Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1([CH2:16][OH:17])[C:13]2([CH2:15][CH2:14]2)[CH:11]2[CH2:12][CH:8]1[CH2:9][CH2:10]2.S(=O)(O)[O-:19].[Na+]>O.CC(C)=O.C(OCC)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH3:6][C:7]1([C:16]([OH:19])=[O:17])[C:13]2([CH2:15][CH2:14]2)[CH:11]2[CH2:12][CH:8]1[CH2:9][CH2:10]2
Reactant: O=S([O-])O
Reactant: CC1(CO)C2CCC(C2)C12CC2
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CC1(C(=O)O)C2CCC(C2)C12CC2
Temperature: 25 °C
Yield: 58 %

Procedure:
To a stirred solution of chromium trioxide (8.0 g, 76 mmol) in water (30 mL) cooled in an ice bath, was added carefully 96% sulfuric acid (6.9 mL, 120 mmol). While continuing to cool and stir the oxidant solution in an ice bath, a solution of (3-methylspiro[bicyclo[2.2.1]heptane-2.1′-cyclopropane]-3-yl)methanol (9.5 g; 57 mmol) in acetone (115 mL) was added over a 20 min period. After complete addition, the reaction mixture was stirred for 3 h while warming to ambient temperature. The reaction was then diluted with water (45 mL) and ethyl acetate (200 mL). Slowly, sodium bisulfite powder was added until the brown color dissipated and the aqueous layer became blue. The phases were then separated, and the aqueous layer was washed with ethyl acetate (2×100 mL). The organic layers were combined and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated to yield a green oil. The oil as purified by silica gel (200 g) column chromatography, using a 0-50% ethyl acetate in hexanes gradient. Selected fractions were combined and concentrated to yield 6.0 g of 3-methylspiro[bicyclo[2.2.1]heptane-2,1′-cyclopropane]-3-carboxylic acid as a white solid (58%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)(Cl)=[O:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:17]=[O:18])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(N)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N=C=O)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To the stirred mixture of 4-chloro-3-methylaniline (F1, 1.01 g, 7.13 mmol) and triethylamine (866 mg, 8.56 mmol) in methylene chloride (20 mL) at −20° C. under nitrogen was added phosgene solution (0.15 weight/weight in toluene, 6.15 g, 9.13 mmol) dropwise over 5 min. After addition, the reaction mixture was warmed up to room temperature over 2 h, and then stirred at room temperature for another 2 h. After this time, the reaction mixture was cooled to 0° C., and slowly quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (100 mL). The organic extract was washed with 2 M hydrochloric acid (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was triturated with methylene chloride (40 mL) and filtered. The filtrate was concentrated under reduced pressure to provide compound F2 as a light brown liquid (1.08 g, 90%): 1H NMR (300 MHz, CDCl3) δ 7.27 (d, J=8.4 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.88-6.84 (m, 1H), 2.34 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6])[CH3:2].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:8])[C@@H:5]([NH:6][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH3:7])[CH3:2]
Reactant: O=S1(=O)CCCO1
Reactant: CCOC(=O)[C@H](C)N
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 41.8 %

Procedure:
To a solution of L-alanine ethyl ester (1.67 g, 14.3 mmol) in tetrahydrofuran (25 mL) was slowly added 1,3-propanesultone (1.42 g, 11.9 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo, affording the title compound (1.19 g, 42%). 1H NMR (D2O, 500 MHz) δ ppm 4.16 (m, 2H), 4.01 (m, 1H), 3.12 (m, 2H), 2.87 (t, 2H, J=7.3 Hz), 2.01 (m, 2H), 1.43 (d, 3H, J=7.3 Hz), 1.14 (t, 3H, J=6.8 Hz). 13C (D2O, 125 MHz) δ ppm 170.22, 63.84, 55.69, 47.94, 44.73, 21.51, 14.05, 13.25. [α]D=−2.4° (c=0.0022 in water), ES-MS 240 (M+1).
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCO[C:38]2[CH:46]=[C:45]3[C:41]([C:42](C4C=CC=CC=4)=C(Br)C3=O)=[CH:40][CH:39]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:7][CH:8]=2)[C:3](=[O:28])[C:2]=1[C:38]1[CH:46]=[CH:45][C:41]([CH3:42])=[CH:40][CH:39]=1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCOCC3)cc21
Agent: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCOCC4)cc3C2=O)cc1
Yield: 80 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-(morpholin-4-yl)ethoxy}-1H-inden-1-one obtained in Step 1 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and p-tolylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (80%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: O=C(O)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a 40 ml vial is added 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-amine (1.5 g, 5.50 mmol), 3-bromobenzoic acid (1.66 g, 8.2 mmol), HBTU (3.13 g, 8.2 mmol) and Hunig's base (2.0 ml, 11.0 mmol). The mixture is dissolved in DMF (10 ml), flushed with argon, sealed and agitated at room temperature for 8 hrs. The crude mixture is diluted with water (100 ml) and partitioned with EtOAc (100 ml). The organic layer is washed with water (100 ml). The combined aqueous layers are extracted with EtOAc (2×50 ml). The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (5% MeOH in ethyl acetate) to afford 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide (1.27 g, 48%). MS: 455 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH:17]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cn(-c2ccc([N+](=O)[O-])c(C)c2)cn1
Reaction time: 36 h
Yield: 74.1 %

