Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH3:18])[CH3:2].C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH2:18][Br:27])[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccccn2)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(Oc2ccccn2)cc1CBr
Yield: 123.7 %

Procedure:
A mixture of 2-methyl-4-(pyridin-2-yloxy)-benzoic acid ethyl ester (529 mg), NBS (440 mg), and BzOOBz (25 mg) in CCl4 (10 mL) was refluxed for 6 h; then cooled, solids were filtered off, filtrate was concentrated to give crude product (855 mg). 1H NMR in CDCl3, δ in ppm: 8.2-7.6 (m, 4H), 7.1-6.95 (m, 3H), 4.94 (s, 2H), 4.39 (q, 2H, J=7.0 Hz), 1.41 (t, 3H, J=7.0 Hz).
Reaction SMILES: [Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:21][C:22]1[C:27]([C@@H:28]([N:30]2[CH2:35][CH:34]([CH3:36])[O:33][C@H:32](O)[C:31]2=[O:38])[CH3:29])=[CH:26][CH:25]=[C:24]([F:39])[N:23]=1.C(N(CC)CC)C.[CH3:47][O:48][C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][C:56]=1[N:57]1[CH:61]=[C:60]([CH3:62])[N:59]=[CH:58]1)[CH:52]=O>C(#N)C>[F:21][C:22]1[C:27]([C@@H:28]([N:30]2[CH2:35][C@H:34]([CH3:36])[O:33]/[C:32](=[CH:52]\[C:51]3[CH:54]=[CH:55][C:56]([N:57]4[CH:61]=[C:60]([CH3:62])[N:59]=[CH:58]4)=[C:49]([O:48][CH3:47])[CH:50]=3)/[C:31]2=[O:38])[CH3:29])=[CH:26][CH:25]=[C:24]([F:39])[N:23]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CC1CN([C@@H](C)c2ccc(F)nc2F)C(=O)[C@@H](O)O1
Agent: [Br-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(/C=C2\O[C@@H](C)CN([C@@H](C)c3ccc(F)nc3F)C2=O)ccc1-n1cnc(C)c1
Yield: 56.6 %

Procedure:
Triphenylphosphonium bromide (6.52 g) was added to a solution of (S)-4-[(S)-1-(2,6-difluoropyridin-3-yl)ethyl]-2-hydroxy-6-methylmorpholin-3-one (4.3 g) in acetonitrile, and the reaction solution was heated under reflux for one hour. Triethylamine (5.28 mL) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (3.42 g) were added to the reaction solution, which was then heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with 2 N aqueous hydrochloric acid and ethyl acetate. Then, the aqueous layer was separated. The organic layer was washed with 2 N aqueous hydrochloric acid. Then, the total aqueous layers were combined and made alkaline with a concentrated sodium hydroxide solution. The organic layer was separated by extraction from the alkaline solution with ethyl acetate, and then washed with saturated sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using NH silica gel (heptane:ethyl acetate=1:1 to 0:100) to obtain 4.06 g of the title compound. The property values corresponded to those in Example 22.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[C:2]1[C:3]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1cc(NC(=O)c2cnn3cccnc23)c(Br)cn1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2Cl)cn1
Yield: 46.1 %

