Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:49])([F:48])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[C:41]4[CH2:45][CH2:46]O)=[CH:32][CH:31]=3)[N:27]=2)=[CH:17][CH:16]=1.[C:50]1(=[O:60])[NH:54][C:53](=[O:55])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[F:48][C:14]([F:13])([F:49])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[C:41]4[CH2:45][CH2:46][N:54]4[C:50](=[O:60])[C:51]5[C:52](=[CH:56][CH:57]=[CH:58][CH:59]=5)[C:53]4=[O:55])=[CH:32][CH:31]=3)[N:27]=2)=[CH:17][CH:16]=1
Reactant: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reaction time: 24 h
Yield: 172.1 %

Procedure:
Diethyl azodicarboxylate (1.86 ml) was added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol (2.00 g), phthalimide (605 mg) and triphenylphosphine (1.08 g) in THF (30 ml) at room temperature, and the mixture was stirred for 24 hr. The reaction mixture was diluted with ethyl acetate, successively washed with 1N aqueous sodium hydroxide solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 2-[2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]ethyl]-1H-isoindole-1,3(2H)-dione (4.31 g) as pale yellow crystals. 2-Aminoethannol (4.31 ml) was added to a solution of the product (3.94 g) in ethanol (70 ml), and the mixture was refluxed for 75 min. The reaction mixture was concentrated, diluted with ethyl acetate, successively washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex, 100-200 mesh, Fuji silicia chemical) (eluent; dichloromethane to dichloromethane:methanol=200:1 to 40:1) to give the titled compound (1.34 g) as a colorless amorphous form.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]([CH3:22])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.COCCOC.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(Cl)Cl.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>[F:23][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([C:34]4[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:20]([F:21])[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[CH3:22]
Reactant: Cn1ncc2c(F)c(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Solvent: ClCCl
Product: Cn1cc(-c2ccc3ncc(Cc4c(F)cc5c(cnn5C)c4F)n3n2)cn1
Reaction time: 0.5 h

Procedure:
In a microwave vial were introduced under argon 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (23 mg, 0.112 mmol) and 6-chloro-3-(4,6-difluoro-1-methyl-1H-indazol-5-ylmethyl)-imidazo[1,2-b]pyridazine (Stage 284.1, 25 mg, 0.075 mmol) with 0.3 mL DME. The solution was degassed with argon, before adding PdCl2(PPh3)2 (1.5 mg) and 2 M K2CO3 (0.101 mL). The RM was then stirred at 80°-90° C. for 30 min. Additional 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (10 mg, 0.048 mmol) and PdCl2(PPh3)2 (1.5 mg) were added. The RM was then diluted with DCM and washed with sat. aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, evaporated to dryness and the residue was purified (CombiFlash® Companion System®, with RediSep® silica gel column, EtOAc/MeOH=100:0->80:20) to afford the title compound as a beige crystalline powder (tR 3.91 min (conditions 3), MH+=380.2, 1H-NMR in DMSO-d6: 8.36 (s, 1H); 8.18 (s, 1H); 8.05 (s, 1H); 8.02 (d, 1H); 7.50 (m, 2H); 7.45 (s, 1H); 4.40 (s, 2H); 3.97 (s, 3H); 3.90 (s, 3H)).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH2:5][CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[C:24]1[C:33]2[N:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.CC1C=CC=C(C)C=1B(O)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>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[C:11]([NH:12][C:34]([C:27]3[C:28]4[N:29]=[CH:30][CH:31]=[N:32][C:33]=4[C:24]([C:18]4[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=4[CH3:16])=[CH:25][CH:26]=3)=[O:35])[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2cccc(N)c2)CC1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cccc(C)c1B(O)O
Product: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4c(C)cccc4C)c4nccnc34)c2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 3-(4-ethylpiperazin-1-yl)-aniline (Step 2.1) and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid. The carboxylic acid was synthesized as described in Steps 1.2-1.7 but using 2,6-dimethylphenylboronic acid and Pd(PPh3)4 in Step 1.4. Title compound: ESI-MS: 466.2 [M+H]+; tR=3.74 min (System 3).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[CH:8]([SH:11])([CH3:10])C.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([N:24]=[C:25]=[O:26])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([N:24]([C:6]2[S:11][CH:8]=[CH:10][CH:7]=2)[C:25]([O:14][CH:15]([CH3:16])[CH3:20])=[O:26])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:13]
Reactant: CCOc1ccc(N=C=O)cc1OCC
Reactant: CCN(CC)CC
Reactant: CC(C)S
Solvent: Cc1ccccc1
Product: CCOc1ccc(N(C(=O)OC(C)C)c2cccs2)cc1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
Triethylamine (1 g) and isopropyl mercaptan (0.8 g) were dissolved in toluene (20 ml). To the resultant solution was dropwise added 3,4-diethoxyphenyl isocyanate (2.1 g) in 5 minutes under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene as the eluent to give isopropyl N-(3,4-diethoxyphenyl)thiolcarbamate (Compound No. 88) (2.7 g) in a yield of 95%. M.P., 110°-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]3[N:16]=[C:17]([NH:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:18]=[C:19]([N:20]([CH:30]4[CH2:32][CH2:31]4)CC4C=CC(OC)=CC=4)[C:14]3=[N:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]3[N:16]=[C:17]([NH:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:18]=[C:19]([NH:20][CH:30]4[CH2:32][CH2:31]4)[C:14]3=[N:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2cc(NC3CCOCC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccnc(Cl)c1)c1cnc2c(NC3CC3)cc(NC3CCOCC3)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
A solution of N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)-6-(tetrahydro-2H-pyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (7 mg, 0.013 mmol) in DCM (1 mL) was treated with TFA (0.5 mL, 6.49 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=35.169 minutes) was isolated and lyophilized to dryness to afford N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)-6-(tetrahydro-2H-pyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (2.5 mg, 35.9%). 1H NMR 400 MHz, DMSO-D6) δ ppm 11.40 (1H, s), 8.38 (1H, d, J=5.54 Hz), 7.97 (1H, s), 7.75 (1H, s), 7.70 (1H, d, J=5.79 Hz), 7.65 (1H, s), 7.10 (1H, d, J=6.55 Hz), 6.00 (1H, s), 3.85-4.06 (3H, m), 1.93-2.08 (2H, m), 1.43-1.61 (2H, m), 0.71-0.81 (2H, m, J=5.54 Hz), 0.57-0.68 (2H, m). HPLC Rt=4.160 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=428.0.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:3]=1.CN.[C:27]([BH3-])#[N:28].[Na+].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>CO.C(O)(=O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:28][CH3:27])[C:12]=2[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1OCC(F)(F)F
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1OCC(F)(F)F
Yield: 47.6 %

