Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([O-:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.CO.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>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:33]2[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)c1nn(Cc2ccccc2Br)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2ccccc2-c2ccc([N+](=O)[O-])cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 49.2 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(2-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 78(b), 75 mg, 0.177 mmol), (4-nitrophenyl)boronic acid (29.5 mg, 0.177 mmol), potassium carbonate (73.3 mg, 0.530 mmol), and tetrakis(triphenylphosphine)palladium (0) (6.13 mg, 5.30 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (4 ml), acidified with 1N HCl (1 ml), and diluted with methanol (2 ml) then filtered to remove any residue followed by purification by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N-({5-hydroxy-6-(1-methylethyl)-2-[(4′-nitro-2-biphenylyl)methyl]-3-oxo-2,3-dihydro-4-pyridazinyl}carbonyl)glycine (41 mg, 0.087 mmol, 49.2% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 10.04 (t, J=5.43 Hz, 1H), 8.27 (ddd, J=9.03, 2.40, 2.21 Hz, 2 H), 7.69 (ddd, J=9.03, 2.40, 2.21 Hz, 2H), 7.37-7.48 (m, 2H), 7.20-7.34 (m, 2H), 5.27 (s, 2H), 4.03 (d, J=5.81 Hz, 2H), 3.10 (sept, J=6.86 Hz, 1H), 1.09 (d, J=6.82 Hz, 6 H). MS (ES+) m/e 467 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.CO>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: C[C@@H](O)c1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of 1-(4-bromophenyl)ethanone (5.0 g, 25 mmol) and (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole (1.25 mL, 1 M) in 80 mL of anhydrous dichloromethane was added Borane-methyl sulfide complex (2.1 g, 27 mmol) over 1 hour at −200C. After addition completed, the mixture was stirred at −20° C. for 2 hours, then stirred at room temperature for 12 hours. After the reaction, 20 mL of methanol was added, and stirred for 0.5 hour. Then the mixture was diluted with 100 mL of water and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give (R)-1-(4-bromophenyl)ethanol (4.6 g, 92%) as the white solid.
Reaction SMILES: [OH-].[Na+].C(O[C:6]([C:8](C)([C:17](=[O:19])[CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12][S:13]([OH:16])(=[O:15])=[O:14])=O)C>O.CO>[CH3:6][CH:8]([C:17](=[O:19])[CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12][S:13]([OH:16])(=[O:14])=[O:15]
Reactant: CCOC(=O)C(C)(CCCCS(=O)(=O)O)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)C(C)CCCCS(=O)(=O)O
Temperature: 50 °C
Reaction time: 15 h

Procedure:
A solution of 290 mg of NaOH in 3 ml water was added to the mixture of 710 mg (2.53 mmol) of 5-ethyloxycarbonyl-5-methyl-6-oxo-1-heptanesulfonic acid in 15 ml of methanol. The obtained mixture was stirred for 15 hours at 50° C. Methanol was removed by a rotary evaporator, residue was acidified to pH 1 and then solvent was removed until dry to yield 5-methyl-6-oxo-1-heptanesulfonic acid. The product thus obtained (940 mg, 4.5 mmol), 1.02 g (5.4 mmol) of 4-hydrazinobenzenesulfonic acid, and 15 ml of acetic acid was refluxing for 16 hours. The insoluble precipitate was filtered and the filtrate was evaporated. The obtained residue was column purified (RP-18, water) to yield 840 mg of the 2,3-dimethyl-3-(4-sulfobutyl)-3H-5-indolesulfonic acid (IVd). δH (200 MHz, DMSO-d6): 7.66 (1H, s, arom H), 7.6 (1H, d, 8.0 Hz, arom H), 7.4 (1H, d, 7.8 Hz arom H), 2.66 (2H, t, 6.8 Hz, CH2SO3H), 2.32 (3H, s, 2-CH3), 2.10-1.78 (2H, m, CH2), 1.53-1.26 (2H, m, C H2), 1.31 (3H, s, 3-C H3), 0.83-0.41 (2H, m, CH2).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].[I-].[K+].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[O:15].O>CS(C)=O>[O:2]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[O:15]
Reactant: O=C(CCCCCBr)Nc1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])O
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=CCCCCC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
A solution of sodium bicarbonate (0.250 g), potassium iodide (0.050 g), and 6-bromo-N-[4-(trifluoromethyl)phenyl]hexanamide (1.00 g) in dimethylsulfoxide (15 mL) was heated at 125°-130° C. for 3.5 hours while stirring under a nitrogen atmosphere. The reaction was treated with water (75 mL) and extracted with ether. The ether extract was washed with brine (50 mL), dried over sodium sulfate after adding dichloromethane (30 mL), filtered, and concentrated in vacuo. Chromatography using 50/50 ethyl acetate/hexane gave a white solid (Rf 32 0.2 in same solvent system, 0.326 g), identified as the title compound. m.p.: 129.5°-131.0° C.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[S:20](Cl)([Cl:23])(=[O:22])=[O:21]>>[C:1]1([C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][S:20]([Cl:23])(=[O:22])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: C=C(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)C=C(c1ccccc1)c1ccccc1
Temperature: 90 °C
Yield: 29 %

