Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br.C(=O)([O-])O.[Na+]>CO>[Br:16][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]2=[N:10][CH:9]=1
Reactant: BrBr
Reactant: Cc1ccn2ccnc2c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccn2c(Br)cnc2c1
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
A cooled (−10° C.) suspension of 7-methylimidazo[1,2-α]pyridine (26 g, 0.2 mol) and sodium acetate (24.3 g, 0.3 mol) in methanol (150 ml) was treated with bromine (ca. 10 ml, 0.2 mol) added dropwise until the first permanent colour change occurred. Stirring was continued for a further 20 minutes before the reaction was poured into saturated aqueous sodium hydrogencarbonate (2 l). The resulting solid was filtered, washed with water and dried. Trituration with 5% ether in isohexane furnished 3-bromo-7-methylimidazo[1,2-α]pyridine as a red-brown powder (41.5 g, 100%). 1H NMR (360 MHz, CDCl3) δH 2.43 (3H, s), 6.76 (1H, d, J 7), 7.37 (1H, s), 7.53 (1H, s), 7.55 (1H, s), 8.00 (1H, d, J 7); m/z (ES+) 210/212 (M++H).
Reaction SMILES: O.[Br:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([Br:12])[C:4]=1[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:14]#[N:15]>C1COCC1>[NH2:9][C:7]1[CH:6]=[C:5]([Br:12])[C:4]([CH:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:14]#[N:15])=[C:3]([Br:2])[CH:8]=1
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Br)cc([N+](=O)[O-])cc1Br
Solvent: O
Solvent: C1CCOC1
Product: N#CC(c1ccc(Cl)cc1)c1c(Br)cc(N)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.5 %

Procedure:
A solution of 15% TiCl3 in water (0.13 mol) was added dropwise at RT to a solution of (±)-2,6-dibromo-α-(4-chlorophenyl)-4-nitrobenzeneacetonitrile (0.026 mol) in THF (200 ml). The mixture was stirred at RT for 2 hours, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, washed with H2O and with K2CO3 10%, dried, filtered and the solvent was evaporated. A part of this residue (2 g) was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 1.3 g (±)-4-amino-2,6-dibromo-α-(4-chlorophenyl)benzeneacetonitrile (interm. 47).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1.C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.Cl>CCCCCC.CCOCC>[CH:3]1[C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][C:2]=1[B:21]([OH:26])[OH:22]
Reactant: Ic1ccc2c(ccc3ccccc32)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1ccc2c(ccc3ccccc32)c1
Temperature: -60 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
Under an argon atmosphere, 98 g of 2-iodophenanthrene and 3 L of dehydrated ether were loaded, and then the reaction solution was cooled to −60° C. After that, 210 mL of a 1.6-M solution of n-butyllithium in hexane were added to the reaction solution. The reaction solution was stirred for 1 hour while its temperature was increased to 0° C. The reaction solution was cooled to −60° C. again, and then a solution of 151 g of triisopropyl borate in 100 mL of dehydrated ether was dropped to the reaction solution. The reaction solution was continuously stirred for 5 hours while its temperature was increased to room temperature. Subsequently, 1 L of a 10% aqueous solution of hydrochloric acid was added to the reaction solution, and then the mixture was stirred for 1 hour. The water layer was removed, and the organic layer was washed with water and a saturated salt solution, and was then dried with magnesium sulfate. After magnesium sulfate had been separated by filtration, the organic layer was concentrated. The resultant solid was washed with hexane and toluene. Thus, 42 g of phenanthrene-2-boronic acid as a target were obtained (in 58% yield).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2]1.FC(F)(F)S(O[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].C(OCC)(=O)C>C(#N)C>[C:25]1([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:2]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.7 %

Procedure:
To a solution of tert-butyl 1,2,3,4-tetrahydroquinolin-3-ylcarbamate (0.3 g, 1.2 mmol) in acetonitrile (5 mL) was added 2-(trimethylsilyl)phenyl trifluoromethane sulfonate (397 mg, 1.33 mmol, 1.1 eq) and cesium fluoride (365 mg, 2.4 mmol, 2.0 eq). The mixture was stirred at room temperature for 3 days. Ethyl acetate was then added and the organic layer washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash column (eluted with 10% ethyl acetate in hexane) to give tert-butyl 1-phenyl-1,2,3,4-tetrahydroquinolin-3-ylcarbamate as a white solid (400 mg, 99%). M.p.=139-141° C. 1H NMR (DMSO) 400 MHz δ 7.33 (m, 2H), 7.18 (dd, J=1.2 and 7.6 Hz, 2H), 7.09-6.87 (m, 4H), 6.68-6.58 (m, 2H), 3.80 (s, br, 1H), 3.64 (m, 1H), 3.29 (m, 1H), 2.94 (dd, J=5.2 and 10.8 Hz, 1H), 2.72 (m, 1H), 1.34 (s, 9H). LCMS m/e 325 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1
Reactant: Cc1cc(CCCCCBr)no1
Reactant: COc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(OCCCCCc2cc(C)on2)c(Cl)c1
Yield: 48.7 %