Procedure:
4-Chloro-2-[3-formyl-2-(2,2,2-trifluoroethoxy)phenoxy]benzonitrile (0.12 g, 0.33 mmol), methylamine (33% in ethanol, 0.4 mL, 3.2 mmol) and sodium cyanoborohydride (40 mg, 0.6 mmol) were stirred at ambient temperature in a solution of glacial acetic acid (0.5 mL) in methanol (25 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (39 mg, 0.34 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration and dried to give 4-chloro-2-[3-methylaminomethyl-2-(2,2,2-trifluoroethoxy)phenoxy]-benzonitrile fumarate (76.5 mg, 47%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([OH:28])[C:20]5=[N:19][C:18]=4[CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:32]([Cl:43])(=[O:42])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].[OH-].[Na+]>O.ClCCl>[ClH:43].[ClH:43].[F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][C:32](=[O:42])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:20]5=[N:19][C:18]=4[CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OC1CCCn2c1nc(C)c(CCN1CCC(c3noc4cc(F)ccc34)CC1)c2=O
Product: Cl
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a stirred solution of 1.2 parts of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one in 21 parts of dichloromethane and 5 parts of water were simultaneously added dropwise a solution of 1.1 parts of decanoyl chloride in 13 parts of dichloromethane and a solution of 1 part of sodium hydroxide in 6 parts of water. Upon complete addition, stirring was continued for 2 hours at room temperature. Another portion of 1.1 parts of decanoyl chloride was added and stirring was continued overnight at room temperature. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The product was filtered off and dried, yielding 0.9 parts (45.9%) of [3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl]decanoate dihydrochloride; mp. 221.4° C. (Compound 6)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12][Mg]Cl.O>C1COCC1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([OH:3])([CH3:12])[CH3:1])=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)(C)O)cc1
Temperature: 12.5 °C
Yield: 93.9 %