Procedure:
A mixture of 5-fluoro-2nitrotoluene (1.05 g), 4-methylimidazole (556 mg) and sodium carbonate (753 mg) in dimethylformaldehyde (23 ml) was heated under stirring for 36 hours. The reaction mixture was distilled under reduced pressure to remove solvent. The residue was dissolved in water and the solution was acidified with 4N HCl solution to pH 5 and extracted with chloroform. The water layer was made to pH 10 with 2.5N sodium hydroxide solution, extracted with chloroform, dried with MgSO4 and filtered. The solution was distilled to give 1.09 g (74%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([OH:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([O:13][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccnc2c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc2cccnc2c1OCc1ccccc1
Yield: 77 %

Procedure:
7-Methyloxy-8-hydroxyquinoline (1.10 g; 6.29 mmol) and K2CO3 (1.30 g; 9.43 mmol) in 30 ml of dry acetonitrile are stirred for 10 minutes under argon. Benzyl chloride (0.87 ml, 7.54 mmol) is then added and the reaction medium is heated under reflux overnight. After returning to ambient temperature, the precipitate is filtered, washed with CH2Cl2 and the filtrate is concentrated under reduced pressure. The oil obtained is dissolved again in CH2Cl2 (50 ml) and washed in succession with an aqueous solution of NaOH 2 N (4×50 ml) and water (1×50 ml). The organic phase is dried over anhydrous Na2SO4 and the solvent is evaporated under reduced pressure to yield 7-methyloxy-8-[(phenylmethyl)oxy]quinoline in the form of a brown oil (1.28 g; 4.84 mmol, yield=77%). NMR-1H (250 MHz, CDCl3) δ, ppm: 8.94 (dd, 3J (H, H)=4.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.06 (dd, 3J (H, H)=8.5 Hz, 4J (H, H)=1.5 Hz, 1H); 7.59-7.51 (m, 3 H); 7.36-7.24 (m, 5H); 5.40 (s, 2H); 3.92 (s, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 151.3 (CH); 149.5 (Cq); 142.9 (Cq); 141.2 (Cq); 137.4 (Cq); 135.3 (CH); 127.9 (CH); 127.4 (CH); 127.1 (CH); 123.6 (Cq); 122.9 (CH); 118.5 (CH) 114.8 (CH); 75.2 (CH2); 56.1 (CH3). MS (CID, NH3): m/z=266 (MH+). Analysis (%) for C17H15NO2.0.05 CHCl3: calculated C, 75.49. H, 5.59. N, 5.16. found C, 75.74. H, 5.40. N, 5.33.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:13]3[NH:21][C:20]4[CH2:19][CH2:18][NH:17][C:16](=[O:22])[C:15]=4[CH:14]=3)[C:6]([F:12])=[CH:7][CH:8]=2)[N:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:65][N:66]1[CH:70]=[C:69](B2OC(C)(C)C(C)(C)O2)[CH:68]=[N:67]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:12][C:6]1[C:5]([C:13]2[NH:21][C:20]3[CH2:19][CH2:18][NH:17][C:16](=[O:22])[C:15]=3[CH:14]=2)=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([C:69]3[CH:68]=[N:67][N:66]([CH3:65])[CH:70]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: O=C1NCCc2[nH]c(-c3c(F)ccc4ccc(Cl)nc34)cc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc3ccc(F)c(-c4cc5c([nH]4)CCNC5=O)c3n2)cn1
Temperature: 130 °C
Yield: 1.8 %

