Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@H:17]3[CH2:21][O:20][C:19]([C:22]4[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=4[F:29])=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.CO.C[O-].[Na+].C(O)(=O)C>O>[F:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:29])[C:22]=1[C:19]1[O:20][CH2:21][C@H:17]([C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([SH:4])=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)[N:18]=1
Reactant: CN(C)C(=O)Sc1ccc(-c2ccc([C@H]3COC(c4c(F)cccc4F)=N3)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Fc1cccc(F)c1C1=N[C@@H](c2ccc(-c3ccc(S)cc3)cc2)CO1
Temperature: 60 °C
Reaction time: 72 h
Yield: 59.7 %

Procedure:
A mixture of 0.60 g of (S)-S-[4'-[2-(2,6-difluorophenyl)-4,5-dihydro-4-oxazolyl][1,1'-biphenyl]-4-yl] dimethylcarbamothioate, 5 mL of methanol, and 0.30 g of 25% NaOMe solution was heated at 60° C. for 7 h and allowed to stand at ambient temperature for 3 d. After adding 0.5 mL of acetic acid and 5 mL of water, the product was filtered, washed with water, and suction-dried to afford 0.30 g of product, m.p. 133-135° C. The 1H NMR (CDCl3) spectrum was the same as that of the racemic product of Example 5.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:13][CH2:14][C@:15]1([F:28])[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[Cl:12][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([NH:13][CH2:14][C@:15]2([F:28])[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16]2)[N:11]=1
Reactant: Clc1cc2ncccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CN)C1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(CNc2nc(Cl)cc3ncccc23)C1
Temperature: 110 °C
Reaction time: 17 h

Procedure:
A mixture of 5,7-dichloro-1,6-napthyridine (1 eq, 1 wt), 1,1-dimethylethyl (3R)-3-(aminomethyl)-3-fluoro-1-piperidinecarboxylate (1.1 eq, 1.28 wt), and diisopropylethylamine (2 eq, 1.75 vol) in NMP (6 vol) is stirred at 110±5° C. for 17 h. The solution is cooled to 70-75° C. and water (6 vol) added over 47 min at 65-75° C. The mixture is aged at 65-75° C. for 50 min, then cooled to 45° C. to give a slurry. The mixture is slowly cooled to 20-25° C. then aged for 2.25 h. The solid is collected under suction. The filter cake is washed with 1:2 v/v NMP/water (2 vol) then water (2×4 vol) and dried in vacuo at 40±5° C. As the solid still contains significant NMP (16.2% w/w) it is reslurried in 1:1 v/v NMP/water (7.3 vol). The slurry is heated to 65° C. and stirred at 65-66° C. for 1 h. The slurry is cooled to 20-25° C. and aged for 3 days. The solid is collected under suction. The filter cake is washed with 1:2 v/v NMP/water (2 vol) then water (2×4 vol) and dried in vacuo at 40±5° C.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)O1>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([C:37]2[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=[CH:39][CH:38]=2)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccnc3ccccc23)OC1(C)C
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(-c3ccnc4ccccc34)nc21

Procedure:
Following General Procedure A for Suzuki coupling, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline were reacted to give 475. LCMS: M+H+=501.3
Reaction SMILES: Br.C[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O.C>C(O)(=O)C.C(#N)C>[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cccc2c1CCC2N1CCCCC1
Agent: Br
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: Oc1cccc2c1CCC2N1CCCCC1
Temperature: 0 °C

