Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([S:4]([O-:7])(=[O:6])=[O:5])[CH3:3].[Na+].[CH2:9]([CH2:11][NH2:12])[OH:10]>O.C(O)C>[OH:10][CH2:9][CH2:11][NH:12][CH2:3][CH2:2][S:4]([OH:7])(=[O:6])=[O:5]
Reactant: NCCO
Reactant: CC(Br)S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)(O)CCNCCO
Reaction time: 17.5 h

Procedure:
A solution in 2 liters of water of 315 g of sodium bromoethanesulphonate (Organic Synthesis, Coll. Vol. II, p. 558) and 450 g of ethanolamine was heated to 60°-70° C. for 30 minutes. Excess ethanolamine and water were then distilled off under vacuum, and the residue dissolved in 250-270 ml of water. 2.2 Liters of concentrated hydrochloric acid was added and the solution kept in a refrigerator for 15-20 hours. The precipitated sodium chloride was filtered off using a filter pump, and the solution concentrated until a viscous oil was obtained. The oil was diluted with 60 ml of water and ethanol (about 500 ml) then added to precipitate the reaction product. After the mixture has been left one night in a refrigerator, precipitation was almost complete. The product obtained was filtered off with a filter pump. About 130-140 g of crystalline product was obtained, having a melting point of 180°-183° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH:31]=O)=[CH:25]2.N1CCCCC1>C(O)C>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH:31]=[C:10]1[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]1=[O:16])=[CH:25]2
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: CN(C)CCOc1ccc2[nH]c(C=O)cc2c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccc(-c5ccccc5)cc43)cc2c1
Temperature: 100 °C
Yield: 68.5 %

Procedure:
A mixture of 5-phenyl-2-oxindole (41 mg, 0.2 mmol), 5-(2-dimethylamino-ethoxy)-1H-indole-2-carbaldehyde (46 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 58 mg (68%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Br-].Cl.O1CC[CH2:17][CH2:16]1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]([OH:8])[CH:16]=[CH2:17])[CH:9]=1
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: Cl
Agent: [Br-]
Product: C=CC(O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: -78 °C
Yield: 73 %

Procedure:
5-Hydroxy-2-nitrobenzaldehyde (6.0 g) is dissolved in dry tetrahyrofuran (90 ml) and thereto is added dropwise vinylmnagnesium bromide (2.3 equivalents) with stirring at −78° C. The temperature of the reaction mixture is raised gradually. After completion of the reaction, 1N HCl is added to the reaction mixture, and the mixture is extracted with ethyl acetate, and the organic layer is separated, washed with an aqueous saturated saline solution, dried over sodium sulfate, and then distilled off the solvent. The residue is purified with a silica gel column chromatography to give 1-(5′-hydroxy-2′-nitrophenyl)-2-propen-1-ol (5.09 g) as yellowish brown powders.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][OH:28]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:25][CH2:26][CH2:27][OH:28])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCCCOc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.4 %

Procedure:
1.45 g (corresponding to 5.0 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 50 mL of N,N-dimethylformamide, and 2.07 g (corresponding to 15.0 mol) of potassium carbonate was added thereto. The mixture was supplemented with 680 μL (corresponding to 7.5 mmol) of 3-bromo-1-propanol, and then the solution was stirred at room temperature for 17 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was recrystallized from methanol to obtain 1.28 g (corresponding to 3.67 mmol) of 6-bromo-2-[4′-(3″-hydroxypropoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 1-2, Step 3).
Reaction SMILES: C([Li])CCC.[Br-].[N:7]1([CH2:12][CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.C(OC[N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[C:42]([C:44]1[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=1)=O)C>CCCCCC.C1COCC1>[NH:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH:42]([C:44]1[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=1)[CH2:13][CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: c1ccc([P+](CCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOCn1ccnc1C(=O)c1ccc(C)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(CCN2CCCC2)c2ncc[nH]2)cc1
Reaction time: 0.08 h
Yield: 106.4 %

