Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[C:10]([OH:20])(=[O:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH2:12].[C:21](O)([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)C.O>[C:13]1([C:11](=[CH2:12])[C:10]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=C(C(=O)O)c1ccccc1
Reactant: CC(C)(C)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C(C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
A stirred suspension of 2-chloro-1-methylpyridinium iodide (3.28 g, 12.8 mmol) in toluene (20 mL) was treated under an atmosphere of nitrogen with atropic acid (1.80 g, 12.2 mol) treated with tert-butanol (0.92 mL, 11.8 mmol), treated with triethylamine (3.6 mL, 25.8 mmol), heated under reflux for 2 hours, cooled to room temperature and treated with water (100 mL) and diethyl ether (100 mL). The layers were separated and the aqueous layer extracted with diethyl ether (50 mL). The organic phases were combined, washed with water (100 mL), dried (MgSO4), evaporated in vacuo, and the residue purified by chromatography [silica; hexane-ethyl acetate (20:1)] to give tert-butyl 2-phenylpropenoate (1.32 g) as an oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:22]=[N:23][NH:24][C:25]=3[F:26])[CH:16]=2)([CH3:14])[CH:10]([CH3:27])[CH2:9]1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:26][C:25]1[NH:24][N:23]=[N:22][C:21]=1[C:17]1[CH:16]=[C:15]([C:11]2([CH3:14])[CH2:12][CH2:13][N:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:9][CH:10]2[CH3:27])[CH:20]=[CH:19][CH:18]=1
Reactant: CCCCCC(=O)N1CCC(C)(c2cccc(-c3nn[nH]c3F)c2)C(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCN1CCC(C)(c2cccc(-c3nn[nH]c3F)c2)C(C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-hexanoyl-4-(3-(5-fluoro-1H-1,2,3-triazol-4-yl)phenyl)-3,4-dimethylpiperidine (Preparation 30, 20 mg, 0.054 mmol) in diethyl ether (0.8 mL) at 0° C. was added lithium aluminium hydride (1.0 M solution in tetrahydrofuran, 54 μL, 0.054 mmol) dropwise. The solution was then heated at reflux under a nitrogen atmosphere for 30 minutes before it was cooled back to 0° C. The reaction was cautiously quenched by the addition of 1 N sodium hydroxide (0.2 mL) and then ethyl acetate (3.0 mL) and solid sodium hydrogencarbonate were added. The mixture was stirred vigorously for 30 minutes and then filtered, washing with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate:hexane (2:1). The title compound was isolated as clear oil (8.0 mg, 40%).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[N:5]([CH2:15][C:16]2[C:17]([O:23][CH3:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:4]=1)[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:1]([C:3]1[C:11]2[C:10]([NH2:12])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]([CH2:15][C:16]2[C:17]([O:23][CH3:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(C)nc2OC)c2cccc([N+](=O)[O-])c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCc1nn(Cc2ccc(C)nc2OC)c2cccc(N)c12
Yield: 63.9 %

Procedure:
A mixture of 3-ethyl-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (186 mg, 0.57 mmol), iron powder (318 mg, 5.7 mmol) and NH4Cl (15.2 mg, 0.285 mmol) in EtOH/water (3 mL/0.75 mL) was heated to reflux for 60 minutes. The reaction mixture was filtered through GF/F paper and concentrated to a residue under reduced pressure. Preparative thin layer chromatography eluting with 2% MeOH 0.25% NH4OH in DCM provided the product (108 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH2:15]([O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][N:21]=1)=[O:19])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:15]([O:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:22][N:21]=1)=[O:19])[CH3:16]
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: CCOC(=O)c1ccc(O)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.9 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (870 mg, 4.6 mmol) in THF (30 mL) was added 5-hydroxy-pyridine-2-carboxylic acid ethyl ester (999 mg, 6.0 mmol) and triphenylphosphine (1.57 g, 6.0 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (2.74 mL, 40% solution in toluene, 6.0 mmol) was added and the reaction mixture was stirred for 24 h at room temperature. The reaction mixture was evaporated and then diluted with water (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated in vacuo. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 2:3) afforded the title compound (481 mg, 31%) as a light yellow solid after trituration with dichloromethane. MS: m/e=339.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([C:21]([O:23]C)=[O:22])[C:13]3[CH:14]=[CH:15][CH:16]=[N:17][C:18]=3[C:19]=2[OH:20])=[O:9])=[C:4]([S:27][CH3:28])[CH:3]=1.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([C:21]([OH:23])=[O:22])[C:13]3[CH:14]=[CH:15][CH:16]=[N:17][C:18]=3[C:19]=2[OH:20])=[O:9])=[C:4]([S:27][CH3:28])[CH:3]=1
Reactant: COC(=O)c1nc(C(=O)NCc2ccc(F)cc2SC)c(O)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CSc1cc(F)ccc1CNC(=O)c1nc(C(=O)O)c2cccnc2c1O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 7-({[4-fluoro-2-(methylthio)benzyl]amino}carbonyl)-8-hydroxy-1,6-naphthyridine-5-carboxylate (0.180 g, 0.448 mmol) in 4 mL of dioxane: methanol (3:1) was added 1.34 mL of a stock solution of 1 N NaOH (1.34 mmol). The reaction was stirred for 3 hours at 80 degrees C. The reaction was determined to be complete by LCMS analysis. The solvent was removed in vacuo and the residue partitioned between 5% HCl and methylene chloride. The organics were reduced to give desired compound as a solid.
