Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH3:2][Si:3]([CH3:29])([CH3:28])[C:4]#[C:5][CH:6]=[CH:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.C(=O)=O.[CH:38]([C@H:40]1[O:44][C:43]2([CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[O:42][C@H:41]1[CH2:50][O:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=O>C1COCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH3:2][Si:3]([CH3:29])([CH3:28])[C:4]#[C:5]/[CH:6]=[CH:7]/[CH:8]=[CH:38]\[C@H:40]1[O:44][C:43]2([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]2)[O:42][C@H:41]1[CH2:50][O:51][CH2:52][C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54]
Reactant: CC(C)(C)OC(=O)COC[C@@H]1OC2(CCCCC2)O[C@@H]1C=O
Reactant: C[Si](C)(C)C#CC=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C=O
Agent: O=P([O-])([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COC[C@@H]1OC2(CCCCC2)O[C@@H]1/C=C\C=C\C#C[Si](C)(C)C
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
A slurry of 5-trimethylsilylpent-2-en-4-ynyltriphenyl-phosphonium bromide, a compound of formula (Q), (67.1 g, 0.14 mol) in THF (875 mL) was stirred under nitrogen, cooled in a dry ice acetonitrile bath (−30° C. internal), and treated with a solution of n-butyllithium (66.5 mL, 0.133 mol, 2M in hexane) via dropwise addition. The dry ice bath was replaced with an ice bath and the reaction was stirred for about 15 minutes until a homogeneous, red-colored mixture was obtained. The dry ice bath was replaced and the reaction mixture was cooled to about −30° C. The reaction mixture was treated with a solution of 1,1-dimethylethyl [[(2S,3S) 3-formyl-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]acetate (40 g, 0.127 mol) in 125 mL of THF. The reaction mixture was stirred for 1 hour with the dry ice bath. With the internal temperature around −30° C., the reaction mixture was diluted with saturated potassium phosphate (pH=5). The aqueous layer was washed with ether (3×). Combined organic layers were washed with water and brine, dried, treated with silica gel, and concentrated. The residue was diluted with about 3:1 mixture of hexane to ethyl acetate to precipitate the impurities. The resulting slurry was filtered and the solid was washed with the hexane/ethyl acetate mixture. The filtrate was concentrated. The procedure was repeated using a mixture of ether and hexane (1:1) and treatment with silica gel to give 50.29 g of 1,1-dimethylethyl [[(2S,3R)-3-[(1Z,3E)-6-(trimethylsilyl)-1,3-hexadien-5-ynyl]-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]ethanoate as an oil. Proton NMR analysis of the product indicated a 2:1 mixture of E,Z- to E,E-isomers. The data for the for the Z,E isomer can be extracted from the mixture: 1H NMR (CDCl3) δ 0.15 (s, 9H), 1.3 (m, 2H), 1.4 (s, 9H), 1.6 (m, 8H), 3.45 (m, 2H), 3.92 (m, 2H), 4.34 (m, 1H), 5.02 (m, 1H), 5.48 (dd, 1H), 5.6 (d, 1H), 6.16 (dd, 1H), 6.82 (dd, 1H) ppm.
Reaction SMILES: FC1C=C(C(C)(C)CC(O)(C(F)(F)F)C=O)C2OCCC=2C=1.[F:23][C:24]1[CH:25]=[C:26]([C:33]([CH3:55])([CH3:54])[CH2:34][C:35]([OH:53])([C:49]([F:52])([F:51])[F:50])[CH:36]=[N:37][C:38]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:39]=2[CH:40]=[CH:41][NH:42][C:43]3=[O:48])[C:27]2[O:31][CH2:30][CH2:29][C:28]=2[CH:32]=1.[BH4-].[Na+]>>[F:23][C:24]1[CH:25]=[C:26]([C:33]([CH3:55])([CH3:54])[CH2:34][C:35]([OH:53])([C:49]([F:51])([F:50])[F:52])[CH2:36][NH:37][C:38]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:39]=2[CH:40]=[CH:41][NH:42][C:43]3=[O:48])[C:27]2[O:31][CH2:30][CH2:29][C:28]=2[CH:32]=1
Reactant: CC(C)(CC(O)(C=Nc1cccc2c(=O)[nH]ccc12)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(CC(O)(CNc1cccc2c(=O)[nH]ccc12)C(F)(F)F)c1cc(F)cc2c1OCC2