Procedure:
In a 5-mL glass microwave tube 2-(2-chloro-7-fluoroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 230; 64 mg, 0.20 mmoles), XPhos (Strem, 5.80 mg, 0.012 mmol), Pd2(dba)3 (5.57 mg, 6.08 μmol), K3PO4 (129 mg, 0.608 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Boron Molecular, Research Triangle, N.C.; 50.6 mg, 0.24 mmol) were purged with argon, treated with dioxane (3 mL) and water (0.60 mL) and heated at 130° C. for 30 min. The mixture was treated with water, extracted with DCM, washed with brine and concentrated. Purification by rpHPLC (20-95% 0.1% TFA/ACN in 0.1% TFA/water, Silicycle Silichrome XT C18 column; 30×150 mm, 5 μm) afforded 2-(7-fluoro-2-(1-methyl-1H-pyrazol-4-yl)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (1.3 mg, 3.60 μmol, 1.8% yield) as an orange amorphous solid: 1H NMR (400 MHz, MeOH-d4) δ ppm 8.60 (1H, d, J=8.8 Hz), 8.57 (1H, s), 8.35 (1H, s), 8.27 (1H, d, J=6.7 Hz), 8.01 (1H, d, J=8.8 Hz), 7.88 (1H, d, J=11.7 Hz), 7.19 (1H, s), 4.05 (3H, s), 3.62 (2H, t, J=6.9 Hz), 3.02 (2H, t, J=6.9 Hz). 19F NMR (376 MHz, MeOH-d4) δ ppm −77.32 (1F, s). m/z (ESI, +ve ion) 362.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[C:31](=[O:32])[CH2:30][NH:29][C:28]1=[O:33]>>[F:25][C:4]1[CH:3]=[C:2]([N:29]2[CH2:30][C:31](=[O:32])[N:27]([CH3:26])[C:28]2=[O:33])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Reactant: CN1C(=O)CNC1=O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CC(=O)N(C)C4=O)cc3F)CC2)nc1C
Yield: 61.8 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (163 mg) described in Preparation Example 128 and 3-methylimidazolidine-2,4-dione (68 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (109 mg) was obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[CH3:10][N:11]([CH3:16])[S:12](N)(=[O:14])=[O:13].N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.C1(C)C=CC=CC=1>[CH3:10][N:11]([CH3:16])[S:12]([NH:3][Si:2]([CH3:9])([CH3:8])[CH3:1])(=[O:14])=[O:13]
Reactant: CN(C)S(N)(=O)=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)N[Si](C)(C)C
Yield: 140.1 %

Procedure:
3 ml (14.4 mmoles) of hexamethyldisilazane were added to a refluxing mixture of 2.48 g (20 mmoles) of N,N-dimethylsulfamide, 9 mg (0.05 mmole) of saccharin and 30 ml of toluene. By the method described hereinbefore, it was established that the calculated amount of ammonia had been evolved after refluxing for one hour and volatile materials were then evaporated under reduced pressure. The residue was dried to room temperature to obtain 3.96 g (101%) of N,N-dimethyl-N'-trimethylsilylsulfamide melting at 83°-86° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C@H:5]1[CH2:8][C@H:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6]1.[Li+].[CH3:19]C([N-]C(C)C)C.CCCCCC.IC>C1COCC1.O>[CH3:1][O:2][C:3](=[O:17])[CH:4]([C@H:5]1[CH2:8][C@H:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:6]1)[CH3:19]
Reactant: COC(=O)C[C@H]1C[C@H](OCc2ccccc2)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CI
Solvent: O
Product: COC(=O)C(C)[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-(3-benzyloxy-cyclobutyl)-acetic acid methyl ester (110 mg, 0.47 mmol) in THF (1 mL) is added 1.09M LDA in THF and hexane (1.51 mL, 1.65 mmol) at −78° C. under nitrogen, and stirred at −78° C. for 30 min. To the mixture, iodomethane (232 ul, 3.76 mmol) is added, and the mixture is stirred at −78° C. for 30 min. The temperature is slowly warmed to room temperature for 3 hours. To the mixture, H2O is added and extracted with AcOEt. The organic layer is dried over MgSO4 and concentrated under reduced pressure to give trans-2-(3-benzyloxy-cyclobutyl)-propionic acid methyl ester (94 mg, 80%); ESI-MS m/z 249 [M+1]+, retention time 2.07 min (condition A).
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:17][CH3:18])[CH:11]=1)[C:3]([O:5]CC)=O.[O-:19][C:20]#[N:21].[K+]>C(O)CCC>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH:2]2[O:1][C:20](=[O:19])[NH:21][C:3]2=[O:5])=[CH:11][C:12]=1[O:17][CH3:18]
Reactant: CCOC(=O)C(O)CCc1ccc(O)c(OC)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CCCCO
Product: COc1cc(CCC2OC(=O)NC2=O)ccc1O
Reaction time: 18 h
Yield: 27.7 %