Procedure:
A solution of n-butyl lithium in hexane (1.6 M, 7.7 ml) was added dropwise under nitrogen with stirring to a suspension of 2-(1-pyrrolidyl)ethyltriphenylphosphonium bromide (5.41 g) in dry THF (75 ml) keeping the temperature at -10° to -5°. The addition was complete after 5 min. The mixture was then stirred at 0° for 20 min. then cooled to -5° and treated with a solution of (1-ethoxymethylimidazol-2-yl)-4-methylphenylmethanone (3.0 g) in dry THF (30 ml). The mixture was stirred at room temperature for 16 h. and then the precipitated triphenylphosphine oxide was filtered off and washed with a little THF (10 ml). The filtrate and washings were combined and concentrated in vacuo to a yellow syrup. This was absorbed from chloroform (3 ml) onto a column of silica gel (Merck Kieselgel 60, 200 g). Removal of the solvent afforded isomers of the title compound as a thick yellow brown syrup (3.52 g) which was used in the next stage without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:39][CH3:40])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([S:37][CH3:38])[CH:28]=2)[C:22](=[O:25])[O:23][CH3:24])[CH:9]=1)([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:49])C=1.OS([O-])=O.[Na+]>C(Cl)Cl>[CH3:24][O:23][C:22](=[O:25])[N:21]([CH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:18])([F:19])[F:17])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:39][CH3:40])[CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[C:29]([S:37]([CH3:38])=[O:49])[CH:28]=1
Reactant: COC(=O)N(Cc1cc(SC)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(S(C)=O)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: -78 °C

Procedure:
Methyl {[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-(methylthio)-5-(trifluoromethyl)benzyl]carbamate (21.7 mg, 0.037 mmol) (Example 129) in CH2Cl2 (1 mL) was cooled to −78° C. Next, m-CPBA (8.3 mg, 0.037 mmol) was added. The reaction was stirred at −78° C. for fifteen minutes, then was warmed to −45° C., and after five minutes at −45° C. was poured into NaHSO3 (10 mL). The mixture was extracted with EtOAc (50 mL), and the organic extracts were washed with water (10mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 50% EtOAc/hexanes afforded methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-(methylsulfinyl)-5-(trifluoromethyl)benzyl]carbamate. Rf=0.20 (50% EtOAc/hexanes). LCMS=602.2 (M+1)+.1H NMR (C6D6, 500 MHz, 70° C.) δ 7.63 (broad singlet, 1H), 7.54 (broad singlet, 1H), 7.48 (broad singlet, 1H), 7.33 (s, 1H), 7.32 (s, 1H), 7.07-7.05 (m, 2H), 6.89 (s, 1H), 6.62 (d, J=8.0 Hz, 1H), 4.41 (broad singlet, 2H), 4.04 (broad singlet, 2H), 3.37 (s, 3H), 3.30 (s, 3H), 2.75 (m, 1H), 1.93 (s, 3H), 1.16 (d, J=6.5 Hz, 6H).
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].Cl.[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1>>[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][CH:15]([N:18]2[CH2:8][CH2:7][CH:2]2[C:3]([O:5][CH3:6])=[O:4])[CH2:14][CH2:13]1
Reactant: CC1(C)CCC(N)CC1
Reactant: COC(=O)C(Br)CCBr
Agent: Cl
Product: COC(=O)C1CCN1C1CCC(C)(C)CC1
Yield: 52 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with 4,4-dimethylcyclohexylamine hydrochloride 18C yielded methyl 1-(4,4-dimethylcyclohexyl)azetidine-2-carboxylate as a brown oil (52%). MS ISP (m/e): 226.3 (100) [(M+H)]+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]=O.[BrH:15]>>[BrH:15].[CH2:13]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]([C:10]([OH:12])=[O:11])[NH:1]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=O
Agent: Br
Product: O=C(O)C1Cc2ccccc2CN1
Temperature: 65 °C
Reaction time: 7 h
Yield: 86.4 %

