Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1>[C:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Solvent: Cc1ccccc1C
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 125 °C
Reaction time: 1 h

Procedure:
116.3 g (0.61 mol) of decanoyl chloride were heated to 125° C. in 300 ml of xylene, and 69.1 g (0.5 mol) of 4-hydroxybenzoic acid were introduced in portions over the course of six hours. The batch was subsequently stirred at 125° C. for one hour, cooled to room temperature, and filtered with suction, and the solid product was washed three times with 45 ml of xylene. The yield after drying under reduced pressure at 100° C. was 108.4 g (74% of theory). According to HPLC and NMR measurement, the product was free from decanoic acid and from unreacted para-hydroxybenzoic acid, but contained 0.4% by weight of byproducts such as dimers and trimers of the para-hydroxybenzoic acid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[C:30]([OH:35])(=[O:34])[CH:31]([CH3:33])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH:31]([C:30]([OH:35])=[O:34])[CH3:33])=[O:24])=[CH:21][CH:20]=1
Reactant: CC(O)C(=O)O
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and allowed to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:11]2[N:12]([CH3:20])[C:13]3[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[C:27]([CH3:38])[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]([C:15]3[CH:16]=[CH:17][C:18]4[C:10]5[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:22][CH2:21][C:11]=5[N:12]([CH3:20])[C:13]=4[CH:14]=3)[C:33](=[O:37])[CH:32]=2)=[C:27]([CH3:38])[CH:26]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: COc1ccc(-c2cc[nH]c(=O)c2)c(C)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: COc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)c(C)c1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
tert-Butyl-7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.35 g, 0.96 mmol), 4-(4-methoxy-2-methylphenyl)pyridin-2(1H)-one (0.21 g, 0.96 mmol) and Cs2CO3 (0.35 g, 1.1 mmol) were suspended in DMSO (5.6 mL), and the resulting suspension was degassed under vacuum for 15 min. The system was then flushed with Ar, and 8-hydroxyquinoline (42 mg, 0.29 mmol) and copper iodide (0.22 g, 1.2 mmol) were added. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The suspension was cooled, diluted with 20% NH4OH/MeOH (10 mL) and stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (100 mL). The solution was filtered through silica gel and concentrated. The concentrate was diluted with CH2Cl2 and washed with brine (4×20 mL). The organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure. Flash column chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and then hold for 5 column volumes, increase to 0:100 over 10 column volumes and hold for 5 column volumes) gave the title compound (0.25 g, 52%) as a yellow film: 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J=8.0 Hz, 1H), 7.42 (d, J=6.5 Hz, 1H), 7.39 (d, J=1.5 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.10 (d, J=7.0 Hz, 1H), 6.82-6.80 (m, 2H), 6.60 (d, J=1.5 Hz, 1H), 6.24 (dd, J=6.5, 1.5 Hz, 1H), 4.67-4.65 (m, 2H), 3.86-3.83 (m, 5H), 3.65 (s, 3H), 2.93 (m, 3H), 2.82-2.84 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]([F:10])[F:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(Cl)Cl.CC([O-])=O.[K+].Br[C:39]1[S:40][C:41]2[C:47]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=3)=[C:46]([C@H:55]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])[C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:45]([CH3:66])=[CH:44][C:42]=2[N:43]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.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:62]([O:61][C@@H:55]([C:46]1[C:45]([CH3:66])=[CH:44][C:42]2[N:43]=[C:39]([C:2]3[C:7]([CH:8]([F:10])[F:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=3)[S:40][C:41]=2[C:47]=1[C:48]1[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=1)[C:56]([O:58][CH2:59][CH3:60])=[O:57])([CH3:63])([CH3:64])[CH3:65]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: FC(F)c1cnc(Cl)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)ncc3C(F)F)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with 4-bromo-2-chloro-5-(difluoromethyl)pyridine (155 mg, 0.64 mmol), Bis(pinacolato)diboron (179 mg, 0.70 mmol), PdCl2(dppf).CH2Cl2 (55 mg, 0.07 mmol), then KOAc (198 mg, 2.00 mmol). The vial was flushed with argon, diluted with dioxane (4 mL), sealed, then heated to 100° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and then a portion of this cooled solution (1.2 mL, 0.19 mmol) was added to a vial that was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (58 mg, 0.12 mmol) and PdCl2(dppf).CH2Cl2 (19 mg, 0.02 mmol). The mixture was diluted with dioxane (0.8 mL) and to this was added 2M aqueous K2CO3 (0.20 mL, 0.40 mmol). The vial was sealed, heated to 100° C. for 1 hour, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-15% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd C28H27Cl2F2N2O3S: 579.1 (M+H+); Found: 579.1 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:16]=[CH:15][C:9]([O:10][CH:11]3[CH2:14][NH:13][CH2:12]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]([C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)[CH3:25])([CH3:20])([CH3:19])[CH3:18].CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1>[C:17]([O:21][C:22](=[O:33])[NH:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([N:13]2[CH2:12][CH:11]([O:10][C:9]3[CH:15]=[CH:16][C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)=[CH:7][CH:8]=3)[CH2:14]2)=[CH:30][CH:31]=1)[CH3:25])([CH3:18])([CH3:19])[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: c1cc(OC2CNC2)ccc1OCC1CC1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(N2CC(Oc3ccc(OCC4CC4)cc3)C2)cc1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