Procedure:
1,1-Diphenylethene (11.3 mmol, 2 ml) was added to a solution of DMF (22.7 mmol, 1.75 ml) and sulfuryl chloride (19.3 mmol, 1.55 ml) at 0° C. The reaction was heated to 90° C. for 4 hr, then cooled to ambient temperature and poured into ice (500 ml). The aqueous layer was extracted with EtOAc (2×100 ml). Then the organic was dried (MgSO4) filtered and concentrated. Flash chromatography (5% EtOAc/hexane) provided 0.92 g (29% yield) of light yellow crystals.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[CH:15]=[C:14]([O:19]CCCNC)[C:13]=2[CH:25]=1.C(N(C(C)C)CC)(C)C.C(OC([NH:42][C:43]([N:52]1[CH:56]=[CH:55][CH:54]=N1)=[N:44]C(OC(C)(C)C)=O)=O)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[CH:15]=[C:14]([O:19][CH2:54][CH2:55][CH2:56][NH:52][C:43]([NH2:42])=[NH:44])[C:13]=2[CH:25]=1
Reactant: CNCCCOc1cc(=O)oc2ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCCOc1cc(=O)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Chloro-4-(3-methylamino-propoxy)-1-benzopyran-2-one trifluoroacetic acid salt (200 mg, 0.543 mmol) is suspended in 7 mL of DCM. Diisopropylethylamine is added dropwise until pH=9 by pH paper. N,N′-Bis(tert-butoxycarbonyl)-1-H-pyrazole-1-carboxamidine (169 mg, 0.543 mmol) is added and is stirred at ambient temperature overnight. The reaction mixture is concentrated in vacuo and Et2O is added to form a white precipitate, which is filtered and is washed with Et2O. The crude material is treated with neat TFA (10 mL) for 30 min at ambient temperature. The TFA is removed under reduced pressure. Et2O is added to precipitate the product, which is filtered, is washed with Et2O, and is dried. The crude material is further purified by reversed-phase HPLC to afford the title compound as the trifluoroacetic acid salt. (108 mg, 48.6%). %). 1H NMR (DMSO-d6, 300 MHz) δ 7.86 (1H, d, J=2.5 Hz), 7.72 (1H, dd, J=2.5, 8.75 Hz), 7.64 (1H, t, J=5.5 Hz), 7.47 (1H, d, J=8.75 Hz), 7.12 (3H, br s), 6.00 (1H, s), 4.26 (2H, t, J=5.75 Hz), 3.36 (2H, m, J=6.25 Hz), 2.04 (2H, m, J=6.25 Hz); MS (ESI, Pos.) calcd for C13H14ClN3O3 m/z [M+H]=296.1, found 296.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:13][C:12]=3[O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[O:8][C:7](=[O:30])[C:6]=2[CH:31]=1.[NH2:32][C:33]1[CH:37]=[C:36]([CH3:38])[O:35][N:34]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:9](=[O:8])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:22][CH:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)=[C:6]([CH:31]=1)[C:7]([NH:32][C:33]1[CH:37]=[C:36]([CH3:38])[O:35][N:34]=1)=[O:30]
Reactant: Cc1cc(N)no1
Reactant: CN1CCC(Oc2cc(N3CCCC3)ccc2-c2nc3ccc(F)cc3c(=O)o2)CC1
Product: Cc1cc(NC(=O)c2cc(F)ccc2NC(=O)c2ccc(N3CCCC3)cc2OC2CCN(C)CC2)no1