Procedure:
Hydrobromic acid (47-49%, 750 ml) is added to a stirred solution of the 4-methoxy-1-piperidinylindan (75 g) in glacial acetic acid (750 ml) under nitrogen. The mixture is refluxed for four hours, allowed to cool and poured into crushed ice and water. The pH of the ice mixture is adjusted to about 9 and the aqueous mixture extracted with methylene chloride. The methylene chloride extract is washed with water thereby forming a precipitate which is filtered and the solid dried. The methylene chloride layer is evaporated yielding an oil. The solid is dissolved in acetonitrile and treated with charcoal. The oil is treated with charcoal and dissolved in acetonitrile. Both dissolved materials are recrystallized from acetonitrile yielding the desired product, M.P. 134.5°-136.5° C.
Reaction SMILES: [OH:1][C@@H:2]([C:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:27](OC(C)=O)([CH3:30])([CH3:29])[CH3:28]>Cl(O)(=O)(=O)=O>[C:27]([O:1][C@@H:2]([C:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:21])=[O:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@@H](O)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of (S)-ethyl 2-hydroxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (560 mg, 1.42 mmol) in t-BuOAc (32.0 mL, 381 mmol) was added 4 drops (catalytic) of 70% HClO4 and the mixture allowed to stir at room temperature for 2 hrs. The mixture was quenched by dumping it into an icy solution of saturated NaHCO3. Extraction with EtOAc (3×20 mL), drying with sodium sulfate and subsequent chromatography on silica gel using EtOAc in Hexanes gave (S)-ethyl 2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. 1H-NMR: 400 MHz, (CDCl3): δ 8.06-8.03 (m, 1H); 7.81-7.78 (m, 1H); 7.67 (s, 1H); 7.59-7.53 (m, 2H); 5.73 (s, 1H); 4.25-4.10 (m, 2H); 2.55 (s, 3H); 1.21 (s, 9H), 1.17 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:15]=2[N:16]=1.[Cl:27][C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:37]=[CH:38][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH2:19][CH2:18]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:24]=[CH:25][CH:26]=[C:3]([O:2][CH3:1])[CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: COc1cccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)c1
Product: COc1cccc(CCc2nc3c(N4CCN(C(=O)COc5ccc(Cl)cc5)CC4)nc(N)nc3s2)c1
Yield: 48 %

Procedure:
This compound was prepared from 2-(3-methoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 48%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:32]3[CH2:33][CH2:34][N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:30][CH2:31]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)nn2-c2ccccc2)cc1

Procedure:
49 mg (62%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (55 mg, 0.187 mmol), 1-phenylpiperazine (0.026 mL, 0.170 mmol), DIPEA (0.030 mL, 0.170 mmol) and NaBH(OAc)3 (108 mg, 0.510 mmol).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[C:9]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:10][CH:11]=[CH:12][CH:13]=2)[O:5][N:4]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[Na+]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.COCCOC>[C:18]([O:17][C:15]([N:14]([C:9]1[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][C:40]3[CH:39]=[CH:38][C:37]([CH2:36][O:35][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=4)=[CH:42][CH:41]=3)[CH:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])=[O:16])([CH3:19])([CH3:21])[CH3:20]
Reactant: OB(O)c1ccc(COc2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(CCl)no1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 77.4 %

