c(Cl)ccc2nsnc12
Reaction time: 3 h

Procedure:
The starting material is obtained as follows: 5 g 5-chloro-N-cyano-2,1,3-benzothiadiazol-4-amine are added to a solution of 0.55 g sodium in 60 ml ethanol and the mixture is reacted with 3 g allyl bromide. The mixture is agitated 3 hours under refluxing and the solvent evaporated under vacuum. The residue is extracted with methylene chloride. N-allyl-5-chloro-N-cyano-2,1,3-benzothiadiazol-4-amine (M.P. 62°-63°) is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1>C1(C)C=CC=CC=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[C:19]([F:18])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])[CH:7]=[CH:6][C:5]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(F)c1
Temperature: 85 °C

Procedure:
To a solution/suspension of the product from part (i) (0.55 g), 5-fluoro-2-methoxy-phenylboronic acid (0.3 g) in toluene (6 ml), ethanol (4 ml) and 2M Na2CO3 (3 ml) was added tetrakis(triphenylphosphine)palladium (0.05 g). The mixture was heated to 85° C. for 3 h, concentrated under reduced pressure to give a crude material. The residue was suspended in water, extracted with ethylacetate, washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification using flash column chromatography (eluent 10% diethylether/hexane) gave the subtitle compound, yield 0.39 g.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C[Al](C)C.[CH3:10][C:11]([C:24]1[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][N:25]=1)([CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:12]([O:14]CC)=O.C(=O)([O-])O.[Na+].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH3:2][O:3][N:4]([CH3:5])[C:12](=[O:14])[C:11]([CH3:10])([C:24]1[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][N:25]=1)[CH2:17][CH:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: CNOC
Reactant: CCOC(=O)C(C)(CC1CCOCC1)c1ccc(SC)cn1
Agent: C[Al](C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CON(C)C(=O)C(C)(CC1CCOCC1)c1ccc(SC)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.5 %

Procedure:
A solution of N-methoxymethanamine hydrochloride (1.00 g) in toluene (10 mL) was cooled to 0° C., and trimethylaluminum (1.4M hexane solution, 7.36 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 1.5 hr, and a solution (10 mL) of ethyl 2-methyl-2-[5-(methylsulfanyl)pyridin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoate (1.11 g) in toluene was added dropwise thereto. The reaction mixture was stirred at room temperature for 24 hr, saturated aqueous sodium hydrogen carbonate and saturated aqueous Rochelle salt solution were added and the mixture was stirred for 1 hr. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (401 mg, yield 35%) was obtained as white crystals from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]#[N:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:17][OH:18].[OH-].[K+]>C(O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14](=[N:17][OH:18])[NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(-c2ccc(C#N)o2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ccc(-c2ccc(C(N)=NO)o2)cc1
Reaction time: 8 h

Procedure:
A mixture of 13 g (0.060 mole) of 5-(p-methylthiophenyl)-2-furonitrile, 4.5 g (0.065 mole) of hydroxylamine hydrochloride, 4.2 g (0.065 mole) of KOH, and 160 ml of absolute ethanol was refluxed for 11/2 hours and then kept overnight at room temperature. The insoluble material was removed by filtration and discarded. The filtrate was added to ice/water and the resulting solid was dissolved in refluxing ethyl acetate, Darcoed, and filtered. The filtrate was heated to reflux and hexane was added to the cloud point. This mixture was cooled in an ice bath with the resulting solid being filtered and air dried to yield 10 g (67%). An analytical sample was prepared by drying a sample in the vacuum pistol at the temperature of refluxing CHCl3, m.p. 148°-150°.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[O-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)N5CCCC5)C4)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)C1)N1CCCC1
Reaction time: 0.03 h