Procedure:
To 10 g of L-phenylalanine suspended in 108 ml of 47% hydrobromic acid, 23 ml of 37% formalin aqueous solution was added dropwise. The reaction mixture was stirred at 65° C. for 7 hours, and subjected to crystallization under ice cooling for 3 hours. The precipitate was filtered off, and dried at 55° C. under reduced pressure to obtain 13.5 g of Compound 2 (yield 86.4%, optical purity 97% ee).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH3:27][C:28]1([CH3:36])[O:32][CH:31]([CH2:33][CH2:34]O)[CH2:30][O:29]1>C1COCC1.C(#N)C>[I:25][CH2:34][CH2:33][CH:31]1[CH2:30][O:29][C:28]([CH3:36])([CH3:27])[O:32]1
Reactant: CC1(C)OCC(CCO)O1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC1(C)OCC(CCI)O1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
Triphenylphosphine (172 mmol, 45 g) and imidazole (172 mmol, 12 g) were dissolved in THF/acetonitrile (3:1, 300 ml). The mixture was cooled under an ice bath, and iodine (172 mmol, 44 g) was added in four portions with vigorous stirring over 20 minutes. The resulting slurry was warmed to 20° C. and then cooled to 0° C. (±)-2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (156 mmol, 25 g) was added dropwise to the reaction mixture over 15 minutes. The mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with 5% sodium bicarbonate solution and extracted with hexane. The combined organic layer was dried with MgSO4 and concentrated. Silica gel chromatography gave 4-(2-iodo-ethyl)-2,2-dimethyl-[1,3]dioxolane as a clear oil; 1H NMR (400 MHz, CDCl3): δ 4.18-4.12 (m, 1H), 4.06 (dd, 1H, J=8.0 Hz, J2=6.1 Hz), 3.55 (dd, 1H, J1=8.0 Hz, J2=6.5 Hz), 3.28-3.17 (m, 2 H), 2.11-1.98 (m, 2H), 1.38 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:14][N:13]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH2:20])=[O:19])[C:12](=[O:24])[CH2:11]1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.N(C)(C)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([CH:29]=[CH:28][CH:27]=1)[O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:14][N:13]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH2:20])=[O:19])[C:12](=[O:24])[CH2:11]1
Reactant: COc1ccc(C2CC(=O)N(c3cccc(C(N)=O)c3)C2)c(O)c1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)C
Solvent: ClCCl
Product: COc1ccc(C2CC(=O)N(c3cccc(C(N)=O)c3)C2)c(Oc2cccc(Cl)c2)c1
Reaction time: 24 h
Yield: 17.9 %

Procedure:
3-[4-(2-Hydroxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]benzamide (32 mg, 0.1 mmol), 3-chlorobenzeneboronic acid (19 mg, 1.2 eq), and copper acetate (1 eq) were added to a dry tube. The mixture was charged with 2 mL CH2Cl2, (CH3)3N (3 eq) followed by addition of 4 Å MS. The mixture was stirred for 24 h and diluted with 10 mL CH2Cl2. After filtration, the mixture was washed with NH4Cl, water, and brine, and then dried. After concentration, the residue was purified by preparative LC-MS to give 7.8 mg of the desired product. Yield: 18%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH:44]=[O:45])=[C:18]([N:22]3[CH:26]=[C:25]([C:27]#[N:28])[C:24]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[O:37])=[CH:32][CH:31]=4)=[N:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C[OH:49]>ClCCl.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH2:44][OH:45])=[C:18]([N:22]3[CH:26]=[C:25]([C:27]([NH2:28])=[O:49])[C:24]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([N:38]5[CH2:39][CH2:40][O:41][CH2:42][CH2:43]5)=[O:37])=[CH:32][CH:31]=4)=[N:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3C=O)ncc2c1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C(N)=O)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(3-(6-tert-Butyl-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-3-[4-(morpholine-4-carbonyl)phenylamino]pyrazole-4-carbonitrile (53 mg, 0.0875 mmol) was dissolved in 6 mL of dichloromethane and 2 mL of methanol. Sodium borohydride solution (8.28 mg, 0.219 mmol) in water (0.5 mL) and methanol (1.0 mL) was added in drops. The mixture was stirred at room temperature for 1 hr. LC/MS showed a clean desired product. The mixture was evaporated to dryness and extracted with dichloromethane and water. The organic layer was dried over sodium sulfate and evaporated to give a pure desired 1-[3-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl]-3-[4-(morpholine-4-carbonyl)phenylamino]-1H-pyrazole-4-carbonitrile (52.8 mg, 100% yield). LC/MS clacd for C34H33N7O4 (m/e) 603.26, obsd 604.1 (M+H, ES+); 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 9H), 3.61-3.77 (m, 8H), 4.35 (br. s., 2H), 6.59 (br. s., 1H), 7.43 (d, J=8.6 Hz, 2H), 7.50 (d, J=8.1 Hz, 1H), 7.58 (d, J=8.6 Hz, 2H), 7.67 (t, J=8.1 Hz, 1H), 7.80 (d, J=1.7 Hz, 1H), 7.83 (dd, J=8.1, 1.3 Hz, 1H), 7.97 (dd, J=8.6, 1.7 Hz, 1H), 8.39 (d, J=0.5 Hz, 1H), 8.48 (d, J=8.6 Hz, 1H), 8.79 (s, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CN(C)C=O.C(Cl)(Cl)(Cl)Cl>[CH2:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:3])=[O:21])=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1