Procedure:
A mixture of 5.5 g (0.0345 mole) of 2-chloro-4-methoxyphenol, 8.0 g (0.0345 mole) of 3-(5-bromopentyl)-5-methylisoxazole (Example 40i), 6 g of potassium carbonate, 0.1 g of potassium iodide and 75 ml of acetonitrile was heated at reflux for 24 hours. The reaction mixture was filtered, concentrated in vacuo, dissolved in 50 ml of methylene dichloride, filtered and again concentrated. The residue was distilled at 135°-200° C.(0.2 mm) and then redistilled, collecting the fraction boiling at 170°-190° C.(0.05 mm). The product crystallized and was recrystallized from ether--pentane to give 5.2 g of 3-[5-(2-chloro-4-methoxyphenoxy)pentyl]-5-methylisoxazole, m.p. 45°-47° C.; MIC vs. rhinovirus Type 2=0.7 μg/ml; and vs. polio-2 virus=1.4 μg/ml.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 24.7 %

Procedure:
Combine 4-carbomethoxyphenylboronic acid (1.021 g, 5.67 mmol), 1-bromo-2,4-difluorobenzene (1.000 g, 5.181 mmol.), Pd(OAc)2 (0.113 g, 0.50 mmol), triphenylphosphine (0.149 g, 0.505 mmol), and sodium carbonate (1.664 g, 0.568 mmol). Purge the reaction vessel with argon. Add dimethylformamide (20 mL) and water (2.0 mL) with stirring. Place sealed reaction in an 80° C. oil bath and allow to stir for 24 hours. Cool reaction to room temperature, dilute with ethyl acetate, and filter through a short plug of celite with additional ethyl acetate. Wash organics with water, dry over magnesium sulfate, filter, and evaporate. Purification by flash column chromatography yields 2′,4′-difluorobiphenyl-4-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in dioxane (5 mL) and add 5M sodium hydroxide (1 mL). Stir vigorously at 50° C. for 15 hours. Upon completion, acidify the reaction with conc. HCl and extract with ethyl acetate. Evaporation of the solvent yields 300 mg (24.7%) of the title compound. MS (m/e): 233.0 (M−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=2)[CH:20]=[CH:21][C:22]=1[CH3:23]>C(O)(C)C>[CH3:23][C:22]1[CH:21]=[CH:20][C:19]([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=2)=[CH:18][C:17]=1[NH:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2nccc(Nc3cc(NC(=O)c4cccc(N(C)C)c4)ccc3C)c2cc1OC
Temperature: 85 °C