Procedure:
A solution of N-((1R,3S)-3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide, 67f, (11.5 g, 19.3 mmol) in THF (150 mL) was added sodium methoxide (4.173 g, 19.31 mmol). After stirring the reaction mixture for 2 minutes, the mixture was poured into an aqueous saturated solution of NaHCO3. The organic phase was washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (10% MeOH/CH2Cl2) to afford 6.5 g of the desired product. The product was converted to an HCl salt by dissolving in MeOH (100 mL) and adding 2.4 mL of 12M HCl solution at room temperature. The solution was stirred at for 1 hour and the HCl salt precipitated out and filtered to provide 7.05 g of the HCl salt: 1H NMR (300 MHz, DMSO) δ 9.36 (s, 2H), 9.05 (d, J=3.0 Hz, 2H), 8.49 (d, J=5.6 Hz, 2H), 8.41 (dd, J=2.6, 1.4 Hz, 2H), 8.31 (d, J=9.5 Hz, 2H), 5.92 (s, 3H), 4.24 (s, 3H), 3.64 (s, 2H), 3.18 (t, J=6.6 Hz, 7H), 2.07 (dt, J=22.7, 11.5 Hz, 4H), 1.87 (t, J=12.6 Hz, 4H), 1.77 (dd, J=8.0, 5.3 Hz, 7H), 1.65-1.13 (m, 8H).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[F:55][C:56]([F:66])([F:65])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[OH:64].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:62]1[CH:61]=[CH:60][C:59]([OH:64])=[C:58]([CH2:57][C:56]([F:65])([F:66])[F:55])[CH:63]=1
Reactant: [Br-]
Reactant: Oc1ccccc1CC(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Br)cc1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 187.3 %

Procedure:
Tetrabutylammonium tribromide (6.56 g) was dissolved in chloroform (50 ml) and added dropwise to a solution of 2-(2,2,2-trifluoroethyl)phenol (2.4 g) in chloroform (50 ml). The reaction mixture was stirred at room temperature for 2 hrs, after which time 5% sodium thiosulfate solution (100 ml) was added and the resultant stirred for 30 mins. The mixture was then partitioned between dichloromethane (100 ml) and 1N HCl (200 ml). The organics were separated and dried over magnesium sulfate. The solvent was then removed in vacuuo, the crude residue was then purified by column chromatography on silica gel eluting with 90:10 hexanes:ethl acetate to afford the title compound as a yellow oil (3.24 g). 1H NMR (CDCl3): δ 3.50 (q, J=21.48 Hz 2H), 6.70 (d, J=2.54 Hz, 1H), 7.32 (d, J=2.54 Hz, 1H), 7.45 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:20][C:21]([CH3:27])=[CH:22][C:23]=1[C:24]([OH:26])=[O:25])=O>>[CH3:27][C:21]1[NH:20][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:23]([C:24]([OH:26])=[O:25])[CH:22]=1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1cc(C(=O)O)c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid to give the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:15]2[C:7](=[CH:8][C:9]3[C:14]2=[CH:13][C:12]([C:27]([F:30])([F:29])[F:28])=[CH:11][CH:10]=3)[C:6]=1[OH:31])=[O:4].[NH2:32][C@H:33]([C:35]([OH:37])=[O:36])[CH3:34].C[O-].[Na+]>COCCO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:16]2[N:15]3[C:7](=[CH:8][C:9]4[C:14]3=[CH:13][C:12]([C:27]([F:30])([F:28])[F:29])=[CH:11][CH:10]=4)[C:6]([OH:31])=[C:5]([C:3]([NH:32][C@@H:33]([CH3:34])[C:35]([OH:37])=[O:36])=[O:4])[C:17]2=[O:18])=[CH:25][CH:24]=1
Reactant: COC(=O)c1c(O)c2cc3ccc(C(F)(F)F)cc3n2n(Cc2ccc(F)cc2)c1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2cc3ccc(C(F)(F)F)cc3n2n(Cc2ccc(F)cc2)c1=O)C(=O)O
Yield: 30.1 %