Procedure:
A 300 ml two-necked flask equipped with a stirrer and a reflux condenser was charged with 100 ml of carbon tetrachloride, 4.5 ml of thionyl chloride and 11.1 g of 4-n-decyloxybenzoic acid obtained by a conventional method, and heated under reflux together with one drop of dimethylformamide for 4 hours. Then, unreacted thionyl chloride was removed under reduced pressure to obtain 4-decyloxybenzoyl chloride as a colorless liquid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>>[CH3:40][O:39][CH2:38][CH2:37][O:36][C:34](=[O:35])[NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COCCOC(=O)Cl
Agent: Cl
Product: COCCOC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and 2-methoxyethyl chloroformate by using the same method as in Example 107.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:2]=[O:1]
Reactant: COC(=O)CBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C=O)cc1OC
Yield: 77 %

Procedure:
Vanillin was alkylated with methyl bromoacetate in DMF in the presence of K2CO3 in the usual way to give a colorless solid (77%). mp 91°-93 ° C. IR(KBr) cm-1 1760, 1682. 1H NMR(300 MHz, CDCl3): 9.86 (s, 1H), 7.44-7.40 (m, 2H), 6.86 (d, 1H, J=8 Hz), 4.79 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H). Anal. Calc'd for C11H12O5 : C, 58.92; H, 5.41; Found: C, 59.02; H, 5.26.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][Si:6]([C:9]#[C:10][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[O:12])([CH3:8])[CH3:7]>CCOCC>[CH3:8][Si:6]([C:9]#[C:10][C:11]([OH:12])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:2]#[CH:1])([CH3:7])[CH3:5]
Reactant: CCCCC(=O)C#C[Si](C)(C)C
Reactant: C#CCBr
Solvent: CCOCC
Product: C#CCC(O)(C#C[Si](C)(C)C)CCCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of 1.29 g of magensium and 10 mg of mercuric chloride in 12 ml of ether is added 0.4 ml of propargyl bromide. The reaction is initiated after stirring at room temperature for a few minutes. The stirred mixture is cooled in an ice-water bath and a solution of 9.64 g of n-butyl trimethylsilylethynyl ketone and 3.51 ml of propargyl bromide in 13 ml of ether is added dropwise so that the mixture is very gently boiling during 40 minutes. After addition, the cooling bath is removed and the mixture is stirred at room temperature for 1.5 hours. The mixture is recooled in an ice bath and 10 ml of saturated ammonium chloride solution is added. The resulting white mixture is filtered through diatomaceous earth. The clear mother liquor is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated to dryness giving 10.5 g of a red liquid. This liquid is Kugelrohr-distilled at 60° C./0.25-0.3 mm. The pale yellow liquid distillate which is the desired product weighs 8.5 g.
Reaction SMILES: Cl.O1CCO[CH:3]1[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[O:13][CH:12]([CH3:19])[CH2:11]2.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCOCC1>[CH3:19][CH:12]1[CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([CH2:7][CH2:3][N:30]3[CH2:29][CH2:28][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:32][CH2:31]3)[CH:9]=2)[C:14](=[O:18])[O:13]1
