Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:21]COCCOC)=[C:9]([C:11]2[N:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:21])=[C:9]([C:11]2[N:12]=[N:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOCOc1ccc(C(C)(C)C)cc1-c1ccc(C(F)(F)F)nn1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1ccc(O)c(-c2ccc(C(F)(F)F)nn2)c1
Yield: 80.7 %

Procedure:
A solution of 3-(5-(tert-butyl)-2-((2-methoxyethoxy)methoxy)phenyl)-6-(trifluoromethyl)pyridazine (0.452 g, 1.18 mmol) in methanol (50 mL) and 1.0M aqueous hydrochloric acid (25 mL) was stirred at 60° C. for 5 hours. The cooled reaction mixture was then concentrated under reduced pressure to remove methanol. The resulting aqueous suspension was partitioned between ethyl acetate (80 mL) and saturated aqueous sodium hydrogen carbonate solution (80 mL), the organic phase separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a cream solid. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 20% ethyl acetate in hexanes to give 4-(tert-butyl)-2-(6-(trifluoromethyl)pyridazin-3-yl)phenol (0.282 g, 81% yield) as a cream solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[OH-].[Na+]>O1CCCC1.CCCCCCC>[C:21]([Si:18]([O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])([CH3:20])[CH3:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1ccc(F)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a flask, 2-fluoro-5-methoxyphenol (6.00 g, 42 mmol), triethylamine (5.77 g, 57 mmol), and tetrahydrofuran (36.0 mL) were added, and the resulting mixture was cooled in an ice water bath under nitrogen atmosphere. To the solution, a solution of tert-butyldimethylsilyl chloride (6.89 g, 44 mmol) in tetrahydrofuran (30.0 mL) was added dropwise, and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, heptane and a 2 N aqueous sodium hydroxide solution were added, and the resulting mixture was extracted. The organic layer was washed with water, and concentrated under reduced pressure to obtain the captioned compound (10.2 g) as a light brownish-red oil.
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.C(O)C.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>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([C:3]2[O:4][C:5]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[C:6](=[O:7])[C:2]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)C3(CCCC3)O2)cc1
Reactant: OB(O)c1ccccc1
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: CCO
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)C3(CCCC3)O2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
To a stirred solution of 3-bromo-2-(4-(methylsulfonyl)phenyl)-1-oxa-spiro[4,4]non-2-en-4-one (77 mg) in 5 ml of toluene and 15 ml ethanol, were added 15 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate solution, and 27 mg of benzeneboronic acid. Then the reaction solution was stirred at 90° C. for 12 hours. The reaction solvent was evaporated off under reduced pressure and the resulting residue was extracted with 20 ml water and dichloromethane (30 ml×1). The organic layer was concentrated in vacuo and the resulting crude product mixture was purified by column chromatography (hexane/ethylacetate) to obtain 57 mg of 2-{4-(methylsulfonyl)phenyl}-3-phenyl-1-oxa-spiro[4,4]non-2-en-4-one as a solid. mp: 184-185° C. NMR: δ2.09 (m, 6H), 2.17 (m, 2H), 3.06 (s, 3H), 7.26 (m, 2H), 7,35 (m, 3H), 7.81 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.1 Hz, 2H). IR (cm−1): 2925, 1695, 1591, 1403, 1150, 771.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[N:12]=[CH:13][C:14]1[C:15]([NH:22][CH2:23][CH3:24])=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH:12][CH2:13][C:14]1[C:15]([NH:22][CH2:23][CH3:24])=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1
Reactant: CCNc1nc(SC)ncc1C=Nc1cc(OC)cc(OC)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1nc(SC)ncc1CNc1cc(OC)cc(OC)c1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Into a suspension of 6.96 g (18.97 mmol) of {5-[(2-chloro-3,5-dimethoxy-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}-ethyl-amine in 200 mL of dry THF cooled to 5° C. was added 18.97 mL (18.97 mmol) of a 1 M solution of LAH in THF. After stirring for 1 hour, the cold reaction was quenched by sequential addition of 0.8 mL of water, 3.0 mL of 25 NaOH, and 1.7 mL of water. The reaction was filtered through Celite, the filter pad washed well with THF, and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane, added silica gel, and concentrated in vacuo. This residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (2:1 v/v), giving 5.15 g (74%) of the title compound: mp 116.5-118.5° C.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([N:10]([CH2:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH2:11][CH3:12])[CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:8]([N:10]([CH2:13][C:14]1[CH:15]=[C:16]([NH:17][C:1]([CH3:2])=[CH:4][C:5](=[O:7])[CH3:6])[CH:18]=[CH:19][CH:20]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: CCN(CC)Cc1cccc(N)c1
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCN(CC)Cc1cccc(NC(C)=CC(C)=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.00 g (9.99 mmol) Acetylacetone, 1.78 g (9.99 mmol) 3-[(diethylamino)methyl]-aniline, and 0.15 g (2.5 mmol) 4-toluenesulfonic acid are dissolved in 100 ml toluene. The reaction mixture is refluxed overnight with a Dean-Stark trap to remove water. 0.05 g (0.83 mmol) 4-toluenesulfonic acid are again added and the mixture is refluxed overnight. As tlc control showed that there is some 3-[(diethylamino)-methyl]aniline left, 0.2 g (2 mmol) acetylacetone are added and refluxing is continued for 4 h. To drive the reaction to completion, 0.6 ml (9.98 mmol) acetic acid and 0.2 g (2 mmol) acetylacetone are added and the mixture is refluxed overnight with a Dean-Stark trap. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane/methanol mixtures as eluent.