Procedure:
N-(5-bromo-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (82.2 mg, 0.247 mmol, 1 eq), 2,5-dichlorophenylboronic acid (122.1 mg, 0.6399 mmol, 2.59 eq), and bis(triphenylphosphine)palladium(II) chloride (15.4 mg, 0.0219 mmol, 0.09 eq) were combined in a microwave vial. To these solids were added sodium carbonate (1.0 mL of a 1.0 M aqueous solution, 1.0 mmol, 4.0 eq) and 3.0 mL acetonitrile. The vial was sealed and subjected to microwave irradiation (120° C., 30 W) for 30 minutes. The reaction was partitioned between ethyl acetate and water, and the organic layer dried over magnesium sulfate and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 45.3 mg (46%) of N-(5-(2,5-dichlorophenyl)-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=398.0; 1H NMR (400 MHz, DMSO-d6) δ: 9.75 (s, 1H), 9.32 (d, 1H), 8.71 (s, 1H), 8.48 (s, 1H), 8.26 (s, 1H), 8.21 (d, 1H), 7.78 (d, 1H), 7.75 (d, 1H), 7.69 (s, 1H), 7.26 (d of d, 1H), 2.55 (s, 3H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:13][C:14]1[CH:30]=[CH:29][C:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:21][CH2:22][C:16]=2[C:15]=1[NH:31][CH2:32][C:33]([CH3:43])([CH3:42])[CH2:34][O:35]C1CCCCO1>CO>[Cl:13][C:14]1[CH:30]=[CH:29][C:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:28])[C:24]([F:26])([F:25])[F:27])[CH2:21][CH2:22][C:16]=2[C:15]=1[NH:31][CH2:32][C:33]([CH3:43])([CH3:42])[CH2:34][OH:35]
Reactant: CC(C)(CNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(CO)CNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 77 %

Procedure:
Add p-toluensulfonic acid monohydrate (538 mg, 2.83 mmol) to a solution of 7-chloro-6-[2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.190 g, 2.57 mmol) in methanol (80 mL). Stir the reaction at RT for 16 hr, concentrate, redissolve in EtOAc, wash with saturated aqueous sodium bicarbonate solution, brine, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:4 EtOAc:hexanes) to give the title compound (750 mg, 79%).
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([Br:12])=[CH:7][CH:8]=2)[C:3]1=O.[C:14]([NH2:22])(=[S:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[Br:12][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH2:11][C:2]3[S:21][C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:22][C:3]=32)=[CH:8][CH:7]=1
Reactant: O=C1c2cc(Br)ccc2CCC1Br
Reactant: NC(=S)c1ccccc1
Solvent: CCO
Product: Brc1ccc2c(c1)-c1nc(-c3ccccc3)sc1CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.3 g of 2,7-dibromo-3,4-dihydro-2H-naphthalen-1-one is dissolved in 10 ml of ethanol and, after addition of 140 mg of thiobenzamide, heated to reflux for 5 h. The reaction mixture is concentrated in vacuo, the residue is suspended in 10 ml of 1 N sodium hydroxide solution and stirred at room temperature for 1 h. The suspension is filtered with suction, thoroughly washed with water and dried in vacuo. 8-Bromo-2-phenyl-4,5-dihydro-naphtho[1,2-d]thiazole is obtained with a melting point of 85° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([C:24]#[C:25][CH3:26])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)[CH2:6][CH2:5]2.[CH2:27]([O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)[CH3:28].[F-].[Cs+]>COCCOC.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>[CH2:27]([O:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH:7]([O:11][C:12]2[CH:13]=[CH:14][C:15]([C@H:18]([C:24]#[C:25][CH3:26])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=2)[CH2:6][CH2:5]3)[CH:33]=[CH:32][CH:31]=1)[CH3:28]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: CC#C[C@H](CC(=O)OC)c1ccc(OC2CCc3cc(Br)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CC#C[C@H](CC(=O)OC)c1ccc(OC2CCc3cc(-c4cccc(OCC)c4)ccc32)cc1
Temperature: 95 °C

Procedure:
A mixture of 59.2 (30 mg, 0.073 mmol), 3-ethoxyphenylboronic acid (14.5 mg, 0.087 mmol) and CsF (55 mg, 0.36 mmol) in 1,2-dimethoxyethane (2 mL) was degassed with N2 for 3 minutes. Pd(PPh3)4 (20 mg, 0.017 mmol) was added, and the resulting mixture was heated to 95° C. for 8 hours. After cooling, the reaction mixture was quenched with water and extracted with EtOAc to obtain the ester 59.3, which was directly hydrolyzed in next step.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]=1[OH:31])[CH:26]=O)[CH3:21].[NH2:35][C:36]([NH2:38])=[O:37].Cl>CCO>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:26]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[NH:38][C:36](=[O:37])[NH:35]2)[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]=1[OH:31])[CH3:21]
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(C(F)(F)F)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 39 %

