Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[C:3]=1[CH:4]=[O:5].[CH3:12][N:13]([CH3:25])[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[NH:19][CH2:18][CH2:17]2.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[Br:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][CH:23]=[C:14]([N:13]([CH3:12])[CH3:25])[CH:15]=3)[C:20]2=[O:24])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Br)cc(F)cc1Br
Reactant: CN(C)c1ccc2c(c1)CCNC2=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C)c1ccc2c(c1)CCN(c1cc(F)cc(Br)c1C=O)C2=O
Yield: 48.9 %

Procedure:
Combined 0.948 g (3.4 mmol, 2 eq) 2,6-Dibromo-4-fluoro-benzaldehyde, 0.320 g (1.7 mmol, 1 eq) 6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one, 29 mg Xantphos (0.050 mmol, 0.03 eq), 19 mg bis(dibenzylideneacetone)palladium (0.033 mmol, 0.02 eq), and 1.09 g Cesium Carbonate (3 mmol, 2.0 eq) in 5 ml dioxane, bubbled argon gas through the mixture for 1 minute, sealed the reaction vessel and heated at 100 C for 3 hours, then cooled to 80 C and heated for 14 hours. Cooled, diluted ethyl acetate, washed water 2×, brine, dried mgso4. Rotovaped, chromatographed (10% to 30% ea in hexanes) to give a solid, 325 mg 2-Bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-4-fluoro-benzaldehyde. MS (ESI) 391.0 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:25]1([C:24]([C:32]2[CH:33]=[CH:34][C:35]([C:36]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:37])=[CH:39][CH:40]=2)=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.807 g, 4.38 mmol) in dry dichloromethane (20 mL) cooled in an ice bath was added N,N-diisopropylethyl amine (1.14 mL). The solution was treated dropwise with a suspension of 4-benzoylbenzoyl chloride (prepared from 3 mmol of 4-benzoylbenzoic acid and oxalyl chloride) in 8 mL of dichloromethane. The solution was stirred overnight at room temperature, diluted with dichloromethane, washed with water, 1 N hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was flash chromatographed over silica gel Merck-60 with a solvent gradient of 5 to 20% of ethyl acetate in hexane to provide the title compound (1.2 g) as a crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:4][CH:3]=1.[CH:15]1([CH2:18][CH2:19]O)[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][O:1][C:2]2[CH:14]=[CH:13][C:5]([O:6][C@@H:7]3[CH2:11][CH2:10][NH:9][C:8]3=[O:12])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: OCCC1CC1
Reactant: O=C1NCC[C@H]1Oc1ccc(O)cc1
Product: O=C1NCC[C@H]1Oc1ccc(OCCC2CC2)cc1

Procedure:
Typical Procedure 3 was followed. Reaction of (R)-3-(4-hydroxy-phenoxy)-pyrrolidin-2-one with 2-cyclopropyl-ethanol provided the title compound. MS ESI+: m/z=262 [M+H]+.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[CH2:14]=O>>[CH2:14]1[O:4][C:3]([CH2:2][C:1]([OH:13])=[O:12])([CH2:8][C:9]([OH:11])=[O:10])[C:5](=[O:7])[O:6]1
Reactant: C=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: O=C(O)CC1(CC(=O)O)OCOC1=O

Procedure:
reacting citric acid with paraformaldehyde to form anhydromethylene citric acid;
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]3[C:25]([N:26]=[C:27]4[C:32]=2[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)C1C=CC=CC=1>C(Cl)Cl>[CH2:31]1[C:32]2[C:27](=[N:26][C:25]3[C:20]([C:19]=2[C:16]2[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=2)=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:28][CH2:29][CH2:30]1
Reactant: c1ccc(COc2ccc(-c3c4c(nc5ccccc35)CCCC4)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2c3c(nc4ccccc24)CCCC3)cc1
Temperature: 25 °C

Procedure:
BBr3 (3.2 mL, 1 M solution in CH2Cl2, 3.2 mmol) was added dropwise to a stirred solution of 9-(4-benzyloxy-phenyl)-1,2,3,4-tetrahydro-acridine (0.23 g 0.64 mmol) in CH2Cl2 (3 mL) at 0° C. The resulting mixture was warmed to room temperature over a period of 3 hours followed by dilution with CH2Cl2 (50 mL). The solution was washed with sat. aq. NaHCO3 until aq. washings were basic (pH˜9). The CH2Cl2 layer was dried over Na2SO4, decanted and concentrated. The residue was washed with hexanes (2×10 mL) and decanted to remove benzyl bromide. The resulting product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([O:31]C)=[O:30])[N:19]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[O:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([OH:31])=[O:30])[N:19]=1
Reactant: COC(=O)Cc1ccccc1OCc1coc(CCc2nc(-c3ccccc3)oc2C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCc1nc(COc2ccccc2CC(=O)O)co1
Temperature: 50 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a mixture of methyl 2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetate (0.44 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1N aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.34 g, 81%) of 2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 109-110° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[C:16]([NH2:24])(=[S:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[N+:11]([C:9]1[CH:10]=[C:5]([C:3]2[N:24]=[C:16]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:23][CH:2]=2)[CH:6]=[C:7]([OH:15])[C:8]=1[OH:14])([O-:13])=[O:12]
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: NC(=S)c1cccnc1
Product: O=[N+]([O-])c1cc(-c2csc(-c3cccnc3)n2)cc(O)c1O
Temperature: 25 °C