Procedure:
Under nitrogen atmosphere, to a mixture of di-tert-butyl {3-[3-(chloromethyl)isoxazol-5-yl]pyridin-2-yl}imidodicarbonate (164 mg, 0.40 mmol), {4-[(pyridin-2-yloxy)methyl]phenyl}boronic acid (138 mg, 0.60 mmol), cesium carbonate (391 mg, 1.20 mmol), copper(I) iodide (3.9 mg, 5 mol %) and 1,2-dimethoxyethane (2.0 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (16.4 mg, 5 mol %), which was stirred at 80° C. for 1.5 hours. {4-[(Pyridin-2-yloxy)methyl]phenyl}boronic acid (46 mg, 0.20 mmol) was added thereto and the solution was further stirred for 4.5 hours. After cooling, ethyl acetate and 5% sodium chloride solution were added thereto, insoluble matter was filtered out, then, the filtrate was transferred to a separatory funnel and separated. After the organic layer was washed with 5% sodium chloride water and dried over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography, so as to obtain the title compound (173 mg) as a pale yellow oily product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].CN(C)CCN(C)C.ICCCCI>C1COCC1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]1=[O:10]
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccccc2N1
Agent: CN(C)CCN(C)C
Agent: ICCCCI
Solvent: C1CCOC1
Solvent: O
Product: O=C1Nc2ccccc2C12CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
To a −25° C. solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm3) of anhydrous THF under N2 was added n-butyllithium (1.6 M in hexanes, 19.7 cm3, 31.5 mmol) drop-wise. To the resulting milky solution was added N,N,N′,N′-tetramethylethylenediamine (4.75 cm3, 31.5 mmol). After 30 min. a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in THF (3 cm3) was added and the reaction mixture was allowed to warm to RT and stirred for 14 h. The reaction mixture was poured into water, extracted with EtOAc (×2), then the combined organic layers were washed with dil. HCl (pH 1), water (×2), dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane 1:4) to afford the title compound (1.4 g, 7.5 mmol, 50%) as a tan solid: 1H NMR (CDCl3) δ 1.8-2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0 Hz, 1H), 7.01 (dd, J=7.5, 1.0 Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[Mg].[Br:9][C:10]1[CH:14]=[C:13](Br)[S:12][C:11]=1[CH3:16]>CCOCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:9][C:10]1[CH:14]=[C:13]([C:2]2[S:3][C:4]([CH3:7])=[CH:5][CH:6]=2)[S:12][C:11]=1[CH3:16]
Reactant: Cc1ccc(Br)s1
Reactant: Cc1sc(Br)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Mg]
Solvent: CCOCC
Product: Cc1ccc(-c2cc(Br)c(C)s2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
A solution of 2-bromo-5-methylthiophene (4.00 g, 22.6 mmol) in anhydrous ether (10 mL) was treated with magnesium turnings (0.577 g, 23.7 mmol) and heated at reflux for 45 min under an N2 atmosphere. The heat source was removed and the reaction mixture was slowly allowed to cool to room temperature when it was transferred to a flame-dried addition funnel via a cannula. A solution of 3,5-dibromo-2-methylthiophene (5.49 g, 21.5 mmol) and Pd(dppf)Cl2 (16.5 mg, 0.023 mmol) in 75 mL anhydrous ether was treated dropwise with the solution of the Grignard reagent over 30 min at 0° C. under an N2 atmosphere using an addition funnel. The resulting solution was allowed to slowly warm to room temperature and stirred for 72 h under an N2 atmosphere, when it was quenched with saturated NH4Cl (50 mL). The aqueous layer was separated and extracted with ether (3×75 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness in vacuo. The crude product was purified by flash chromatography (hexanes) yielding 4.32 g of pure BT3 as a white solid. Yield: 74%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:10]=[C:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].C=C(C)C>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:10]=[C:9]1[CH:24]=[O:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(CO)n2C(=O)OC(C)(C)C)C1
Agent: C=C(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(cc(C=O)n2C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
To a solution of 1,5-bis(t-butoxycarbonyl)-2-hydroxymethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (14.0 mg) in methylene chloride (2.0 ml), Dess-Martin periodinane (34.0 mg) was added at room temperature. The resulting mixture was stirred for 1 hour. To the reaction mixture, ethyl acetate (10 ml), a 10% aqueous solution (10 ml) of sodium thiosulfate and an aqueous solution (10 ml) of sodium bicarbonate were added to cause separation. The water layer was extracted with ethyl acetate (10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by thin-layer preparative chromatography on silica gel (hexane:ethyl acetate=2:1), whereby the title compound (9.8 mg) was obtained as a colorless transparent caramel-like substance. IR(KBr)cm−1: 2976, 2933, 1741, 1697, 1660, 1479, 1413, 1367, 1346, 1298, 1281, 1234, 1165, 1146, 1103, 895, 850, 768. 1H-NMR (CDCl3) δ: 1.48(9H,s), 1.63(9H,s), 2.96(2H,br t,J=5.4 Hz), 3.68(2H,br t,J=5.4 Hz), 4.37(2H,s), 6.97(1H,s), 10.14(1H,br s). MS (FAB/m-NBA) m/z: 351 [(M+H)+], 295 [(M+H-isobutene(56))+], 239 [(M+H)—2×isobutene (56))+].
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:4]([CH:5]=[CH:6][C:7](=[O:20])[C:8]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])#[CH:22].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.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.[Cu]I>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:8]1[C:7](=[O:20])[CH:6]=[CH:5][N:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:22]#[C:21][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])=[CH:3]2
Reactant: C#Cc1ccc(F)cc1F
Reactant: O=c1ccn2cc(Br)ccc2c1-c1c(F)cccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=c1ccn2cc(C#Cc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Temperature: 100 °C