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:45])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:44])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:43])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:42])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:41])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:40])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:39])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:38])=[CH:35]/[CH2:36]O.[CH3:47][O:48][C:49]1[C:54]([O:55][CH3:56])=[C:53]([O:57][CH3:58])[C:52]([O:59][CH3:60])=[CH:51][C:50]=1[CH3:61]>CCCCCC.[N+](C)([O-])=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[CH3:60][O:59][C:52]1[C:51]([CH2:36]/[CH:35]=[C:34](\[CH3:38])/[CH2:33][CH2:32]/[CH:31]=[C:30](\[CH3:39])/[CH2:29][CH2:28]/[CH:27]=[C:26](\[CH3:40])/[CH2:25][CH2:24]/[CH:23]=[C:22](\[CH3:41])/[CH2:21][CH2:20]/[CH:19]=[C:18](\[CH3:42])/[CH2:17][CH2:16]/[CH:15]=[C:14](\[CH3:43])/[CH2:13][CH2:12]/[CH:11]=[C:10](\[CH3:44])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:45])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:46])[CH3:1])=[C:50]([CH3:61])[C:49]([O:48][CH3:47])=[C:54]([O:55][CH3:56])[C:53]=1[O:57][CH3:58]
Reactant: COc1cc(C)c(OC)c(OC)c1OC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: C[N+](=O)[O-]
Solvent: CCCCCC
Product: COc1c(C)c(C/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C)c(OC)c(OC)c1OC
Temperature: 50 °C
Yield: 124.8 %

Procedure:
In a 50 ml four necked flask equipped with a stirrer, thermometer, gas inlet, and a reflux condenser, under argon atmosphere 0.654 g (96.52%, 1 mmol) of solanesol were dissolved in 15 ml of n-hexane and mixed with 1.07 g (5.0 mmol) of 2,3,4,5-tetramethoxy-toluene (TMT) suspended in 7.6 ml of nitromethane. The catalyst, Sc(OTf)3 (2.5 mg, 0.005 mmol), was then added. The two-phase mixture was heated up to 50° C. (internal temperature) under stirring (400 rpm). After 16 hours reaction time the mixture was cooled down to room temperature (21° C.). The hexane layer was separated and washed two times with 4 ml (total 8 ml) of nitromethane. The hexane phase was evaporated and yielded 1.03 g of crude 1,2,3,4-tetramethoxy-5-methyl-6-((2E,6E,10E,14E,18E,22E,26E,30E)-3,7,11,15,19,23,27,31,35-nonamethyl-hexatriaconta-2,6,10,14,18,22,26,30,34-nonaenyl)-benzene (tetramethoxy-CoQ9) as a colorless oil, which was purified by column chromatography on 30 g silica (elution with n-hexane/ethyl acetate=99:1, v/v) yielding 280 mg of a colorless oil which crystallized upon standing. Yield:32%; purity 94%.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C([O-])(O)=O.[Na+]>[F:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:7][CH3:6])=[CH:12][CH:13]=2)=[CH:19][CH:20]=1
Reactant: CN(CCc1ccc(Oc2ccc(F)cc2)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
Entire reaction was performed under argon atmosphere using syringe septa technique. {2-[4-(4-fluoro-phenoxy)-phenyl]-ethyl}-methyl-carbamic acid tert-butyl ester (1.578 mmol, 1 eq) was dissolved in dichloromethane (6 ml) and stirred at 0° C. for 5 min. TFA (15.778 mmol, 10 eq) was added and stirring was continued for 50 hours. Reaction mixture was diluted with 50 ml NaHCO3 (sat.) and extraction with DCM (3×20 ml) followed. Organic layers were combined and evaporated. Crude product was put on a previously conditioned SCX column (5 g). Column was washed with MeOH (2×10 ml) and then with 2M NH3/MeOH to retrieve the product, {2-[4-(4-fluoro-phenoxy)-phenyl]ethyl}-methyl-amine (1.468 mmol, yield=93%, purity=94%). [M+H]+=246.22 1H NMR (300 MHz, CDCl3) δ/ppm 2.43 (s, 3H), 2.72-2.86 (m, 4H), 6.84-7.03 (m, 5H), 7.10-7.17 (m, 2H), 7.24 (s, 1H)
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Br[CH2:10][CH2:11][O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:13][O:12][CH2:11][CH2:10][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Oc1ccccc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COCCOc1ccccc1O

Procedure:
Catechol (10.0 g, 91 mmol), bromoethylmethylether (12.6 g, 91 mmol), and potassium carbonate (12.6 g, 91 mmol) were mixed in ethanol (100 ml) and refluxed for 15 h. The solvent was evaporated and dichloromethane (200 ml) was added. The inorganics were filtered off and the solvent was removed in vacuum. Chromatography on silica gel with 0.5% methanol in dichloromethane as the eluent gave the title compound. Yield 4.5 g, 29%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([Si:16]([CH3:27])([CH3:26])[O:17][CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH:22]=O)([CH3:15])([CH3:14])[CH3:13].C[O-].[Na+]>CO>[C:12]([Si:16]([CH3:26])([CH3:27])[O:17][CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[CH2:21]/[CH:22]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(CC=O)CCO[Si](C)(C)C(C)(C)C