Procedure:
A mixture of ethyl 2-hydroxy-4-(4-hydroxy-3-methoxyphenyl)butanoate (0.73 g), potassium cyanate (KCNO) (0.7 g) and butanol (25 ml) was stirred for 18 hours under reflux. The reaction mixture was concentrated under reduced pressure. The residue was poured into water and acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), followed by distilling off the solvent. The resulting oily product was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-chloroform (1:4, v/v), was obtained 5-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2,4-oxazolidinedione (0.2 g, 28%),
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Mg].C1C2C(=CC=CC=2)C=C1.Br[Mg].[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[B:32]([N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])Cl>O1CCCC1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[B:32]([C:24]1[CH2:25][C:26]2[C:31]([CH:23]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:34]([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:36])[CH3:37]
Reactant: CC(C)N(B(Cl)C1=Cc2ccccc2C1)C(C)C
Reactant: BrC1=Cc2ccccc2C1
Agent: C1=Cc2ccccc2C1
Agent: [Mg]
Agent: [Mg]Br
Solvent: C1CCOC1
Product: CC(C)N(B(C1=Cc2ccccc2C1)C1=Cc2ccccc2C1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 121 %

Procedure:
In a stream of nitrogen, 3.1 g (15.9 mmol) of 2-bromoindene and 1.6 g of magnesium were caused to react with each other in 50 ml of tetrahydrofuran, whereby a reaction solution containing bromomagnesium indene was obtained. The reaction solution was added dropwise to a solution prepared by dissolving 4.11 g (15.7 mmol) of (2-indenyl)(diisopropylamino)chloroborane synthesized in the above section (1) in 30 ml of tetrahydrofuran at 0° C. After the mixture had been stirred at room temperature for 4 hours, the solvent was removed by distillation, and the remainder was extracted twice with 40 ml of hexane and 10 ml of dichloromethane, whereby 6.47 g (19.0 mmol) of bis(2-indenyl)(diisopropylamino)borane as a pale yellow solid were obtained.
Reaction SMILES: [CH2:1]([C:5]1([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15]C)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[Br-].[Al+3].[Br-].[Br-].Cl.C(OCC)C>C1C=CC=CC=1>[CH2:1]([C:5]1([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:15])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CCc2c(OC)cccc2C1=O
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCCC1(CCCC)CCc2c(O)cccc2C1=O
Yield: 119.7 %