Procedure:
This was synthesized using a synthesis based on that described by Archer et al., J. Org. Chem., Vol. 42, No. 13, 1977, page 2282, column 2 (see synthesis of (22)). A solution of 4-methoxy acetophenone (151.18 g, 1 mol) in 300 ml of anhydrous THF was added for 1 h to the solution of 1N methyl magnesium chloride (1360 ml, 1.36 mol) in THF while maintaining the internal temperature at 10-15° C. After completion of the addition, the reaction mixture was heated for about 4.5 hrs. After completion of the reaction (as determined by TLC), 0.2 L of water was slowly added during 3 hrs to quench the reaction while maintaining the internal temperature at <15° C. The reaction mixture was decanted from the precipitate and evaporated under vacuum. The remaining white residue was washed with methyl t-butyl ether (MTBE) (2×200 mL) and evaporated. The combined residue was dissolved in 400 mL of MTBE and 200 mL of water was added. The organic layer was extracted and the aqueous layer was washed with MTBE (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness to afford 156 g of 2-(4-Methoxy-phenyl)-propan-2-ol as yellow oil (94% yield, 96% purity by HPLC).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:14]2[CH2:15][CH2:16][C:3]3[C:4](=[N:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[CH3:1])[CH2:12][CH2:13]2)=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Cc1c2c(nc3ccccc13)CCN(C(=O)c1ccc(Cl)cc1)CC2
Yield: 65 %

Procedure:
3-(p-Chloro-benzoyl)-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline was prepared from 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline and 4-chloro-benzoyl chloride in pyridine.
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.Cl.CC(C)=[O:18].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>O1CCOCC1.O>[CH3:12][O:11][C:9]([C:8]1[CH:13]=[CH:14][C:5]([CH2:4][C:3]([OH:18])=[O:2])=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)=O
Reactant: COC=Cc1ccc(C(=O)OC)cc1
Agent: O=[Cr](=O)=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CC(=O)O)cc1
Temperature: -50 °C
Reaction time: 0.33 h
Yield: 28.1 %

Procedure:
To a solution of methyl 4-(2-methoxyethenyl)benzoate (E9) (2.41 g, 12.5 mmol) in dioxane (50 ml) 1N water solution of HCl (40 ml) was added and the resultant mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate (3×50 ml), the organic extracts were combined, washed with brine (2×30 ml), and dried (Na2SO4). The solvents were evaporated, the residue was dissolved in acetone (70 ml) and cooled to −50° C. To the cold solution at this temperature slowly (ca. for 5 minutes) 2.67 M Jones reagent (CrO3/H2SO4; 7.5 ml, 20.0 mmol) was added and the obtained mixture was stirred at −40 to −50° C. for 1 hour and at −30° C. for 20 minutes. Isopropyl alcohol (2 ml) was added to the reaction mixture and the cooling bath was removed allowing the reaction to warm up for 10 minutes. The mixture was poured into water (150) and extracted with ethyl acetate (3×100 ml). The organic layers were combined, washed with brine (2×50), and dried (Na2SO4). The solvent was evaporated and the residue was dissolved in a small amount of hot dioxane (1-2 ml). Addition of petroleum ether (4-6 ml) caused the formation of a precipitate. The mixture was filtered and the precipitate was washed with dioxane-petroleum ether (1:4). The filtrate was evaporated and the precipitate formation procedure was repeated as described above. Then the filtrate was evaporated and the residue was chromatographed on silicagel (100 g) with petroleum ether-dioxane-acetic acid (2.5:7.5:0.1) to give the title compound (0.681 g, 28%) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 3.68 (2H, s); 3.89 (3H, s); 7.33 (2H, d, J=8.2 Hz); 7.97 (2H, d, J=8.2 Hz); 10.82 (1H, br s).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1>ClCCl.N1C=CC=CC=1>[CH3:28][C:24]1[CH:23]=[C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[O:13])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2cccc(C)c2)c1
Yield: 42 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and m-toluidine (1.24 g, 11.6 mmol) in 10 mL of pyridine. The crude product was recrystallized from ethyl ether-ethyl acetate to yield 1.18 g of the title compound, mp 193°-195° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23].[CH:26]([Mg]Cl)(C)C.[CH3:31][N:32]1[C:36]([C:37]([CH:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47]C(C)(C)C)=O)[CH2:41][CH2:40]2)=[O:38])=[CH:35][N:34]=[CH:33]1>C1COCC1>[OH:38][C:37]([C:36]1[N:32]([CH3:31])[CH:33]=[N:34][CH:35]=1)([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:13])([F:15])[F:14])[C:6]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[C:5]2[C:22]([F:23])([F:24])[F:25])[CH:39]1[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:26])[CH2:41][CH2:40]1
Reactant: CC(C)[Mg]Cl
Reactant: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Reactant: Cn1cncc1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(O)(c2ccc3nc(C(F)(F)F)c(-c4ccccc4)c(C(F)(F)F)c3c2)c2cncn2C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A ˜−70° C. solution of 6-iodo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (150 mg, 0.322 mmol; Intermediate 8, step d) in THF (0.322 mL) was treated with iPrMgCl (2.06 M in THF; 0.156 mL, 0.322 mmol) dropwise via syringe under argon over the course of 30 sec to provide a light amber solution that became a yellow opaque slurry within 2 min. After 8 additional min the reaction was removed from the cold bath and stirred on a room temperature water bath for 10 min, at which point solid 1-(4-(1-methyl-1H-imidazole-5-carbonyl)piperidin-1-yl)ethanone (90.9 mg, 0.386 mmol; Intermediate 53, step c) was added in one portion and the reaction quickly evacuated and flushed with argon four times. After 5 min, additional THF (2.6 mL) was added to aid the dissolution of the ketone, and the reaction became an opaque easily stirred tan slurry within 30 min. After 110 min, the reaction was quenched with D2O (0.2 mL) and partitioned with 5 M NH4Cl (1 mL) and heptane (1 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was flash chromatographed using a DCM to 9:1 DCM/MeOH gradient to provide the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[C:10]([NH2:19])=[N:11][C:12]([NH2:18])=[N:13]3)=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].[CH3:29][C:30](O)=[O:31]>>[C:22]([NH:18][C:12]1[N:11]=[C:10]([NH:19][C:30](=[O:31])[CH3:29])[C:9]2[C:14](=[CH:15][CH:16]=[CH:17][C:8]=2[O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=2)[N:13]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: Nc1nc(N)c2c(OCc3ccc(Cl)cc3)cccc2n1
Product: CC(=O)Nc1nc(NC(C)=O)c2c(OCc3ccc(Cl)cc3)cccc2n1
Temperature: 25 °C