Reactant: CC1Cc2cc(CC3OCCO3)ccc2C(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1Cc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A 1:1 solution of dioxane:3N HCl was added to a flask containing of 780 mg (3.2 mmol) of 6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one. The reaction was then stirred at room temp overnight. The crude reaction mixture was then partitioned between water and DCM. The organic layer was washed with saturated sodium bicarbonate solution, followed by brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. The crude aldehyde was redissolved in DCM. To the solution was added boc-piperazine (671 mg, 3.6 mmol) followed by sodium triacetoxyborohydride (1.9 g, 9.0 mmol). the reaction mixture was allowed to stir overnight before being quenched with 10 mL of MeOH. The excess solvent was removed and the residue was re-redissolved in DCM; washed with water and brine, dried with magnesium sulfate, filtered, concentrated and purified via MPLC (50-100% EtOAc/Hex) to afford 850 mg of tert-butyl 4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate as a golden oil. 1H NMR (500 MHz; CDCl3): 8.02 (d, J=7.8 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.09 (s, 1H), 4.68 (m, 1H), 3.49 (m, 4H), 2.94 (m, 4H), 2.88 (m, 2H), 2.51 (m, 4H), 1.54 (d, J=6.8 Hz, 3H), 1.48 (s, 9H). LC-MS (IE, m/z): 375 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.O>CC(CC)=O>[CH3:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CNC(=O)C=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CNC(=O)C=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
195 mg (1.1 mmol) 3-(4-hydroxy-phenyl)-N-methyl-acrylamide is dissolved in 25 ml ethyl methyl ketone and 304 mg (2.2 mmol) potassium carbonate is added, followed by 289 mg (1.2 mmol) of 4-(trifluoromethyl)benzyl bromide. The reaction mixture is stirred overnight at RT, heated to 50° C. for 3 hours, treated with water and extracted 3 times with dichloromethane. The extract is dried over magnesium sulfate, concentrated and treated with ether to yield 260 mg (70%) of a colorless solid. MS: m/e=336.1 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=[CH:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.[C:25]([C:27]1[C:28](=[C:38]([C:41]#[N:42])[C:39]#[N:40])[O:29][C:30]([CH3:37])([C:33]([F:36])([F:35])[F:34])[C:31]=1[CH3:32])#[N:26]>C(O)C.O1CCCC1>[C:25]([C:27]1[C:28](=[C:38]([C:39]#[N:40])[C:41]#[N:42])[O:29][C:30]([CH3:37])([C:33]([F:36])([F:34])[F:35])[C:31]=1[CH:32]=[CH:23][C:21]1[S:22][C:18]([CH:17]=[CH:16][C:4]2[CH:5]=[C:6]3[C:15]4[N:10]([CH2:9][CH2:8][CH2:7]3)[CH2:11][CH2:12][CH2:13][C:14]=4[C:3]=2[O:2][CH3:1])=[CH:19][CH:20]=1)#[N:26]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: COc1c(C=Cc2ccc(C=O)s2)cc2c3c1CCCN3CCC2
Solvent: C1CCOC1
Solvent: CCO
Product: COc1c(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)cc2c3c1CCCN3CCC2
Temperature: 60 °C
Yield: 77.4 %

Procedure:
In 5 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 135 mg (0.40 mmol) of 5-[2-(8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-yl)vinyl]thiophene-2-carboaldehyde and 110 mg (0.43 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 60° C. for 3.5 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with methanol to give 178 mg of a dark brown crystal (yield: 78.1%; mp: 159-161° C.)