To 0.9 g (4.1 mmol) 3-(4-cyclopropylmethoxy-phenoxy)-azetidine (IX.1), 1.2 g (4.1 mmol) (S)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (I.3), 1.6 g (16.4 mmol) NaOtBu, 0.49 g (1.64 mmol) 2-(di-tert-butylphosphino)biphenyl and 0.38 g (0.41 mmol) tris-(dibenzylideneacetone)-dipalladium(0) are added under an argon atmosphere 25 mL 1,4-dioxane. The mixture is stirred for 12 h at 45° C. The mixture is filtered, washed with MeOH and concentrated. The residue is purified by HPLC (silica gel; PE/ethyl acetate; gradient 9:1→1:1) to yield the desired product.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:19]2([CH3:20])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])[CH2:5][C:4](=[O:22])[CH2:3]1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[CH3:1][C@H:2]1[C@@:19]2([CH3:20])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[OH:21])[CH2:5][C@@H:4]([OH:22])[CH2:3]1
Reactant: C[C@@H]1CC(=O)CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](O)CC2=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A tetrahydrofuran solution of 1β-methyl-5-androstene-3,17-dione is added under nitrogen to a solution of lithium tri-t-butoxyaluminum hydride in tetrahydrofuran. After stirring at room temperature for a period of 18 hours, an aqueous solution of potassium sodium tartrate is added with stirring to form a readily filterable white solid. The reaction mixture is filtered, the filtrate dried over magnesium sulfate, and the solvent removed. The residue is crystallized from an acetone-hexane solution to yield 1β-methyl-5-androstene-3β,17β-diol.
Reaction SMILES: N1C=CC=CC=1[C:7]1[CH:12]=[CH:11]C=CN=1.ClC(Cl)C.[C:17]([Si:21]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[O:22][CH2:23][C:24]([NH:31][C:32]([C:34]1[N:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH2:44][C:45]3[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=3[F:52])[C:37]2=[N:36][C:35]=1[CH3:53])=[O:33])([C:26]1[N:27]=[N:28][NH:29][N:30]=1)[CH3:25])([CH3:20])([CH3:19])[CH3:18].C1(B(O)O)CC1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[C:17]([Si:21]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[O:22][CH2:23][C:24]([NH:31][C:32]([C:34]1[N:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH2:44][C:45]3[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=3[F:52])[C:37]2=[N:36][C:35]=1[CH3:53])=[O:33])([C:26]1[N:27]=[N:28][N:29]([CH:11]2[CH2:12][CH2:7]2)[N:30]=1)[CH3:25])([CH3:18])([CH3:19])[CH3:20]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nn[nH]n1
Reactant: c1ccc(-c2ccccn2)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(Cl)Cl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nnn(C2CC2)n1
Temperature: 70 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
A mixture of 137 mg of copper (II) acetate, 121 mg of 2,2′-bipyridine, and 10 ml of dichloroethane was heated to an inner temperature of 70° C., and to this mixture was added a mixture of 501 mg of N-[1-{[tert-butyl (diphenyl)silyl]oxy}-2-(2H-tetrazol-5-yl)propan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, 135 mg of cyclopropylboronic acid, 182 mg of sodium carbonate, and 10 ml of dichloroethane, followed by stirring at 70° C. for 4 hours. The reaction mixture was left to be cooled to room temperature, and a saturated aqueous ammonium chloride solution and water were then added thereto. The aqueous layer was extracted with chloroform, and the organic layer was then combined and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 280 mg of N-[1-{[tert-butyl (diphenyl)silyl]oxy}-2-(2-cyclopropyl-2H-tetrazol-5-yl)propan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[O:24][CH2:25][CH3:26].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[C:17]([O:24][CH2:25][CH3:26])[CH:18]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCOc1cc(C=O)ccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (5.0 g, 25.0 mmol, 1.0 equiv; commercially available), 4-chloro-3-ethoxy-benzaldehyde (5.54 g, 30.0 mmol, 1.2 equiv; intermediate D3, vide infra) and acetic acid (5.7 mL, 100.0 mmol, 4.0 equiv) in ethanol (25 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyano borohydride (3.14 g, 50.0 mmol, 2.0 equiv), dissolved in ethanol (10 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 10 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.91 g (42%) of the title compound. MS (ISP): 369.0 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:28])[C@H:15]1[CH2:19][C@@H:18]([OH:20])[CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:12][O:13][C:14](=[O:28])[C@H:15]1[CH2:19][C@@H:18]([O:20][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
4-Dimethylaminopyridine (1.21 g) and p-toluenesulfonyl chloride (1.51 g) were added to a solution of N-tert-butoxycarbonyl-cis-4-hydroxy-D-proline methyl ester (A, 971 mg) in dichloromethane (20 mL). After stirrng at room temperature for 4 hr, the solvent was removed in vacuo. The residue was diluted with ethyl acetate, and washed with 10% citric acid, water, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform:ethyl acetate=1:50, v/v) to give the title compound (1.65 g) as a colorless oil.