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]([OH:8])[CH2:4][CH2:5][C:6]#[CH:7].C(N(CC)CC)C.O([Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])S(C(F)(F)F)(=O)=O.O>C(Cl)Cl>[C:27]([Si:24]([CH3:26])([CH3:25])[O:8][C@H:3]([CH:2]=[CH2:1])[CH2:4][CH2:5][C:6]#[CH:7])([CH3:30])([CH3:29])[CH3:28]
Reactant: C#CCC[C@H](O)C=C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C#CCC[C@@H](C=C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
The crude (S)-hept-1-en-6-yne-3-ol (3a) was dissolved in DCM and cooled to 0° C. Triethylamin (1.55 mL, 1.132 g, 11.182 mmol) and tert-Butyldimethylsilyl triflate (2.15 mL, 2.475 g, 9.362 mmol) were added and the solution was stirred for 1 hour at 0° C. before it was warmed to room temperature. After stirring for another hour water was added and the solution was extracted with DCM (3×). The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. Chromatography (pentane/ether 200/1) furnished 489 mg of compound (4a) as clear colourless oil with 58% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:16].[C:17]1(B(O)O)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[C:17]1([C:2]2[CH:7]=[C:6]([CH:8]3[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]3)[CH:5]=[CH:4][C:3]=2[NH2:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: Nc1ccc(C2CCS(=O)(=O)CC2)cc1Br
Reactant: OB(O)C1=CCCCC1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ccc(C2CCS(=O)(=O)CC2)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 2-bromo-4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-phenylamine (as prepared in the previous step, 150 mg, 0.493 mmol), cyclohexen-1-yl boronic acid (70 mg, 0.542 mmol) and Pd(PPh3)4 (57 mg, 0.0493 mmol) in 5 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (2.0 mL, 4.0 mmol). The resulting mixture was stirred at 80° C. for 8 h under Ar, and then cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×15 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-5% EtOAc/DCM) gave 130 mg (86%) of the title compound as a brown solid. 1H-NMR (CDCl3; 400 MHz): δ 6.89 (dd, 1H, J=8.4, 2.3 Hz), 6.84 (d, 1H, J=2.3 Hz), 6.65 (d, 1H, J=8.4 Hz), 5.74 (m, 1H), 3.74 (br s, 2H), 3.08-3.17 (m, 4H), 2.66 (dddd, 1H, J=12.1, 12.1, 3.1, 3.1 Hz), 2.29-2.42 (m, 2H), 2.13-2.25 (m, 6H), 1.73-1.81 (m, 2H), 1.65-1.73 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C17H23NO2S, 306.1 (M+H), found 306.1.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=[CH:16][C:17]2[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.CN1CCOCC1.ClC(OCC)=O.Br.[NH2:42][CH2:43][CH2:44][O:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[C:49]#[N:50]>O.CN(C)C=O.C(O)C>[C:49]([C:48]1[CH:47]=[C:46]([CH:53]=[CH:52][CH:51]=1)[O:45][CH2:44][CH2:43][NH:42][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([CH:16]=[C:13]2[CH2:12][CH2:11][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:15][CH2:14]2)=[CH:26][CH:25]=1)#[N:50]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: COC(=O)c1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Br
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(C(=O)NCCOc3cccc(C#N)c3)cc2)CC1
Reaction time: 18 h

Procedure:
6 ml of 1 N sodium hydroxide and 18 ml of ethanol were added to 331 mg (1.0 mmol) of methyl 4-[(1-t-butoxycarbonylpiperidine-4-ylidene)methyl]benzoate, and they were stirred for 18 hours. The reaction liquid was acidified with 1 N hydrochloric acid. After the extraction with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated. 5 ml of dimethylformamide, 0.22 ml (2.0 mmol) of N-methylmorpholine and 0.10 ml (1.0 mmol) of ethyl chloroformate were added to the residue under cooling with ice, and they were stirred for 30 minutes. 243 mg (1.0 mmol) of 3-(2-aminoethoxy)benzonitrile hydrobromide was added to the resultant mixture at that temperature. The temperature was elevated to room temperature, and they were stirred for one hour. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was successively washed with water, 1 N hydrochloric acid and saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:11]1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:11][CH2:12][CH:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:14][CH2:15]1