Procedure:
Analogously to Example 1, 4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is converted with 5-aminoisoquinol-2(1H)-one into 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]isoquinol-1(2H)-one, which is reduced with sodium borohydride to the product.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)=[N:10][C:9]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:10][C:9]=1[C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Nc2nc(-c3ccc(OC)cc3)c(Cc3ccccc3)s2)cc1
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccc(O)cc2)c(Cc2ccccc2)s1)c1ccc(O)cc1
Yield: 67.9 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-4-methyoxy-benzamide prepared in Example 27 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a white solid in a yield of 67.9%, mp: 254-255 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.20 (2H, s, CH2), 6.84 (4H, t, J=7.80 Hz, ArH), 7.20˜7.28 (3H, m, ArH), 7.33 (2H, t, J=8.08 Hz, ArH), 7.47 (2H, d, J=8.64 Hz, ArH), 7.97 (2H, d, J=8.60 Hz, ArH), 9.61 (1H, s, OH), 10.29 (1H, s, OH), 12.34 (1H, s, CONH); EI-MS m/e (%): 402.0 (M+, 82), 282.1 (74), 121.0 (100); HREI-MS Calcd. for C23H18N2O3S: 402.1038. found: 402.1027.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[NH:20][CH2:19][CH2:18][N:9]2[C:10](=[O:17])[C:11]2[N:12]([CH:14]=[CH:15][CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C.[NH4+].[Cl-]>[Si:31]([O:30][CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[NH:20][CH2:19][CH2:18][N:9]2[C:10](=[O:17])[C:11]2[N:12]([CH:14]=[CH:15][CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: O=C1c2cccn2CC2(c3ccc(O)cc3)NCCN12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C23Cn4cccc4C(=O)N2CCN3)cc1
Temperature: 100 °C
Yield: 105.9 %

Procedure:
To a suspension of 10a-(4-hydroxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (50 mg, 0.19 mmol) and potassium carbonate (77 mg, 0.56 mmol) in DMF (1 mL) was added (2-bromoethoxy)-tert-butyldimethylsilane (120 μL, 0.56 mmol). The mixture was heated at 100° C. The outcome of the reaction was monitored by LCMS. After completion (45 minutes) the mixture was diluted with a saturated aqueous solution of NH4Cl (6 mL) and extracted with ethyl acetate (3×2.5 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield a pale yellow solid that was purified by flash chromatography (Biotage SP4, 12 g silica cartridge, gradient 0-10% MeOH in CH2Cl2) to give 10a-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (86 mg, quantitative yield). ESI-MI m/z [M+H]+ 428.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24](Cl)=[CH:25][C:26]5[N:27]4[CH:30]=[N:31][N:32]=5)=[CH:22][CH:21]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:12]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([C:36]5[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=5)=[CH:25][C:26]5[N:27]4[CH:30]=[N:31][N:32]=5)=[CH:22][CH:21]=3)[CH:14]=[C:15]([F:17])[CH:16]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Cl)cc5nncn5c4c3)c2)CCOCC1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(-c5cccnc5)cc5nncn5c4c3)c2)CCOCC1
Temperature: 80 °C

Procedure:
To 5d (50 mg, 0.11 mmol) in DME:H2O (2:1, 2 mL) was added 3-pyridineboronic acid (20 mg, 0.16 mmol) and potassium carbonate (37 mg, 0.27 mmol). The mixture was degassed with N2 for 5 minutes, and then Pd(PPh3)4 (12 mg, 0.01 mmol) was added, and the mixture was degassed with N2 for an additional 5 minutes. The reaction was then heated to 80° C. overnight. After cooling to room temperature, the reaction was concentrated and purified by silica gel chromatography (10% MeOH in EtOAc) to give the desired product, 5e.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[BrH:11].BrBr>>[BrH:11].[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: CC(=O)c1cnccc1C
Agent: Br
Agent: BrBr
Product: Cc1ccncc1C(=O)CBr
Yield: 85 %

Procedure:
The title compound was synthesised according to Example E 1-(4-methyl-pyridin-3-yl)-ethanone and HBr/bromine in 85% yield as grey solid. MS (m/e): 214.0 (M+H, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:15])=[C:10]2[O:14][CH:13]=[CH:12][C:11]=12)=[O:5])C.[OH-].[Na+]>CO.O>[F:15][C:9]1[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:11]2[C:10]=1[O:14][CH:13]=[CH:12]2
Reactant: CCOC(=O)c1ccc(F)c2occc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(F)c2occc12
Temperature: 55 °C