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C/C=C1\C(=O)Nc2cc(Cl)ccc21)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the mixture of 6-chlorooxindole (3.3 g, 20 mmol) (Crescent) and 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentanal (6.5 g, 26.6 mmol) in methanol (150 mL) was added a methanolic solution (25%, Aldrich) of sodium methoxide (10 g, 46 mmol) dropwise. The reaction mixture was stirred at room temperature for 10 min. The solvent was removed, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography (25-33% EtOAc in hexanes) to give E/Z-3-[5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentylidene]-6-chloro-1,3-dihydro-indol-2-one as a off white solid (Yield 3.6 g, 46%).
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:8]2[C:9](=[O:14])[NH:10][CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[C:19]=1[CH:20]=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O>[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N:10]2[C:9](=[O:14])[C:8]3[CH:15]=[CH:16][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=3[O:13][CH2:12][CH2:11]2)[C:19]=1[CH:20]=[O:21]
Reactant: CC(C)(C)c1ccc2c(c1)OCCNC2=O
Reactant: O=Cc1c(Br)cccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc2c(c1)OCCN(c1cccc(Br)c1C=O)C2=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
8-tert-Butyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (600 mg, 2.74 mmol, 2,6-Dibromo-benzaldehyde (3.62 g, 5eq), Xanthphos (71 mg, 0.045eq), and cesium carbonate (1.25 g, 1.4 eq) were taken up in dioxane (5.3 mL) and a stream of Argon gas was bubbled through the mixture for 10 minutes. The catalyst Pd(dba)2 (47 mg, 0.03 eq) was added and the resulting mixture was placed under argon and stirred at 100° C. for three hours. By TLC, the reaction was complete and after cooling the mixture to room temperature, ethyl acetate (150 mL) and water (50 mL) were added and the layers were partitioned and separated. The organic layer was further washed with water (3×50 mL) and finally washed with brine (1×50 mL) before it was dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography on silica gel eluting with a gradient of 5% ethyl acetate to 30% ethyl acetate afforded the title compound as an off-white powder (793 mg) (M+H)+=404.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[CH:30]1([CH2:33][N:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[C:44]([CH2:46][NH2:47])[CH:43]=[C:42]([C:48]4[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=4)[N:41]=3)[CH2:36][CH2:35]2)[CH2:32][CH2:31]1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:47][CH2:46][C:44]3[CH:43]=[C:42]([C:48]4[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:55])[F:56])=[CH:50][CH:49]=4)[N:41]=[C:40]([N:37]4[CH2:36][CH2:35][N:34]([CH2:33][CH:30]5[CH2:31][CH2:32]5)[CH2:39][CH2:38]4)[CH:45]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCN(CC3CC3)CC2)c1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2cc(-c3ccc(C(F)(F)F)cc3)nc(N3CCN(CC4CC4)CC3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.5 %

Procedure:
A solution of acid 18 (463 mg, 1.5 mmol) in THF (30 mL) was added with DEPC (0.23 mL, 1.0 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27G (560 mg, 1.04 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (40 mL) and washed with water (50 mL) and brine. The separated organic phase was dried over Na2SO4 and evaporated under reduced pressure and the residue was purified by flash chromatography (9:1 EtOAc:methanol) to afford a white solid (220 mg) after crystallization from diethyl ether. Yield=21.5%, 1HNMR (DMSO, 200 MHz) δ 0.40 (m, 2H), 0.65 (bm, 2H), 0.94 (m, 1H), 1.12 (m, 2H), 1.28 (t, 3H), 1.40 (bm, 2H), 3.04 (bm, 4H), 3.39 (bm, 4H), 3.43 (bm, 2H), 3.44 (m, 4H); 4.40 (bm, 4H), 6.87 (s, 1H), 7.30 (m, 2H), 7.60 (d, 1H, J=3.2), 7.82 (d, 2H, J=8.2), 8.25 (bm, 3H). [M+1] 682.98 (C31H35ClF3N5O3S2 requires 682.22).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([N:6]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:4]([F:13])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 46.4 %