Procedure:
A mixture of 2-phenyl-1-(4-(trifluoromethyl)phenyl)ethanone (commercially available) (200 mg, 0.76 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (145 mg, 0.69 mmol), urea (124 mg, 2.06 mmol), conc. HCl (0.06 mL, 0.69 mmol) in EtOH (5 mL) was refluxed overnight. Followed a standard aqueous/EtOAc workup, then purified by preparative HPLC to give Compound 113 (135.34 mg, yield 39%). 1H NMR (DMSO-d6 400 MHz): δ 8.83 (d, J=1.6 Hz, 1H), 7.60-7.56 (m, 3H), 7.40-7.39 (m, 3H), 7.13 (s, 1H), 7.06-7.00 (m, 3H), 6.83-6.80 (m, 2H), 5.23 (d, J=2.4 Hz, 1H), 4.06-3.97 (m, 2H), 1.30 (t, J=7.2 Hz, 3H); MS (ESI): m/z 500.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17]=[O:18].C[Mg+].[Br-].[CH2:22](OCC)C>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=2)[S:4][C:3]=1[CH:17]([OH:18])[CH3:22]
Reactant: CCOCC
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O
Reaction time: 2 h

Procedure:
To a solution of 3-methyl-5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (0.130 g, 0.481 mmole) in THF (5 mL), is injected 3.0 M MeMgBr in ethyl ether (0.27 mL, 0.810 mmole) dropwise. The reaction is stirred for 2 hours. The reaction is quenched with saturated NH4Cl(aq) (10 mL), then the aqueous solution is extracted with ethyl acetate (3×15 mL). The combined organic solution is washed with brine (3×50 mL), dried over Na2SO4 and concentrated. The crude product is purified on a silica gel column, eluting with 0-20% ethyl acetate in hexane and concentrated to provide the titled compound as yellow solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[Na+].COC1C=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:19])[CH2:16]2)=[CH:11][CH:10]=1.CI.O.[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1>CCOC(C)=O>[CH3:25][O:26][C:27]1[CH:23]=[C:24]2[C:12]([CH2:17][CH2:16][C:15](=[O:19])[C:14]2([CH3:13])[CH3:1])=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Temperature: 25 °C

Procedure:
A slurry of sodium tert butoxide (21.1 g, 220 mmol) in THF (100 mL) was cooled to 0° C. A solution of 7-methoxy-3,4-dihydro-1H-napthalen-2-one (17.6 g, 100 mmol) and methyl iodide (30.1 g, 220 mmol) in THF (100 mL) was added dropwise over 40 min, and the reaction mixture was warmed to room temperature after 10 min. Water (200 mL) and EtOAc (600 mL) was added. The layers were separated, the organic layer was washed with water (5×100 mL) and saturated NaCl (100 mL), filtered and dried with Na2SO4 to provide the title compound (20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=O)[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C([O:36][CH2:37][CH2:38][O:39][NH2:40])(=O)C.CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=[N:40][O:39][CH2:38][CH2:37][OH:36])[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC(=O)OCCON
Reactant: CC#CC(=O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC#CC(=NOCCO)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (VII-4, 10 g) was dissolved in 300 ml of 1,4-dioxane, 1.5 equivalent of 2-(acetoxy)ethoxyamine was added, and 28 ml of 2 mol/L aqueous methanesulfonic acid solution was added, followed by stirring at 60° C. for 17 hours. The reaction mixture was poured into aqueous saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over sodium sulfate. The residue obtained by concentrating the filtrate was recrystallized from hydrous ethanol-water, filtered, and dried to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-(2-hydroxyethoxyimino)-2-butyn-1-yl)quinazoline (VIII-33, 7.6 g) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:24]=2)=[CH:17][CH:16]=1>ClCCCl.C1COCC1>[CH3:21][C:19]1[N:20]=[C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])[CH:16]=[CH:17][C:18]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:24]=1
Reactant: CCC(=O)Nc1cc(Oc2ccc(N)nc2C)ccn1
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2C)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.048 g, 0.477 mmol) in DCE (2 mL) was treated with oxalyl chloride (0.042 mL, 0.477 mmol), stirred at RT for 0.5 h, then heated at 75° C. for 1 h. The mixture was cooled to RT, added to a solution of Example A6 (0.10 g, 0.367 mmol) and TEA (0.1 mL, 0.744 mmol) in THF (2 mL) and stirred at RT for 1 h. The mixture was concentrated to dryness, the residue treated with EtOAc, the solid collected via filtration, washed with water and EtOAc and dried to afford N-((6-methyl-5-((2-propionamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (87 mg, 59%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 10.49 (s, 1H), 10.41 (br s, 1H), 8.17 (d, J=5.7 Hz, 1H), 7.90 (m, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 6.65 (dd, J=5.7, 2.4 Hz, 1H), 2.33 (q, J=7.5 Hz, 2H), 2.23 (s, 3H), 1.22 (s, 9H), 0.99 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 400.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:20])[CH:15](Br)[CH2:16][CH2:17][CH3:18])[CH3:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH2:11]([O:13][C:14](=[O:20])[CH:15]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: CCCC(Br)C(=O)OCC
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Temperature: 140 °C
Yield: 84.3 %