Procedure:
5-(4-Chlorobenzyloxy)-quinazoline-2,4-diamine (Example 2) (75 mg; 0.25 mmol) is dissolved in 1:1 HOAc: acetic anhydride and heated to 130° C. for 5 hours. After allowing the reaction to room temperature, the solvent is removed under N2 purge. The resulting solid is dissolved in minimal hot ethanol and allowed to cool to room temperature and the resulting crystals are filtered and dried under vacuum overnight to yield 20 milligrams of N-[2-acetylamino-5-(4-chlorobenzyloxy)quinazolin-4-yl]acetamide.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:14][C:15]1[C:16](=[O:27])[C:17]2[C:22]([C:23](=[O:26])[C:24]=1[Cl:25])=[CH:21][CH:20]=[CH:19][CH:18]=2>C(O)C>[ClH:14].[Cl:25][C:24]1[C:23](=[O:26])[C:22]2[C:17]([C:16](=[O:27])[C:15]=1[N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: CNCCN(C)Cc1ccccc1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Solvent: CCO
Product: CN(CCN(C)C1=C(Cl)C(=O)c2ccccc2C1=O)Cc1ccccc1
Product: Cl
Temperature: -10 °C
Reaction time: 16 h

Procedure:
A 4.5 g portion of methyl 2-[methyl (phenylmethyl)-amino]ethylamine was added to a stirred slurry of 5.6 g of 2,3-dichloro-1,4-naphthoquinone in 150 ml of absolute ethanol. Stirring was continued for 16 hours, then the mixture was heated at reflux for one hour and filtered while hot. The mixture was then cooled at -10° C. and filtered. This filtrate was diluted with 100 ml of ether and cooled at -10° C. The resulting precipitate was collected, washed with ether and dried in vacuo at 100° C., giving 3.5 g of the desired product as orange crystals, mp 188°-190° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([F:20])[CH:12]=1.[C:21](=O)([O-])[O-:22].[K+].[K+].[C]=O>C1(OC)C=CC=CC=1.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.C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:21]([C:14]2[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][C:13]=2[F:20])=[O:22])=[C:4]([F:9])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc(Br)ccc1I
Reactant: OB(O)c1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C]=O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: O=C(c1ccc(Br)cc1F)c1ccc(Br)cc1F
Yield: 47.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.15 g, 0.13 mmol) was dissolved in anisole (15 mL). 1-Bromo-3-fluoro-4-iodobenzene (2.0 g, 6.6 mmol), 4-bromo-2-fluorobenzeneboronic acid (1.45 g, 6.6 mmol) and potassium carbonate (2.7 g, 19.9 mmol) together with another 15 mL anisole were added. The above mixture was stirred for 16 h at 80° C. under 10 bar carbon monoxide pressure. The reaction mixture was allowed to cool, added to a toluene/water mixture (120 mL, 1:1) the phases were separated and the water phase was extracted twice with toluene. Organic phases were pooled, washed with brine and the solvent was evaporated. Crystallization from hexane afforded the title compound as white crystals (1.17 g, 47%).