Procedure:
4-Chloro-2-fluoro-5-isopropoxyaniline (1.3 g) and 3,4,5,6-tetrahydrophthalic anhydride (1.12 g) were dissolved in acetic acid (10 ml) and refluxed for 3 hours. The resultant mixture was allowed to cool to room temperature and poured into water, followed by extraction with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain 1.0 g of N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (Compound No. 1). M.P., 81°-82° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([NH2:22])=[N:3]1.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=O.[BH4-].[Na+].O>C(O)C>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([NH:22][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][OH:23])=[N:3]1
Reactant: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Reactant: O=CCCCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1cccc(OCCCNc2nc(NCCCCCO)nn2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Methyl-N5 -[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (1.0 g) and 5-hydroxypentanal (1.9 ml) were heated at reflux in ethanol (30 ml) for 5 h. The solution was cooled at 5° and treated with sodium borohydride (0.76 g). The resulting suspension was stirred at room temperature for 16 h, treated with water and reduced in volume in vacuo. The aqueous solution was extracted with ethyl acetate, and the organic extracts were distilled to give the title compound as a pale yellow oil (0.47 g) b.p. 250°/0.5 mm. TLC silica; ethyl acetate:isopropanol:water: 0.88 ammonia 25:15:8:2, Rf 0.6.
Reaction SMILES: C(N1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17]N(C(OC(C)(C)C)=O)[CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.F[C:26](F)(F)C(O)=O.CCN=C=NCCCN(C)C.Cl.C1(CC(O)=O)C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1>ClCCl>[CH2:12]([N:11]([CH:10]([CH3:9])[CH3:26])[CH:14]([CH3:17])[CH3:15])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC(N2CCN(Cc3ccccc3)CC2)C1
Reactant: O=C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)Cc1ccccc1
Solvent: ClCCl
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
450 mg (1.36 mmol) of tert-butyl 3-(4-benzylpiperazin-1-yl)azetidine-1-carboxylate (XXIe) were dissolved in dichloromethane (8 ml) and, while stirring at room temperature, trifluoroacetic acid (8 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. 286 mg (1.49 mmol) of EDCl were added to a solution of 642 mg (1.36 mmol) of 6-chloro-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]phenylacetic acid (XIIIa), 276 mg (2.03 mmol) of HOBt, the residue obtained above, and 2.13 ml (12.2 mmol) of ethyldiisopropylamine in 50 ml of dichloromethane while cooling in ice.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:30]([NH:34][C:35](=[O:56])[CH2:36][N:37]1[C:46](=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[C:43](I)[CH:44]=2)[N:39]=[C:38]1[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=1)([CH3:33])([CH3:32])[CH3:31].[CH2:57]([OH:61])[CH2:58][CH:59]=[CH2:60]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[C:30]([NH:34][C:35](=[O:56])[CH2:36][N:37]1[C:46](=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([CH:60]=[CH:59][CH2:58][CH2:57][OH:61])[CH:44]=2)[N:39]=[C:38]1[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: C=CCCO
Reactant: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(I)cc2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(C=CCCO)cc2c1=O
Yield: 47.5 %

Procedure:
A solution of palladium (II) acetate (82 mg, 0.37 mmol, 10 mol %) and tris (o-tolyl)phosphine (145 mg, 0.48 mmol) in anhydrous acetonitrile (40 mL) was sparged with argon for 5 minutes. Triethylamine (5.10 mL, 36.60 mmol) was added, followed by N-tert-butyl-2-[2-(3-chlorophenyl)-6-iodo-4-oxo-4H-quinazolin-3-yl]acetamide (INTERMEDIATE IV.12) (1.81 g, 3.66 mmol) and 3-buten-1-ol (1.57 mL, 18.30 mmol). The resultant mixture was heated at reflux temperature for 18 h. The resultant green suspension was concentrated in vacuo, and the residue was treated with ethyl acetate (100 mL) and filtered. The black precipitate was washed with ethyl acetate (2×50 mL), and the combined filtrates were washed with 1N HCl (aq.) (2×100 mL), brine (100 mL), dried (MgSO4) and concentrated to give the crude product as yellow-orange foam. Trituration with ether provided N-tert-butyl-2-[2-(3-chlorophenyl)-6-(4-hydroxybut-1-enyl)-4-oxo-4H-quinazolin-3-yl]acetamide (766 mg, 1.74 mmol, 48%) as an off-white powder.