Procedure:
To a solution of 7-bromo-1-(2,6-difluorophenyl)-2H-quinolizin-2-one (100 mg) was added 1ethynyl-2,4-difluorobenzene (82 mg), triethylamine (0.17 ml), dichlorobis(triphenylphosphine)palladium (25 mg), CuI (6 mg) in DMF was heated to 100° C. until reaction complete. The mixture was diluted with ethyl acetate, washed with water (4×), brine, dried over MgSO4, and concentrated to yield crude material. The crude material was purified by silica gel chromatography (100% ethyl acetate) to yield the title compound.
Reaction SMILES: [Cl-].C[Al+]C.CCCCCC.[CH3:11][C:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[CH:15]([C:20]([CH3:22])=[CH2:21])[C:14]([CH3:24])([CH3:23])[CH:13]=1.[CH:25](=[O:28])[CH2:26][CH3:27]>ClCCl>[CH2:26]([CH:25]([OH:28])[CH2:21][C:20](=[CH2:22])[CH:15]1[C:16]([CH3:18])([CH3:19])[CH2:17][C:12]([CH3:11])=[CH:13][C:14]1([CH3:24])[CH3:23])[CH3:27]
Reactant: CCC=O
Reactant: C=C(C)C1C(C)(C)C=C(C)CC1(C)C
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Product: C=C(CC(O)CC)C1C(C)(C)C=C(C)CC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
Dimethylaluminum chloride (60 mL of a 1M hexane solution) was added dropwise to a solution of 1,3,3,5,5-pentamethyl-4-(1-methylethenyl)-1-cyclohexene (7.70 g, 0.04 mol) and propionaldehyde (2.30 g, 0.04 mol) in dichloromethane (150 mL) at 25°-30° C. over a 15 min period. The mixture was stirred at 25° C. for 16 h. Work-up (as described in Example 2) and chromatography provided 2.20 g of α-ethyl-2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol, bp (kugelrohr bath) 125° C., 0.5 mm, (GLC purity, two isomers, 40.7% and 57.9%). 1H-NMR (60 MHz, CDCl3) δ0.98 and 1.03 (12H, 2s), 1.02 (3H, t, J=4 Hz), 1.63 (3H, s), 1.1-2.6 (8H, m), 3.5-3.9 (1H, m), 5.0-5.3 (3 H, broad s); IR (film) vmax 3350, 2950, 1640, 1460, 1380, 1360 cm-1 ; MS m/e 250, 235, 217, 125, 107, 96. The mass spectra of the diastereomers were nearly identical.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].Cl.N>O.CO.CC(O)C>[CH3:9][NH:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[CH:3]=1
Reactant: CNc1cc(Cl)ncn1
Reactant: N#Cc1cccc(N)c1
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: CNc1cc(Nc2cccc(C#N)c2)ncn1
Temperature: 25 °C

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-methylamine (1.44 g, 10 mmol), 3-amino-benzonitrile. (1.18 g, 10 mmol), 2-propanol (10 mL) and conc. HCl (0.45 mL, ˜5 mmol) is stirred for 36 h at 90° C. After cooling to room temperature, CH3OH is added and the reaction mixture is basified with conc. aqueous ammonia solution. The precipitate which forms upon addition of H2O is filtered off, washed with H2O and dried in vacuo to afford the title compound.
Reaction SMILES: [H-].[Na+].[N:3]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N+:4]=[N-:5].[CH3:19]I>C1COCC1>[N:3]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[N+:4]=[N-:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCOCCN=[N+]=[N-])C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
Sodium hydride (60% oil dispersion, 9.1 g, 228 mmol) was placed in a round bottom flask and washed with hexanes (3×) under N2. The dried sodium hydride was treated with 800 mL of anhydrous THF. A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (41.9 g, 182 mmol) in 200 mL of THF was then added to the stirred sodium hydride solution over 40 min. After addition was complete, the reaction was stirred an additional 20 min followed by addition of methyl iodide (13.6 mL, 218 mmol). After stirring overnight, the reaction was quenched with 300 mL of saturated NaHCO3 solution. The reaction mixture was then treated with 200 mL of H2O and 1 L of Et2O . The organic phase was separated and washed with H2O and brine. The organic portion was then dried over MgSO4 and concentrated under reduced pressure to give 41.9 g of tert-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate as a yellow liquid.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH2:22][CH:23]([CH3:25])[CH3:24])[O:11][C:10](=[O:12])[C:9]([O:13]CC3C=CC=CC=3)=[C:8]2[OH:21])=[CH:3][CH:2]=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH2:22][CH:23]([CH3:25])[CH3:24])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:21])=[CH:3][CH:2]=1
Reactant: CC(C)CC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CC(C)CC1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Yield: 69.4 %

Procedure:
Hydrogenolysis of 350 mg of 5-[(1,1'-biphenyl)-4-yl]-4-hydroxy-3-phenylmethoxy-5-(2-methylpropyl)-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide 190 mg (69% yield) of a white powder: mp 198-199° C. dec. (CHCl3 /hexanes). 1H NMR (acetone-d6) δ 7.73-7.34 (m, 9H), 2.44-2.28 (m, 1H), 1.50-0.80 (m,8H). 13C NMR (acetone-d6) δ 169.21, 155.47, 140.81, 139.57, 129.17, 127.73, 127.18, 127.08, 126.04, 118.47, 86.01, 40.66, 23.72, 12.11, 11.87. Anal Calcd for C20H20O4 +0.125 H2O: C, 73.55; H, 6.25. Found: C, 73.25; H, 6.36.