Reactant: CC(=O)NC1CCN(c2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC1CCN(c2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of N-[1-(2-nitro-phenyl)-piperidin-4-yl]-acetamide (as prepared in the previous step) (55 mg, 0.21 mmol) in methanol (10 mL) was added 10% palladium on carbon (50 mg) and the mixture stirred at RT for 1 h under hydrogen (1 atm). The mixture was filtered through a short column of Celite and the solvent removed in vacuo to yield 48 mg (100%) of the title compound as a purple solid. 1H-NMR (400 MHz, CDCl3): δ 6.82-6.67 (m, 4H), 4.44 (m, 1H), 3.78 (m, 1H), 3.35 (br s, 2H), 3.21 (m, 1H), 2.91 (m, 1H), 2.11 (s, 3H), 2.12-2.04 (m, 2H), 1.75 (br s, 1H), 1.41 (m, 2H). LC-MS (ESI, m/z): Calcd. for C13H20N3O, 234.2 (M+H); found: 234.0.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9](=[O:24])[CH2:10][C:11]1[C:12]([CH3:23])=[N:13][NH:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[Cl:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1.Cl>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:7][O:8][C:9](=[O:24])[CH2:10][C:11]1[C:12]([CH3:23])=[N:13][N:14]([C:29]2[CH:28]=[N:27][C:26]([Cl:25])=[N:31][CH:30]=2)[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: COC(=O)Cc1c(C)n[nH]c1-c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1c(C)nn(-c2cnc(Cl)nc2)c1-c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
0.515 g (3 mmol) of copper(II) acetate and 0.306 ml (4 mmol) of pyridine were added to 0.5 g (2 mmol) of methyl[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]acetate in 10 ml of dichloromethane. 0.598 g (4 mmol) of 2-chloropyrimidine-5-boronic acid was then added, and the mixture was stirred at 20° C. for 24 h. The mixture was then added to 1 M HCl and extracted with dichloromethane. The combined organic phases were dried with magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC. This gave 0.015 g of product (2% of theory).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=[O:5].[CH3:17][CH2:18][Mg+].[Br-].O>CCOCC>[O:10]1[C:9]2([CH2:8][CH2:7][CH:6]([C:4](=[O:5])[CH2:17][CH3:18])[CH2:15][CH2:14]2)[O:13][CH2:12][CH2:11]1
Reactant: CON(C)C(=O)C1CCC2(CC1)OCCO2
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: O
Product: CCC(=O)C1CCC2(CC1)OCCO2
Yield: 30.4 %

Procedure:
To a solution of N-methoxy-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide (1 g, 0.0043 mol) in anhydrous Et2O (20 mL) was added EtMgBr (9 g, 0.043 mol). The reaction mixture was refluxed overnight, and then 200 mL water was added. The mixture was extracted with ethyl acetate. The extract was concentrated and purified by silica gel column chromatography (CH2Cl2:MeOH=150:1) to give the desired product (0.259 g, 26% yield).
Reaction SMILES: NC1C=C[C:5]([CH3:12])=[C:6]([NH:8][C:9](=O)C)C=1.CC1(C)[C:40]2[C:35](=[C:36](P(C3C=CC=CC=3)C3C=CC=CC=3)[CH:37]=[CH:38][CH:39]=2)[O:34][C:16]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(N(C)C)=O>[CH3:16][O:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:9][NH:8][CH:6]2[CH2:5][CH2:12]2)=[CH:39][CH:40]=1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CC(=O)Nc1cc(N)ccc1C
Agent: [Cu]I
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNC2CC2)cc1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 496.5 %

Procedure:
DMA (1.5 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was degassed by bubbling argon through it for 10 minutes. 1G (0.15 g, 0.42 mmol), N-(5-amino-2-methylphenyl)acetamide (0.104 g, 0.636 mmol), copper(I) iodide (0.040 g, 0.212 mmol), xantphos (0.049 g, 0.085 mmol), and Pd2(dba)3 (0.039 g, 0.042 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was then heated to 125° C. for 45 min. and then cooled to room temperature. The solids were removed via filtration through CELITE®, washing with THF. The filtrate was then diluted with water and EtOAc. The layers were separated, and the aqueous phase extracted EtOAc (3×10 mL). The organics were combined, washed with water and brine, and dried over anhydrous sodium sulfate. Filtration and concentration afforded a tan solid, which was triturated in DCM and cooled to 0° C. The resulting precipitate was filtered and washed with cold DCM. The filtrate was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 0% EtOAc/DCM to 60% EtOAc/DCM, 24 g column, 30 mL/min, 20 min gradient, monitoring at 254 nm). The appropriate fractions were pooled and concentrated under reduced pressure. The material isolated from chromatography, and the solid were combined, suspended in DCM (3 mL) and treated with triethylsilane (0.68 mL, 4.24 mmol) and TFA (0.3 mL). After 30 minutes, the suspension was cooled in an ice bath and filtered. The solid was suspended in EtOAc (20 mL) and stirred with saturated aqueous sodium bicarbonate (15 mL). After 30 minutes, the solid was isolated via filtration, washed with water and EtOAc, and dried overnight in vacuo to afford Example 1 (0.154 g, 0.422 mmol, 100%) as a white solid. HPLC: Rt=3.496 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=362.