Procedure:
A mixture of 7-fluoro-benzofuran-4-carboxylic acid ethyl ester (1.54 mmol) and sodium hydroxide (2.31 mmol) in MeOH (1.7 mL) and water (1.7 mL) is heated to 55° C. for 90 min. The mixture is concentrated in vacuo and made acidic by addition of hydrochloric acid (1.0 M). The obtained precipitate is filtered off and dried in vacuo to give the desired product. 1H-NMR (DMSO-d6): δ=13.19 (bs, 1H); 8.25 (s, 1H); 7.89-7.94 (m, 1H); 7.41 (s, 1H); 7.36 (t, J=9.5 Hz, 1H).
Reaction SMILES: [CH:1]([N:4]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])[C:5](=[O:8])[CH2:6][OH:7])([CH3:3])[CH3:2].Cl[C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.[OH-].[K+]>C(O)(C)C>[CH:1]([N:4]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])[C:5](=[O:8])[CH2:6][O:7][C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1)([CH3:3])[CH3:2]
Reactant: CCOCCON(C(=O)CO)C(C)C
Reactant: Clc1nc2ccccc2o1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCOCCON(C(=O)COc1nc2ccccc2o1)C(C)C
Reaction time: 6 h
Yield: 94 %

Procedure:
First 20.5 g (0.1 mole) of hydroxyacetic acid N-isopropyl-N-(2-ethoxyethoxy)-amide and then 15.4 g (0.1 mole) of 2-chlorobenzoxazole were added dropwise to a solution of 6.2 g (0.11 mole) of potassium hydroxide in 200 ml of isopropanol at 0° to 5° C., and the mixture was then subsequently stirred for 6 hours, without cooling. The solvent was then distilled off in vacuo, the residue was dissolved in 200 ml of toluene and the solution was extracted by shaking once with 100 ml of water. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was subjected to incipient distillation at 60° C. under a high vacuum. 30.3 g (94% of theory) of benzoxazol-2-yl-oxyacetic acid N-isopropyl-N-(2-ethoxy-ethoxy)-amide were obtained in this manner in the form of a light brown oil with a refractive index nD22 of 1.4986.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:20](OCC)=[O:21])([CH3:19])[CH3:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[Na]>CCOCC.O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]([CH3:19])([CH3:18])[CH2:20][OH:21])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(CO)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
A solution of 4-(1-ethoxycarbonyl-1-methyl-ethyl)-piperazine-1-carboxylic acid benzyl ester (3.5 g, 10.5 mmol) in 10 mL of dry ether was slowly added to a suspension of lithium aluminium hydride (0.3 g, 105 mmol) in tetrahydrofuran at −15° C. under nitrogen and the resulting mixture was stirred at 0° C. for 3 hours. On cooling, the mixture was treated dropwise with water (0.3 mL), aqueous sodium hydroxyde (0.3 mL, 4N), and water (0.9 mL) and filtered. The filtrate was concentrated under reduced pressure to yield 4-(2-hydroxy-1,1-dimethyl ethyl)piperazine-1-carboxylic acid benzyl ester as a white solid (1.2 g, 41%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:15]([C:12]1[CH:11]=[N:10][C:9]([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)=[N:14][CH:13]=1)[CH2:16][CH3:17]
Reactant: CCCc1cnc(Cl)nc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1cnc(N2CCC(O)CC2)nc1
Temperature: 110 °C