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (15 g, 0.1 mol), 2-bromo-pentanoic acid ethyl ester (27 g, 0.13 mol) and K2CO3 (27 g, 0.2 mol) in DMF (100 mL) was heated at 140° C. for 1 h. After cooled to room temperature, the mixture was poured into water and the aqueous phase was extrated with EtOAc thrice. The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a colorless oil (24 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].Cl[CH2:12][C:13](Cl)=[O:14].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C1COCC1>[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:12][C:13]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:14])[CH3:17]
Reactant: CCNCC
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
A solution of 3-nitroaniline (1.00 g, 7.24 mmol) in THF (20 ml) was cooled to 4° C. in an ice bath. To this stirred mixture TEA (1.47 g, 14.50 mmol), then chloroacetyl chloride (0.98 g, 8.70 mmol) were sequentially added. The reaction was allowed to warm up to room temperature and after 2 and a half hours diethylamine (1.59 g, 21.7 mmol) was added in ice bath and the resulting mixture stirred overnight at room temperature. After completion (TLC 5% MeOH in DCM), solvent was evaporated in vacuo. The crude product was dissolved in DCM (75 ml), washed 3 times with saturated aqueous NaHCO3 solution (50 ml), dried (MgSO4), filtered and taken to dryness in vacuo. The crude product thus obtained was purified by flash column chromatography (0%-5% MeOH in DCM) to give 2-(diethylamino)-N-(3-nitrophenyl)acetamide 4 as a yellow semi-solid (0.92 g, 50%); Rf 0.26 [5% MeOH in DCM]; δH (CDCl3, 400 MHz) 9.68 (1H, s, NH), 8.36-8.35 (1H, m, ArH), 8.05-8.03 (1H, m, ArH), 7.93 (1H, dd, J1=8.4 Hz, J2=1.6 Hz, ArH), 7.51.7.57 (1H, m, ArH), 3.18 (2H, s, CH2), 2.67 (4H, quartet, J=7.2 Hz, 2×CH2), 1.10 (6H, t, J=7.2 Hz, 2×CH3); δC (CDCl3, 100 MHz) 169.95 (C═O), 147.27 (Ar—C), 138.64 (Ar—C), 129.61 (Ar—CH), 110.74 (Ar—CH), 109.17 (Ar—CH), 105.92 (Ar—CH), 58.14 (CH2), 48.79 (2×CH2), 12.39 (2×CH3); LC-MS (5 min) m/z 252.37 [C12H17N3O3+H]+ (100), Rt 0.83 min; HRMS m/z calc C12H18N3O3 [M+H]+252.1353. found [M+H]+252.1358; anal. CHN calc. C12H17N3O3. C, 57.4%; H, 6.8%; N, 16.7%. found C, 57.3%; H, 7.1%; N, 16.6%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[N:19]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:3]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: Oc1ccccc1-c1nc(Cl)c2ccccc2n1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Oc1ccccc1-c1nc(N2CCNCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
To a solution of 2-(4-chloroquinazolin-2-yl)phenol (2.0 g, 7.8 mmol) in CH2Cl2 at 0° C. was rapidly added a solution of piperazine (2.01 g, 23.4 mmol) and triethylamine (2.17 mL, 15.6 mmol) in 10 mL CH2Cl2. The reaction was warmed to room temperature and stirred for 5 hours. The reaction was quenched with 25 mL of water and extracted with (3×15) mL of CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (1.98 g, 83%). LC/MS: m/z 307.3 (M+H)+ at 1.47 min (10%-99% CH3CN (0.035% TFA)H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=10.1 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.85 (m, 2H), 7.53 (m, 1H), 7.38 (m, 1H), 6.95 (m, 2H), 3.85 (t, J=4.8 Hz, 4H), 2.94 (t, J=4.8 Hz, 4H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7]1(O)[CH:12]=[CH:11][C:10]([S:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.CN(C)C=O.