Procedure:
4-Chloro-6,7-dimethoxyquinoline (WO 98/13350 A1) (150 mg) and N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (199 mg) were stirred in isopropanol (5 ml) and heated to 85° C. for 18 hours. After cooling to room temperature the precipitated solid was isolated and washed with isohexane. Filtered solid was impure and so was purified by eluting through a silica column with 10% methanol in methylene chloride. The title compound was obtained as a solid (35 mg); NMR: 2.14 (s, 3H), 2.94 (s, 6H), 3.89 (s, 3H), 3.93 (s, 3H), 6.05 (m, 1H), 6.90 (m, 1H), 7.18 (m, 1H), 7.22 (m, 1H), 7.3 (m, 1H), 7.61 (m, 1H), 7.73 (s, 1H), 7.78 (m, 1H), 8.18 (d, 1H), 8.47 (s, 1H), 10.1 (s, 1H); m/s: M+H+ 457.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([OH:26])=O)[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:50][NH:51][CH2:52][C:53]1[CH:66]=[CH:65][C:56]([CH2:57][N:58]2[CH2:62][CH:61]([OH:63])[CH:60]([OH:64])[CH2:59]2)=[CH:55][CH:54]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:51]([CH2:52][C:53]3[CH:54]=[CH:55][C:56]([CH2:57][N:58]4[CH2:62][CH:61]([OH:63])[CH:60]([OH:64])[CH2:59]4)=[CH:65][CH:66]=3)[CH3:50])=[O:26])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CC(O)C(O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)Cc3ccc(CN4CC(O)C(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (35 mg, 0.09 mmol), EDCI (25 mg, 0.13 mmol), HOBt (19 mg, 0.19 mmol) DIPEA (0.03 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}pyrrolidine-3,4-diol dihydrochloride (30 mg, 0.11 mmol) and DCM (10 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:36])([CH3:35])[C:29]([NH:31][CH2:32][C:33]#[CH:34])=[O:30]>CN(C=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:34]#[C:33][CH2:32][NH:31][C:29](=[O:30])[C:28]([CH3:36])([CH3:35])[CH3:27]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C#CCNC(=O)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCC#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 57.9 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (212 mg, 0.5 mmol) and 2,2-dimethyl-N-prop-2-ynyl-propionamide (139 mg, 1 mmol) (prepared by following the procedure described in Org. Lett. 2004, 6, 3593) in DMF/triethylamine (5:1, 6 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1 to 7:3 gradient) to obtain 7-chloro-6-[3-(2,2-dimethyl-propionylamino)-prop-1-ynyl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (120 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].N1C=CC=CC=1.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:42]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:23])(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
188 mg (0.40 mmol) of (−)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-1a-1)) was dissolved in 8 ml of methylene chloride, followed by the addition of 39 μl (0.48 mmol) of pyridine and 51 μl (0.44 mmol) of benzoyl chloride under 0° C. The reaction mixture was stirred at room temperature for 1.5 hours. To the reaction solution, 10 ml of saturated aqueous solution of ammonium chloride was added and extracted with 50 ml of methylene chloride. The extract was washed with 20 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:1 mixture of ethyl acetate and hexane) to obtain 228 mg of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:31])=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][CH:23]=[C:24]4[S:28][C:27](=[O:29])[NH:26][C:25]4=[O:30])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[H][H]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:31])=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][CH2:23][CH:24]4[S:28][C:27](=[O:29])[NH:26][C:25]4=[O:30])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](OCC=C2SC(=O)NC2=O)C1
Reactant: [H][H]
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](OCCC2SC(=O)NC2=O)C1

Procedure:
Hydrogenation of the compound 5-(2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}ethylidene)thiazolidine-2,4-dione, mentioned in Example Example XXII, with hydrogen gives the compound 5-(2-{cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyl-oxy}ethyl)thiazolidine-2,4-dione:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[O:7]2.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH:16]2[O:18][CH2:17]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[O:7]2
Reactant: Cc1ccc(O)c2oc(=O)ccc12
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(OCC2CO2)c2oc(=O)ccc12

Procedure:
5-Methyl-8-hydroxycumarin (synthesized from isovanilin in 4 steps) is allowed to react with epibromohydrin in methyl ethyl ketone in the presence of potassium carbonate to give 5-methyl-8-(2,3-epoxypropoxy)-cumarin [cf. Chem. Phar. Bull. 20,205 (1972)].
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH:45]=O>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=2)[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Reactant: O=Cc1ccccn1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NCc1ccccn1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure F using 2-pyridinecarboxaldehyde. The final product was obtained in 26% yield.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[C:11]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O[CH:30]1[CH2:39][CH2:38][C:33]2([O:37][CH2:36][CH2:35][O:34]2)[CH2:32][CH2:31]1)(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:8][N:9]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[C:11]=1[O:17][CH3:18])[CH:30]1[CH2:39][CH2:38][C:33]2([O:37][CH2:36][CH2:35][O:34]2)[CH2:32][CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: COc1c(NOCc2ccccc2)ccnc1C
Product: COc1c(N(OCc2ccccc2)C2CCC3(CC2)OCCO3)ccnc1C
Yield: 70 %

Procedure:
Prepared analogously to Example 5 from 4-(O-benzylhydroxylamino)-3-methoxy-2-methylpyridine and 8-tosyloxy-1,4-dioxaspiro[4.5]decane. Yield: 70%
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](#[N:17])[CH:15]=[CH2:16]>C(OCC)C>[CH2:3]([O:13][CH2:16][CH2:15][C:14]#[N:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCO
Reactant: C=CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCCCOCCC#N
Temperature: 60 °C
Yield: 41.3 %

Procedure:
Sodium hydride (200 mg, 5 mmol; washed three times with hexane) was treated with 1-decanol (12 mL, 63 mmol) for 1 hour at room temperature. Acrylonitrile (10 mL, 152 mmol) was added dropwise and the resulting paste warmed to 60° C. for 2 hours. After cooling to room temperature, the paste was dissolved in diethyl ether and washed with copious water, one portion of brine, dried over magnesium sulfate, filtered and concentrated. Chromatography of the crude residue on silica gel using 25-75 ethyl acetate-hexane as eluant gave the title compound (5.5 g) as a water-white liquid. The structure was supported by NMR, infrared spectroscopy, elemental analysis and mass spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[N:12][C:24](=[O:25])[CH2:23][O:22][CH3:21])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 78.6 %