Procedure:
A suspension of piperidin-4-ol (12 g, 119 mmol), 2-chloro-5-propylpyrimidine (20.44 g, 131 mmol) and potassium carbonate (49.2 g, 356 mmol) in DMF (100 mL) was heated at 110° C. for 12 h and cooled to rt. The mixture was diluted with EtOAc (250 ml) and washed with H2O (3×). After drying over Na2SO4, the organic layer was evaporated to give a yellow oil. The crude oil was purified on a flash chromatography (SiO2, 0 to 10% MeOH/CH2Cl2) to give a yellow solid. MS (ESI) 222 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:25])[O:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:7][O:6]1)=[O:4].O[Li].O>O1CCCC1.CO.O>[CH3:25][C:5]1([C:3]([OH:4])=[O:2])[O:6][CH2:7][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:9][O:10]1
Reactant: COC(=O)C1(C)OCC(CCCCON=C(C)c2ccccc2)CO1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=NOCCCCC1COC(C)(C(=O)O)OC1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
To a solution of. Methyl-2-methyl-5-[4-(1-phenyl-ethylideneaminooxy)-butyl]-[1,3]dioxane-2-carboxylate (prepared as per example 1) (1.38 g) in a mixture of tetrahydrofuran and methanol was added another solution of LiOH.H2O (332 mg) in water and the reaction mixture was stirred at ambient temperature for about 18 hours. Solvent was evaporated under reduced pressure, water was added to the residue, acidified with 1N HCl to pH 6 and extracted with ethyl acetate. The combined organic extract was washed with water, brine solution, dried over sodium sulphate and evaporated under reduced pressure. Crude product was chromatographed (flash) over silica-gel using 25% ethyl acetate in hexane as an eluent to obtain 1 g of pure product.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[ClH:20].[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[CH:23]([CH2:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=1)=[O:31])[CH2:22]2>CN(C=O)C.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]>[ClH:20].[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:36]2[CH:35]=[CH:34][C:33]([NH:32][C:30](=[O:31])[CH2:29][CH:23]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:28][CH2:27]4)[CH2:22]3)=[CH:38][CH:37]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(CC1CN2CCC1CC2)Nc1ccc(Br)cc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(-c2ccc(NC(=O)CC3CN4CCC3CC4)cc2)c1
Temperature: 80 °C
Reaction time: 0.14 h

Procedure:
43.8 mg (0.24 mmol) of 3-(acetamido)phenylboronic acid, 0.33 ml (0.66 mmol) of 2M aqueous sodium carbonate solution and 8.1 mg (0.01 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride are added to a solution of 80 mg (0.22 mmol) of 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(4-bromophenyl)acetamide hydrochloride in 1.5 ml of DMF. The reaction mixture is stirred at 80° C. for 0.14 h, cooled, filtered through kieselguhr and then purified by preparative HPLC. The product fractions are concentrated, taken up in methanol, mixed with 4M HCl in dioxane and again concentrated. Drying under high vacuum results in 23 mg (20% of theory) of the title compound.
Reaction SMILES: CC1(C)OC(=O)[CH:5]([C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:10])[C:4](=O)[O:3]1>C1(C)C=CC=CC=1>[O:3]=[CH:4][CH2:5][C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)CC=O
Temperature: 80 °C

Procedure:
ArgoGel-OH (45 g, 0.49 meq/g, 22 mmol) was suspended in toluene (400 mL) and tert-butyl (2S)-2-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)carbonyl]-1-pyrrolidinecarboxylate (60. g, 176 mmol) was added. The sealed reaction tube was heated at 80° C. for 23 h. The reaction mixture was allowed to cool to room temperature and filtered. The resin was washed (DMF then DCM then ether; 8× each) then dried at 40° C. overnight under high vacuum (63 g; 0.44 meq/g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[C:21]1([CH2:27][CH2:28][CH2:29][Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:21]1([CH2:27][CH2:28][CH2:29][CH:17]([C:16]2[CH:19]=[CH:20][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:14][CH:15]=2)[OH:18])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: Br[Mg]CCCc1ccccc1
Solvent: C1CCOC1
Product: OC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of the aldehyde from Step I, (1.34 g) in THF at 0° was added dropwise the 3-phenylpropylmagnesium bromide (1.1 mol. equiv., from above). After 30 mins, the reaction was quenched by the addition of 25% aqueous NH4OAc solution. The mixture was then extracted with ethyl acetate (×2), the organic phase was washed with brine (×2), dried and evaporated under reduced pressure. The title compound was obtained after recrystallization from ethyl acetate/hexane, m.p. 118°-119°.
Reaction SMILES: CNC.C([Li])CCC.CCCCCC.CN(C)P(=O)(N(C)C)N(C)C.[Br:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([CH3:35])[CH:28]=1.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)#[N:37].[ClH:44]>O1CCCC1>[ClH:44].[NH2:32][C:31]1[C:30]2[C:29](=[CH:28][C:27]([Br:26])=[CH:34][CH:33]=2)[CH:35]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[N:37]=1
Reactant: N#Cc1ccccn1
Reactant: Cc1cc(Br)ccc1C#N
Agent: CNC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Nc1nc(-c2ccccn2)cc2cc(Br)ccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.5 g (0.23 mol) of dimethylamine in 80 ml of tetrahydrofuran, 100 ml of 15% (w/v) n-butyl lithium in hexane (0.23 mol) were added under a nitrogen atmosphere. After 30 minutes, 18 g (0.1 mol) of hexamethylphosphoric triamide (HMPTA) were added, after which the mixture was cooled to -78° C. To the light-yellow solution obtained, 19.6 g (0.1 mol) of 4-bromo-2-methylbenzonitrile in 60 ml of anhydrous tetrahydrofuran were added in the course of 10 minutes, after which the deep red solution was stirred for another 15 minutes. Subsequently 15.7 g (0.15 mol) of 2-cyanopyridine in 60 ml of anhydrous tetrahydrofuran was added dropwise in the course of 10 minutes. The reaction mixture was heated to 60° C. for one hour and it was then hydrolysed with 400 ml of 10% (w/v) hydrochloric acid. The yellow precipitate obtained was filtered off, the filtrate was washed with diethyl ether, neutralised with sodium hydroxide and extracted with chloroform. The solvent was distilled off from the extract and the residue was sublimed. The product obtained was converted into the hydrochloride, as described in Example VII, and the hydrochloride was combined with the yellow precipitate and crystallised from ethanol. 1-Amino-6-bromo-3-(2-pyridyl)isoquinoline hydrochloride was obtained, melting point 257.5° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][C:14]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[OH:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:1]([O:16][CH:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:14]([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:28][CH:27]=1)([CH2:23][CH3:24])[CH2:25][CH3:26])(=[O:3])[CH3:2]
Reactant: CCC(CC)(Cc1ccc(Cl)cc1)C(O)c1cccnc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(CC)(Cc1ccc(Cl)cc1)C(OC(C)=O)c1cccnc1
Temperature: 80 °C