Procedure:
A suspension of 2.91 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone is treated with 1.31 g of thionicotinamide in 50 ml of alcohol and heated to boiling under reflux for 2 hours. After cooling to room temperature the crystals are filtered under suction and recrystallized from N,N-dimethylformamide/alcohol. There is obtained 3-nitro-5-[2-(3-pyridyl)-4-thiazolyl]pyrocatechol of m.p. 279°-281°.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10]Cl)[CH2:2][CH2:3][CH3:4].[Cl:22][C:23]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10][O:31][C:29]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([Cl:22])[CH:30]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
3.2 g 4-Butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole and 1.5 g 2-Chloro-4-hydroxybenzaldehyde were dissolved in 150 ml dimethylformamide. 4.7 g cesiumcarbonate were added and the reaction mixture stirred at room temperature for four hours. The reaction mixture was then diluted by adding 300 ml ethyl acetate and washed three times with 50 ml water, saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo to provide 3.0 g 4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-benzaldehyde as oil.
Reaction SMILES: ClCCN(CCCl)C(Cl)=O.[Cl:11][CH2:12][CH2:13][N:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:15][CH2:16][Cl:17].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1)[NH2:27].C1(C)C=CC=CC=1>C(O)C>[Cl:17][CH2:16][CH2:15][N:14]([C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:13][CH2:12][Cl:11].[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:21]([NH:20][C:18]([N:14]([CH2:13][CH2:12][Cl:11])[CH2:15][CH2:16][Cl:17])=[O:19])=[S:22])[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)N(CCCl)CCCl
Agent: O=C(N=C=S)N(CCCl)CCCl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N(CCCl)CCCl)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
[Di(2-chloroethyl)amino]methanoyl isothiocyanate was prepared using commercially available N,N-di(2-chloroethyl)carbamic chloride (80 mg) as a starting compound according to the description of the literature. [Di(2-chloroethyl)amino]methanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (51 mg, yield 60%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[N:3]1[CH2:21][CH2:22][CH2:23][CH2:24][OH:25].[C:27](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.CN(C)C=O>CN(C)C1C=CN=CC=1.CCOCC.O>[O:20]=[C:4]1[N:3]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:2]([CH3:26])([CH3:1])[C:6](=[O:7])[N:5]1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:17])([F:18])[F:19])[CH:9]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Yield: 76.2 %

Procedure:
370 mg of the product of Example 58, 307 mg of trityl chloride in the presence of 10 mg of 4-dimethylaminopyridine, 0.25 ml of triethylamine and 4 ml of dimethylformamide were stirred at ambient temperature for 16 hours. The mixture was heated to 40° C. for 4 hours, poured into water and extraction was carried out with ether. The extracts were washed with water and dried and the solvent was eliminated under reduced pressure. The residue was chromatographed on silica (eluant: cyclohexane--ethyl acetate 75-25) to obtain 467 mg of the expected product with a Rf=0.25.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:29]=2[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:20]=1)[C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:50]([O:53][CH2:54]Cl)(=[O:52])[CH3:51].[I-].[Na+].C(N(CC)CC)C>CC(C)=O.CN(C=O)C>[C:50]([O:53][CH2:54][O:16][C:15](=[O:17])[C:14]1[CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:29]=2[O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:20]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=1)(=[O:52])[CH3:51]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)O)c1
Reactant: CC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)OCOC(C)=O)c1
Yield: 23.5 %

Procedure:
A mixture of 0.5 g (0.75 mmol) of 3-(decyloxy)-5-[[6-[2,3-bis (phenylmethoxy)phenyl]hexyl]oxy]benzoic acid, 0.25 g (2.25 mmol) of chloromethyl acetate, 0.23 g (1.5 mmol) of sodium iodide and 0.31 ml (2.25 mmol) of triethylamine in 15 ml of acetone and 5 ml of DMF was stirred at reflux under argon for 19 hours. The solvent was removed under reduced pressure, NaHCO3 solution was added to the residue and the product was extracted with ethyl acetate. The dried extract was concentrated to an oil which was purified by HPLC using 10% ethyl acetate-hexane to give 0.13 g of 3-(decyloxy)-5-[[6-[2,3-bis(phenylmethoxy)phenyl]hexyl]oxy]benzoic acid (acetyloxy)methyl ester as an oil. A mixture of 0.13 g of 3-(decyloxy)-5-[[6-[2,3-bis (phenylmethoxy)phenyl]hexyl]oxy]benzoic acid (acetyloxy)methyl ester and 0.1 g of 10% palladium on carbon in 15 ml of ethyl acetate was stirred under a hydrogen atmosphere for 3.5 hours when uptake ceased. The usual workup gave 0.07 g of 3-(decyloxy)-5-[[6-(2,3-dihydroxyphenyl)hexyl]oxy]benzoic acid (acetyloxy) methyl ester as an oil. The structure was confirmed by the nmr and mass spectra.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (300 mg, 0.83 mol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (156 mg, 0.83 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (239 mg, 1.25 mmol) and 1-hydroxybenzotriazole hydrate (127 mg, 0.83 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (283 mg, 64%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1cc(F)cc(F)c1
Product: N#Cc1cc(-c2cc(F)cc(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (66 mg, 82%), MS (ISN) m/z=324.5 [(M+H)+], mp 264° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3,5-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:21]#[N:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([CH:18]=1)[C:21]#[N:22]
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.3 %