Procedure:
100 mg (0.5 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulfoximide (Example 1b) are dissolved in 3.33 ml dichloromethane, cooled in the ice-bath and treated with 0.1 ml (0.75 mmol) triethylamine. 0.068 ml (0.75 mmol) 2-methoxy-acetyl chloride are added dropwise with ice cooling. The mixture is stirred for 30 minutes in the ice-bath and for 15 hours at room temperature. After chromatographic purification (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)), 107 mg (79%) of the desired product is obtained.
Reaction SMILES: [O:1]([CH2:8][CH:9]([NH2:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]1[N:17]=[C:16](Cl)[C:15]2[N:19]=[CH:20][N:21]([C@@H:22]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@H:23]3[OH:30])[C:14]=2[N:13]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[O:1]([CH2:8][CH:9]([NH:11][C:16]1[C:15]2[N:19]=[CH:20][N:21]([C:14]=2[N:13]=[CH:12][N:17]=1)[C@@H:22]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@H:23]1[OH:30])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)COc1ccccc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(COc1ccccc1)Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
1-Phenoxy-2-propylamine (0.33 g, 2.18 mmol) was reacted with 6-chloropurine riboside (i.e. 9-β-D-ribofuranosyl-9H-purine)(0.5 g, 1.7 mmol) in dioxan (30 ml) in the presence of diisopropylethylamine (0.28 g, 2.2 mmol). The reaction mixture was heated at reflux for 5 h, cooled and evaporated. The residue was purified by flash chromatography on silica gel to provide the N-(1-Phenoxy-2-propyl)adenosine (a mixture of diastereoisomers) as a foam (0.06 g, 7%), 1H NMR (DMSO-d6)δ 1.32 (3H, d, --CH3), 3.52-3.60 (1H, m, H-5'a), 3.64-3.71 (1H, m, H-5'b), 3.93-3.99 and 4.12-4.20 (4H, 2m, m, H-4', H-3' and --CH2 --), 4.62 (1H, q, H-2'), 4.68-4.82 (1H, m, --C HCH3), 5.40 (1H, t, 5'-0H), 5.20, 5.45 (2H, 2d, 2'- and 3'-OH), 5.90 (1H, d, H-1'), 6.88-6.98 (3H, m, Ar--H), 7.23-7.31 (2H, t, Ar--H), 7.85, 8.21, 8.38 (3H, 3s, H-2, H-8 and N--H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]([C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(NCC(=O)c1ccco1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)c1ccco1
Yield: 64.9 %

Procedure:
24.0 g of N-(4-fluorobenzoyl)-(2-furylcarbonyl)methylamine, 4.7 g of 61% sodium hydride and 18.4 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 21.0 g of ethyl 3-(4-fluorobenzoylamino)-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 64.8%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:27][CH2:26][CH2:25][C@:9]32[N:13]([CH3:14])[C:12](=[O:15])[N:11]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:10]3=[O:24])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([N:11]2[C:10](=[O:24])[C@:9]3([CH2:25][CH2:26][CH2:27][C@H:8]3[C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)=[CH:3][CH:4]=3)[N:13]([CH3:14])[C:12]2=[O:15])[CH:21]=[C:20]([Cl:22])[CH:19]=1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(-c2ccc(F)cc2)cc1
Yield: 14.6 %

Procedure:
Using the procedure described in Example 8 (5R*,6S*)-6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (80 mg, 0.17 mmol) (Example 1) was reacted with 4-fluorophenylboronic acid (71.4 mg, 0.51 mmol) to yield the above-titled compound (12 mg) as a white solid. 1H NMR (CDCl3) δ 7.45–7.55 (4H, m), 7.05–7.25 (5H, m), 6.62 (2H, m), 3.46 (1H, dd, J1=12.9 Hz, J2=6.3 Hz), 3.18 (3H, s), 2.5–2.75 (1H, m), 1.85–2.45 (5H, m).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=2)=[N:16][CH:17]=1)([CH3:10])[CH3:9].C(OC(=O)C)(=O)C>>[CH:8]([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH:25]([NH:27][C:3](=[O:4])[CH3:2])[CH3:26])=[CH:21][CH:20]=2)=[N:16][CH:17]=1)([CH3:9])[CH3:10]
Reactant: CC(N)COc1ccc(Oc2ccc(OC(C)C)cn2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(C)COc1ccc(Oc2ccc(OC(C)C)cn2)cc1

Procedure:
2-[4-(5-Isopropoxypyridin-2-yloxy)phenoxy]-1-methylethylamine trifluoroacetate (624 mg, 1.5 mmol) was reacted with acetic anhydride in analogy to example 2a. Yield: 251 mg (49%), M+H+: 345.12.