Procedure:
10.2 g (0.10 mol) of acetic anhydride are added dropwise to a solution of 12.1 g (0.04 mol) of 2-(4chlorobenzyl)-2-ethyl-1-(3-pyridyl)-1-butanol in 50 ml of pyridine at room temperature, and the mixture is then heated at 80° C. for 8 h. The reaction mixture is concentrated, the residue is taken up in 200 ml of dichloromethane, and the solution is washed with saturated NaHCO3 solution and then with water. The organic phase is dried and concentrated, and the remaining black oil is purified on silica gel (mobile phase: 5:1 cyclohexane/ethyl acetate). 11.2 g (81% of theory) of the title compound are obtained as a viscous yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[Br:17])=O)[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][CH2:7][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[Br:17])[CH3:2]
Reactant: CCOC(=O)CCC(=O)c1ccc(OC)cc1Br
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCc1ccc(OC)cc1Br
Temperature: 55 °C
Yield: 87.5 %

Procedure:
A solution of 4-(2-bromo-4-methoxy-phenyl)-4-oxo-butyric acid ethyl ester (Intermediate 150, 6.45 g, 20.5 mmol) in trifluoroacetic acid (32 mL, 409 mmol) was treated with triethylsilane (14.4 mL, 90 mmol) and the resulting reaction mixture was heated at 55° C. for 3 h. The reaction mixture was then cooled to ambient temperature, neutralized with solid sodium bicarbonate, diluted with water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (5.4 g, 88%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([CH3:7])[CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:14].CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C(Cl)Cl.Cl[Cu]>[C:24]([N:4]1[CH:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]([CH3:7])[N:2]([CH3:1])[C:3]1=[O:14])(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: CC1C(c2ccccc2)NC(=O)N1C
Agent: Cl[Cu]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1C(=O)N(C)C(C)C1c1ccccc1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of (4 S, 5 R)1,5-dimethyl-4-phenyl-2-imidazolidinone (45.0 g, 237 mmole) and (i-Pr)2NEt (62 mL, 355 mmole) in CH2Cl2 (1200 mL) was added CuCl (50 mg, 0.51 mmole) then acryloyl chloride (29 mL, 355 mmole), and the mixture was heated to reflux. After 2 hr the mixture was cooled to RT, washed with H2O (3×400 mL), dried over MgSO4, and concentrated. The resulting solid was triturated with Et2O (300 mL) and collected by filtration to give the title compound (45.15 g, 78%): 1H NMR (300 MHz, CDCl3) δ 7.72 (dd, J=17.0, 10.5 Hz, 1 H), 7.20-7.38 (m, 3 H), 7.10-7.20 (m, 2 H), 6.40 (dd, J=17.0, 2.1 Hz, 1 H), 5.77 (dd, J=10.4, 2.0 Hz, 1 H), 5.36 (d, J=8.5 Hz, 1 H), 3.85-4.00 (m, 1 H), 2.85 (s, 3 H), 0.82 (d, J=6.6 Hz, 3 H); MS (ES) m/e 245 (M+H)+.