Procedure:
A mixture of 4-(4-fluoro-benzyl)-1-hydroxy-3-oxo-6-trifluoromethyl-3,4-dihydro-4,4a-diaza-fluorene-2-carboxylic acid methyl ester (compound 43 d) (100 mg, 0.23 mmol), L-alanine (205 mg, 2.3 mmol) and sodium methoxide (99 mg, 1.84 mmol) in 2-methoxyethanol (3.5 mL) was microwaved at 150° C. for 2 h and concentrated. Residue was dissolved in water (80 mL), acidified to pH=3-4 using 1 N HCl solution and extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography (15%-70% EtOAc (with 0.075% HOAc)/hexanes (with 0.1% HOAc)) to provide the title compound 34 mg. ESI (m/z): 490.03 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+]([O-])=O)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+].[H-]>ClCCl.CN(C=O)C>[N+:1]([C:4]1[CH:12]=[C:11]([O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of 2,4-dinitrobenzoic acid [Aldrich] (1.06 g, 5 mmol) in dichloromethane (20 ml) was treated with oxalyl chloride (2 ml) and 1 drop DMF. Vigorous evolution of gas occurred which ceased after 1 hour. The solution was evaporated to the yellow acid chloride. A solution of phenol (1.5 g, 15.5 mmol) in DMF (20 ml) was introduced into a second flask charged with sodium hydride (480 mg, 60% oil dispersion, 12 mmol). When all the hydride had dissolved this solution was treated with the acid chloride, portionwise over five minutes. The solution was then heated to 60° C. for 12 h, cooled, the solvents removed by evaporation in vacuo, and the residue treated with a solution of 40% sodium hydroxide (50 ml) and ethanol (50 ml). The mixture was stirred at RT for 12 hours then acidified to pH 2 with (2M aq HCl) and extracted into ethyl acetate (3×100 ml). The combined organic phase was washed with saturated brine (50 ml), dried (MgSO4), filtered, and evaporated to a yellow solid. This was purified by flash chromatography (ethyl acetate-hexane) to give 2-nitro-4-phenoxy-benzoic acid (894 mg, 69%);
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31]([C:33]1[CH:34]=[N:35][NH:36][CH:37]=1)#[CH:32].C(N(CC)CC)C.CO>CN(C=O)C.C(OCC)(=O)C.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>[CH3:30][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:32]#[C:31][C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)[CH:3]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: C#Cc1cn[nH]c1
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(C#Cc5cn[nH]c5)c4)n3n2)cc(OC)c1OC
Temperature: 150 °C
Yield: 22 %