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (1H, s), 9.21 (1H, s), 8.10 (1H, s), 7.81 (1H, s), 7.64 (2H, s), 7.11 (1H, d, J=8.03 Hz), 6.25 (1H, s), 2.52-2.55 (1H, m), 2.15 (3H, s), 2.06 (3H, s), 0.75-0.82 (2H, m), 0.61-0.68 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[CH2:10][O:11][C:12]1[CH:13]=[C:14]([F:21])[C:15]([C:18]([OH:20])=O)=[N:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:26]=1[OH:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O.CN(C=O)C>[OH:32][C:26]1[CH:27]=[C:28]([OH:31])[CH:29]=[CH:30][C:25]=1[NH:24][C:18]([C:15]1[N:16]=[CH:17][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:22])=[CH:13][C:14]=1[F:21])=[O:20]
Reactant: Nc1ccc(O)cc1O
Reactant: C[C@@H](COc1cnc(C(=O)O)c(F)c1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](COc1cnc(C(=O)Nc2ccc(O)cc2O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A mixture of 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-3-fluoropyridine-2-carboxylic acid (357 mg), 4-aminobenzene-1,3-diol hydrochloride (184 mg), HATU (432 mg), N,N-diisopropylethylamine (0.391 mL) and DMF (5 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (321 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:22][CH:23]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[CH2:24][N:25]([CH3:27])[CH3:26])C1C=CC=CC=1>Br>[Cl:34][C:30]1[CH:29]=[C:28]([CH:23]([NH:22][C:12]2[C:11]3[C:16](=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=[C:9]([OH:8])[CH:10]=3)[N:15]=[CH:14][N:13]=2)[CH2:24][N:25]([CH3:27])[CH3:26])[CH:33]=[CH:32][CH:31]=1
Reactant: CN(C)CC(Nc1ncnc2c(C(N)=O)cc(OCc3ccccc3)cc12)c1cccc(Cl)c1
Agent: Br
Product: CN(C)CC(Nc1ncnc2c(C(N)=O)cc(O)cc12)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
In a 20 mL scintillation vial 6-Benzyloxy-4-[1-(3-chloro-phenyl)-2-dimethylamino-ethylamino]-quinazoline-8-carboxylic acid amide was taken in 5 ml of aqueous HBr solution and stirred at room temperature for 2 h. Reaction was concentrated and dissolved in methanol and the crude was purified on preparative HPLC to give the product, (7.0 mg, 13% yield). LCMS (ESI) 386 (M+H)
Reaction SMILES: [CH:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[O:26])([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:15])[C:5]1=[O:35])=O.Cl.[NH2:37][OH:38].C([O-])(=O)C.[Na+]>CO.O>[OH:38][N:37]=[CH:1][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:24][C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[O:26])([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:15])[C:5]1=[O:35]
Reactant: NO
Reactant: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC=NO)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
In 1 ml of methanol was dissolved 0.050 g of (+)-1-formylmethyl-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one, and a solution of 0.021 g of hydroxylamine hydrochloride and 0.021 g of sodium acetate in 1 ml of water was added thereto. The resulting mixture was stirred at room temperature for 1 hour and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate=1/1) to give 0.045 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH:25](=O)[CH:26]([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:25]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:24]3)=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1)[CH:26]([CH3:28])[CH3:27]
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)CN1CC=C(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1
Reaction time: 8 h

Procedure:
In a 4 mL were mixed N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (50 mg, 0.157 mmol) and isobutyraldehyde (0.014 ml, 0.157 mmol) in anhydrous dichloroethane (2 ml) at room temperature. Sodium triacetoxyborohydride (46.4 mg, 0.219 mmol) was added, and reaction was stirred overnight. The reaction mixture was diluted with water, ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with brine. The organic layer was diluted with methanol, dried with sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35 (s, 1H), 7.53-7.55 (m, 2H), 7.30-7.38 (m, 6H), 6.06-6.08 (m, 1H), 4.77 (s, 4H), 3.01-3.03 (m, 2H), 2.57 (t, J=5.6 Hz, 2H), 2.41-2.47 (m, 2H), 2.14 (d, J=7.3 Hz, 2H), 1.77-1.88 (m, 1H), 0.88 (d, J=6.5 Hz, 6H); MS (ESI(−)) m/e 374 (M−H)−.