Procedure:
A mixture of 2,2-dibutyl-3,4-dihydro-5-methoxy-1(2H)-naphthalenone (2.321 g) and aluminium bromide (7.0 g) in dried benzene (40 ml) was refluxed for 40 minutes and allowed to cool in an ice-water bath. The cooled mixture was poured into a mixture of 1N aqueous hydrochloric acid (150 ml) and diethyl ether (100 ml) with stirring. The organic layer was washed with brine, dried, and concentrated in vacuo to yield 2,2-dibutyl-3,4-dihydro-5-hydroxy-1(2H)-naphthalenone (2.643 g) as a crude syrup.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:29][CH3:30])[CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:7][CH:6]=1)(=O)C.C1(C)C=CC(S(O)(=O)=[O:38])=CC=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+].Cl>C(O)C>[CH2:29]([N:15]([CH2:14][CH2:13][CH2:12][S:11]([C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1)=[O:38])[CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCN(CCCSc1ccc(OC(C)=O)cc1)CC(O)COc1ccc(C#N)cc1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCO
Product: CCN(CCCS(=O)c1ccc(O)cc1)CC(O)COc1ccc(C#N)cc1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A solution of 4-[3-[[3-[[4-(acetyloxy)phenyl]thio]propyl]ethylamino] -2-hydroxypropoxy]-benzonitrile (3.80 g, 8.8 mmol) and toluene-4-sulfonic acid (1.67 g, 8.8 mmol) in ethanol (100 ml) was stirred and chilled to -15 ° C. To the chilled solution was added a solution of 3-chloroperbenzoic acid (2.05 g, 8.8 mmol) in ethanol (10 ml). The solution was stirred at room temperature for 2 h. Sodium hydroxide (8.8 g, 0.22 mol) was added and the solution was stirred for 1 h. The pH was adjusted to about 7 with hydrochloric acid. After evaporation the residue was treated with 2M hydrochloric acid and washed with diethylether. The acidic aqueous layer was treated with sodium hydroxide solution to pH =9 and extracted with three portions of ethyl acetate. The combined ethyl acetate fractions were dried over sodium sulfate and evaporated. The oily residue was purified by column chromatography on silica gel. Yield: 0.9 g of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:11][C:12]1[CH:19]=[CH:18][C:17]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:35])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH2:31][NH:30][CH2:29][CH2:28]4)[N:21]=2)=[CH:16][C:13]=1[C:14]#[N:15])[CH3:10].[C:36]([O:40][CH2:41][CH3:42])(=[O:39])[CH:37]=[CH2:38].N12CCCN=C1CCCCC2>C(#N)C>[C:14]([C:13]1[CH:16]=[C:17]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:35])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH2:31][N:30]([CH2:38][CH2:37][C:36]([O:40][CH2:41][CH3:42])=[O:39])[CH2:29][CH2:28]4)[N:21]=2)[CH:18]=[CH:19][C:12]=1[O:11][CH:9]([CH3:8])[CH3:10])#[N:15]
Reactant: C=CC(=O)OCC
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
A mixture of 2-[(1-methylethyl)oxy]-5-[3-(5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl)-1,2,4-oxadiazol-5-yl]benzonitrile trifluoroacetic acid salt (Example 11; 100 mg, 0.20 mmol), ethyl acrylate (31 mg, 33 μl, 0.31 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 187 mg, 185 μl, 1.23 mmol) in acetonitrile (3 ml) was stirred at room temperature for 3 hours. The solvent was evaporated and the residue dissolved in ethyl acetate (10 ml); the solution was washed with water (5 ml), dried and evaporated. Purification of the residue by chromatography on silica gel, eluting with 10% ethyl acetate in cyclohexane gave the title compound as a colourless oil (86 mg).
Reaction SMILES: [C:1]12[CH:10]=[C:4]([CH2:5][C:6]=1[C:7](O)=O)[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]2=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>O.CN(C)C=O>[C:1]12[CH2:10][C:4](=[CH:5][C:6]=1[CH2:7][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]2=1
Reactant: O=C(O)C1=C2C=C(C1)c1ccccc12
Reactant: C1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C1=C2CC(=C1CN1CCCCC1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Benzobicyclo[2.2.1]heptenecarboxylic acid (0.4 g) was combined with piperidine (1 ml), diethylcyanophosphonate (1 ml), triethylamine (2 ml) and dimethylformamide (10 ml) and stirred for 2 hours at room temperature. Water (15 ml) was added and the mixture was extracted with ether (3×15 ml). The combined ether solutions were washed with water (2×25 ml) and the ether solution was dried over magnesium sulfate and the ether removed on a rotary evaporator. The residue was combined with tetrahydrofuran (25 ml) and lithium aluminum hydride (0.2 g) and heated to reflux for 12 hours. The mixture was cooled in an ice bath, treated with ethanol (1 ml) and water (0.5 ml) and the solids were removed by filtration. The filtrate was concentrated on a rotary evaporator and the residue was dissolved in 6N HCl (20 ml). The acidic solution was washed with ether (2×25 ml) and the aqueous solution was made basic with 50% sodium hydroxide solution. The mixture was extracted with ether (3×25 ml) and the combined ether solutions were dried over magnesium sulfate and the ether removed on a rotary evaporator. The residue was distilled on a Kugelrohr apparatus (80° C. at 0.05 mm Hg) to provide the product as a colorless oil. Analytical data are reported in Table I.