Procedure:
To a solution of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (27 mg, 0.05 mmol) in DMF (1.0 mL) was added 4-ethynyl-1H-pyrazole (6.9 mg, 0.07 mmol), bis(triphenylphosphine)-palladium (II) chloride (4.0 mg, 0.006 mmol), copper (I) iodide (2.0 mg, 0.01 mmol) and triethyl amine (0.06 mL, 0.43 mmol). In a sealed reaction vessel, the mixture was heated with microwave radiation at 150° C. for 20 minutes. After cooling to room temperature, removed solvent under reduced pressure to give an oily residue which was treated with methanol (5 mL) forming a suspension. Filtered solids and washed with ethyl acetate (10 mL) and DMF (1 mL). The combined filtrate was concentrated under reduced pressure and resulting brown oil was dissolved in ethyl acetate (50 mL), washed with 0.1N HCl (3×50 mL), saturated NaHCO3 aqueous solution (2×50 mL) and brine (1×50 mL). Dried over MgSO4, filtered and solvent removed under reduced pressure to give a light brown oil. Dissolved oil in hot ethyl acetate and silica gel (2.0 g) was added followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to isocratic elution using ethyl acetate:hexanes (50:50) followed by ethyl acetate:methanol (85:15) using a Biotage silica gel cartridge (8.0 g). The appropriate fractions were combined and concentrated under reduced pressure to give 5-methyl-7-[3-(1H-pyrazol-4-ylethynyl)phenyl]-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.0053 g) as a tan solid. MS m/z 482 (M+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]([O:33][C@H:34]5[CH2:38][CH2:37][NH:36][CH2:35]5)=[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].C(N(CC)C(C)C)(C)C.FC(F)(F)S(O[CH2:54][CH:55]([F:57])[F:56])(=O)=O>C(Cl)Cl>[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]([O:33][C@H:34]5[CH2:38][CH2:37][N:36]([CH2:54][CH:55]([F:57])[F:56])[CH2:35]5)=[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])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCNC1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(CC(F)F)C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a solution of (S)-1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy]phenyl}urea (0.198 g, 0.38 mmol) and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.128 g. 0.6 mmol) and it was stirred at 40° C. for 1 hour. It was quenched with saturated NaHCO3 and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with 70-85% EtOAc/hexane as eluants to afford (S)-1-(5-tert-Butylisoxazol-3-yl)-3-(3-{7-[1-(2,2-difluoroethyl)pyrrolidin-3-yloxy]-6-methoxyquinazolin-4-yloxy}phenyl)urea as solid (0.098 g, 44%). 1H NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 8.62 (s, 1H), 7.81 (s, 1H), 7.65 (t, 1H), 7.54 (s, 1H), 7.40 (t, 1H), 7.33 (m, 1H), 7.19 (s, 1H), 7.00 (d, 1H), 5.93 (tt, 1H), 5.87 (s, 1H), 5.05 (m, 1H), 4.03 (s, 3H), 3.20 (m, 1H), 3.89-3.09 (m, 4H), 2.8 (m, 1H), 2.5 (m, 1H), 2.15 (m, 1H), 1.33 (s, 9H); LC-MS (ESI) m/z 583 (M+1-1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6](O)[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3]1.[NH:13]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[N:15]=[CH:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[CH3:21][O:20][C:18]([C:16]1[N:15]([CH:6]2[C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[O:3][C:2]2([CH3:12])[CH3:1])[CH:14]=[N:13][CH:17]=1)=[O:19]
Reactant: CC1(C)Oc2ccccc2C1O
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2ccccc2OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2-dimethyl-2,3-dihydro-benzofuran-3-ol (375 mg, 2.28 mmol) in THF (20 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 432 mg, 3.42 mmol), followed by triphenylphosphine (896 mg, 3.42 mmol). The reaction is cooled to 0° C. and di-t-butyl azodicarboxylate (787 mg, 3.42 mmol) is added. The reaction is permitted to warm to room temperature and stirred for 2 hours. The reaction mixture is then cooled to 0° C. and quenched with 4 N HCl in dioxane (5 mL, 20 mmol) and stirred for 30 minutes. The reaction is concentrated to near dryness and diluted with ethyl acetate. The organic layer is extracted three times with 1 N aqueous HCl. The aqueous extracts are combined, neutralized with Na2CO3, and extracted three times with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:5) to furnish 3-(2,2-dimethyl-2,3-dihydro-benzofuran-3-yl)-3H-imidazole-4-carboxylic acid methyl ester; HRMS: (ESI) m/z 245.0934 [(M+H)+: Calcd for C13H13N2O3: 245.0926]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05 (s, 3H), 1.57 (s, 3 H), 3.92 (s, 3 H), 6.32 (s, 1 H), 6.92 (d, J=8.1 Hz, 1 H), 6.95-7.02 (m, 2 H), 7.25 (s, 1 H), 7.32-7.40 (m, 1 H), 7.80 (s, 1 H).
Reaction SMILES: Cl.[N:2]([O-:4])=O.[Na+].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14](=[O:23])[CH2:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCO>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14](=[O:23])[CH:15]([NH:2][OH:4])[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(=O)CC(=O)c1c(Cl)cccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C(NO)C(=O)c1c(Cl)cccc1Cl

Procedure:
Slowly bubble N2O3 gas (generated by the dropwise addition of concentrated HCl into an aqueous solution of sodium nitrite) into a stirred solution of ethyl 4-(2,6-dichlorophenyl)-2,4-dioxobutanoate (14.4 g, 50 mmol) in EtOH (300 mL) until the reaction is complete (as determined by TLC). Remove the EtOH by evaporation under reduced pressure and partition the residue between EtOAc and water. Dry the organic extract over MgSO4 and evaporate in vacuo to obtain the title compound which is used in the next step without further purification.