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.O>[C:29]1([CH2:28][O:21][C:18]2[CH:19]=[CH:20][C:15]([S:14][S:13][C:10]3[CH:11]=[CH:12][C:7]([O:4][CH2:1][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:8][CH:9]=3)=[CH:16][CH:17]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(SSc2ccc(O)cc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: c1ccc(COc2ccc(SSc3ccc(OCc4ccccc4)cc3)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To solid potassium carbonate (11.59 g, 83.89 mmol) was added 4,4′-dithiodiphenol (7.00 g, 27.96 mmol), as a solid under argon, followed by N,N-dimethylformamide (130 ml). The stirred suspension was then heated to 80° C. over 2.25 h. Benzyl chloride (7.24 ml, 62.91 mmol) was then added over 2-3 minutes and the mixture stirred at 80° C. overnight. The mixture was then allowed to cool slowly to room temperature over the weekend. The resulting mixture was then poured into water (800 ml) and extracted with dichloromethane (3×250 ml). The organic extracts were combined and dried over sodium sulfate, filtered and evaporated to give a pale yellow solid which was tritureated with hot methanol (80 ml) which was allowed to cool slowly overnight to afford the title compound (D47). 1H-NMR (CDCl3) d 7.43-7.33 (14H, m), 6.90 (4H, dd, J 6.8 Hz, 2.0 Hz), 5.05 (4H, s).
Reaction SMILES: Br[CH:2]([CH:16]1[CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])=[O:4].Cl.[CH3:20][O:21][CH2:22][C:23](=[NH:25])[NH2:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH:16]1([C:2]2[N:24]=[C:23]([CH2:22][O:21][CH3:20])[NH:25][C:3]=2[C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=2[CH3:15])[C:8]([O:10][CH3:11])=[O:9])[CH2:18][CH2:17]1.[CH:16]1([C:2]2[N:24]=[C:23]([CH2:22][O:21][CH3:20])[O:4][C:3]=2[C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=2[CH3:15])[C:8]([O:10][CH3:11])=[O:9])[CH2:18][CH2:17]1
Reactant: COCC(=N)N
Reactant: COC(=O)c1ccc(C)c(C(=O)C(Br)C2CC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCc1nc(C2CC2)c(-c2cc(C(=O)OC)ccc2C)[nH]1
Product: COCc1nc(C2CC2)c(-c2cc(C(=O)OC)ccc2C)o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 21 %
Yield: 41 %

Procedure:
Into a 100-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(2-bromo-2-cyclopropylacetyl)-4-methylbenzoate (compound 4.6, 150 mg, 0.48 mmol), 2-methoxyacetimidamide hydrochloride (compound 4.7, 90 mg, 0.72 mmol), potassium carbonate (200 mg, 1.44 mmol), and N,N-dimethylformamide (15 mL). The resulting mixture was stirred at 80° C. for 3 h, then diluted with ethyl acetate (100 mL). The mixture was washed with brine (3×30 mL) and water (3×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) as the eluent to yield methyl 3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 4.8) (30 mg, 21%) and methyl 3-(4-cyclopropyl-2-(methoxymethyl)oxazol-5-yl)-4-methylbenzoate (compound 4.9) (60 mg, 41%), both as a yellow oils.