Reaction SMILES: C[NH:2]CCO.F[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:2][C:13]1[CH:14]=[CH:7][CH:8]=[CH:9][C:10]=1[CH:11]=[O:12]
Reactant: O=Cc1ccc(F)cc1
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ccccc1C=O
Temperature: 95 °C

Procedure:
A reactor is charged with 2-(methylamino)ethanol (134 g, 1.8 moles), 4-fluorobenzaldehyde (74.4 g, 0.6 mole), potassium carbonate (82.8 g, 0.6 mole) and dimethylsulfoxide (750 ml), and the mixture is heated at 95° C for 72 hours. The product mixture is cooled and poured into three liters of ice water The yellow solid that precipitates is filtered, washed with water, and dried in a vacuum oven, mp 72° C. The 4-[N-(2-hydroxyethyl)-N-methylamino]benzaldehyde product is recrystallized from water as needle-like crystals.
Reaction SMILES: C1COCC1.Cl[Si](C)(C)C.Br[CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH:20]1([NH:26][C:27]2[CH:36]=[C:35]3[C:30]([C:31](=[O:44])[C:32]([CH:42]=[O:43])=[CH:33][N:34]3[CH:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[CH:29][C:28]=2[F:45])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>[Zn].O>[CH:20]1([NH:26][C:27]2[CH:36]=[C:35]3[C:30]([C:31](=[O:44])[C:32]([CH:42]([OH:43])[CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:33][N:34]3[CH:37]([CH2:38][CH3:39])[CH2:40][CH3:41])=[CH:29][C:28]=2[F:45])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)/C=C/CBr
Reactant: CCC(CC)n1cc(C=O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/CC(O)c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.0 ml of THF and 0.071 ml of chlorotrimethylsilane were added to 73 mg of zinc, followed by stirring at room temperature for 15 minutes. Then, 200 mg of ethyl (2E)-4-bromobut-2-enoate was added thereto, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde, followed by overnight stirring at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 30 mg of ethyl (2E)-5-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]-5-hydroxypent-2-enoate.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:15][CH3:16])[C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=O.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C([N+]#[C-])C1C=CC=CC=1>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([NH:17][CH:1]([C:8]([O:10][CH3:11])=[O:9])[C:3]2[CH:4]=[C:5]([O:15][CH3:16])[C:6]([O:13][CH3:14])=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(N)cc1
Reactant: COC(=O)c1cc(C=O)cc(OC)c1OC
Agent: [C-]#[N+]Cc1ccccc1
Product: COC(=O)c1cc(C(Nc2ccc(C#N)cc2)C(=O)OC)cc(OC)c1OC

Procedure:
In analogy to Example 1.1, methyl 5-formyl-2,3-dimethoxy-benzoate (F. Y. Wu, D. L. b rink, J. Agric. Food Chem. (1977) 25 692) was reacted with 4-aminobenzonitrile and benzyl isonitrile to give methyl (RS)-5-[(4-cyano-phenylamino)-methoxycarbonyl-methyl]-2,3-dimethoxy-benzoate.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O1CCCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:18])[CH:24]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Reactant: Nc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)o2)c1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-aminophenylboronic acid, using tetrakis(triphenylphosphine)palladium (0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by flash chromatography using 5-20% 3.5M methanolic ammonia/chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions and extraction into chloroform followed by evaporation to gave the title compound; MS (ES+) 312 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Si:11]([O:18][CH:19]1[CH2:20][CH2:21][CH:22]([CH:25]=[O:26])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(C=O)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.93 g (7.31 mmol) of oxalyl chloride is dissolved in 50 ml of dichloromethane and cooled to −78° C., and 1.14 g (14.63 mmol) of dimethyl sulfoxide are added slowly. A solution of 1.49 g (4.88 mmol) of the compound from Example 10A (incl. subsequent syntheses), dissolved in 10 ml of dichloromethane, is then added. The reaction mixture is stirred at −78° C. for 1 h. 3.4 ml (24.38 mmol) of triethylamine are then added slowly, and the mixture is warmed to RT over a period of 1 h. 50 ml of ethyl acetate and 30 ml of sodium bicarbonate solution are then added to the mixture. The phases are separated, and the aqueous phase is extracted twice with in each case 20 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is purified chromatographically on silica gel 60 (mobile phase: gradient cyclohexane/ethyl acetate 50:1→10:1).