Procedure:
4-(5-Cyano-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2.45 g) described in Preparation Example 102 was dissolved in dichloromethane (15 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 6 hr. The solvent was evaporated from the reaction mixture, aqueous potassium carbonate solution was added, and the mixture was extracted with chloroform. The solvent was evaporated from the organic layer, the obtained residue was purified by NH-coated silica gel silica gel column chromatography (hexane:ethyl acetate) to give the title compound (1.07 g).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18](O)[CH2:19][Si](C)(C)C)=[C:12]([Br:25])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]=[CH2:19])=[C:12]([Br:25])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CC(O)CCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 4-(4-benzenesulfonyl-2-bromo-phenyl)-1-trimethylsilanyl-butan-2-ol (4.38 g) in DCM (80 mL) was added BF3.OEt2 (3.76 mL) at 0° C. under N2 atmosphere. The reaction was stirred at 0° C. for 1 h it was then quenched by addition of NaHCO3 (saturated solution). The mixture was extracted twice with DCM and the combined extracts were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (hexane/EtOAc, 9/1) to afford 4-benzenesulfonyl-2-bromo-1-but-3-enyl-benzene (3.38 g, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([Sn](CCCC)(CCCC)CCCC)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:28]=[CH:27][C:26](I)=[C:25]([CH3:30])[C:22]=1[C:23]#[N:24]>C1(C)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>[NH2:20][C:21]1[CH:28]=[CH:27][C:26]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:25]([CH3:30])[C:22]=1[C:23]#[N:24]
Reactant: Cc1c(I)ccc(N)c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(Cl)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(Cl)s2)ccc(N)c1C#N
Reaction time: 18 h
Yield: 53.6 %

Procedure:
A solution of 5.9 grams (0.015 mole) of (5-chlorothien-2-yl)tributyl tin and 3.0 grams (0.015 mole) of 2-amino-5-iodo-6-methylbenzonitrile in 150 mL of toluene was stirred, and 0.2 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0) was added. The reaction vessel was evacuated, and then back-filled with dry nitrogen gas. This process was repeated two more times. The reaction mixture was then heated to reflux where it was stirred for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride, and the solution was filtered through a fiber-glass pad to remove the catalyst. The filtrate was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.0 grams of 2-amino-6-methyl-5-(5-chlorothien-2-yl)benzonitrile, mp 108°-110° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:23]([CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26])[C:10]2=[O:12]
Reactant: O=C(O)c1cccc(OCc2cccc(Cl)c2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cccc(Cl)c4)c3C2=O)C(=O)N1
Yield: 36.4 %

Procedure:
A mixture of 3-(3-chloro-benzyloxy)-phthalic acid (1.6 g, 5.1 mmol), alpha-amino-glutarimide hydrochloride (0.87 g, 5.3 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(3-chloro-benzyloxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (0.74 g, 37% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 6.44 min (99.8%); mp, 249-251° C.; 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H, CHH), 2.54-2.62 (m, 2H, CH2), 2.83-2.91 (m, 1H, CHH), 5.12 (dd, J=6, 12 Hz, 1H, CH), 5.39 (s, 2H, CH2), 7.40-7.87 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.92, 48.77, 69.05, 115.72, 116.69, 120.10, 125.65, 126.85, 127.84, 130.42, 133.18, 133.26, 137.07, 138.76, 155.19, 165.32, 166.74, 169.89, 172.75. Anal Calcd For C20H15N2O5Cl+0.1H2O: C, 59.96; H, 3.82; N, 6.99; Cl, 8.85. Found: C, 59.93; H, 3.54; N, 6.91; Cl, 9.00.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]1[OH:65]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][C@@H:59]5[CH2:64][CH2:63][CH2:62][CH2:61][C@@H:60]5[OH:65])=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: N[C@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCC[C@@H]2O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and cis-(±)-2-aminocyclohexanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.93 (m, 18 H) 3.31 (s, 3 H) 3.73-3.91 (m, 2 H) 3.95 (s, 3 H) 4.06 (t, J=13.39 Hz, 2 H) 4.47 (m, 1 H) 4.70 (br. s., 1 H) 7.47 (d, J=8.0 Hz, 1 H) 7.53 (s, 1 H) 7.79 (d, J=7.83 Hz, 1 H) 7.90 (s, 1 H) 8.21 (s, 1 H) 8.27 (d, J=8.34 Hz, 1 H). [M+H] calculated for C28H36F2N6O4, 559; found 559.