Procedure:
Using methods substantially equivalent to those described in Example 91-G, 5-fluoro-N-(5-methylisoxazol-3-yl)-2-[2-(1-methylpiperidin-4-ylxy)-4-(pyrrlidin-1-yl)-benzoylamino]benzamide was prepared from 6-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one and 3-amino-5-methylisoxazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:9]([OH:11])=[O:10])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)C(CC(=O)OCc1ccccc1)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: O=C(CC(C(=O)O)c1ccc(Br)cc1)OCc1ccccc1
Yield: 86.6 %

Procedure:
A suspension of 4-benzyl 1-tert-butyl 2-(4-bromophenyl)succinate (3.00 g, 7.15 mmol) and silica gel (35.7 g) in toluene (230 mL) was heated at reflux for 3 h. The crude mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane/methanol (8:2; 2×100 mL) then the organic filtrates were combined and evaporated to dryness to give the title compound as a white solid (2.25 g, 87%). LC/MS: 3.41 min; z/e 361 and 363, calcd (M−1) 361 and 363. 1H NMR (400 MHz: CDCl3): 7.40 (2H), 7.30 (5H), 7.15 (2H), 5.10 (2H), 4.05 (1H), 3.15 (1H), 2.70 (1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=O)[C@@H:10]2[CH3:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[S:33])[C@@H:10]2[CH3:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@@H]2C)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@@H]2C)CC1
Yield: 167.6 %

Procedure:
(3R,4S)-4-(1-Ethoxycarbonylcyclopropyl)-3-methyl-1-[(S)-1-phenylethyl]-2-pyrrolidone (1.85 g, 5.87 mmol) was dissolved in benzene (100 ml), and the solution was mixed with Lawesson's reagent (1.31 g, 3.24 mmol) and heated under reflux for 20 minutes. After completing the reaction, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography (silica gel, 160 ml; ethyl acetate:hexane=1:4), to thereby obtain 1.80 g (92%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][C:4]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10](=[O:13])[CH:11]=[CH2:12])=[N:3]1.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH2:28][C:29]1[S:33][C:32]([CH:34]=[O:35])=[N:31][CH:30]=1.C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][C:4]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10](=[O:13])[CH2:11][CH2:12][C:34]([C:32]2[S:33][C:29]([CH2:28][O:27][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][O:21]3)=[CH:30][N:31]=2)=[O:35])=[N:3]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1cc(SC)n(C)n1
Reactant: O=Cc1ncc(COC2CCCCO2)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1cc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)nn1C
Yield: 61.1 %

Procedure:
A mixture of 4-[1-methyl-5-(methylsulfanyl)-1H-pyrazol-3-yl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.60 g), 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-2-carbaldehyde (0.48 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (54 mg), triethylamine (0.11 mL), tetrahydrofuran (6 mL) and ethanol (6 ml) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography to give the title compound (0.65 g, yield 60%) as a yellow oil from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 522 (MH+).
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[O:16]1[CH2:35][CH:17]1[CH2:18][O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[C:28]([O:30][CH2:31][CH:32]1[O:34][CH2:33]1)=[O:29])=[O:21]>C(O)(C)(C)C>[CH2:1]([N:5]([CH2:33][CH:32]([OH:34])[CH2:31][O:30][C:28]([CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[C:20]([O:19][CH2:18][CH:17]([OH:16])[CH2:35][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]1[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]1)=[O:21])=[O:29])[CH:6]1[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OCC1CO1)C1CCCCC1C(=O)OCC1CO1
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Solvent: CC(C)(C)O
Product: CCCCN(CC(O)COC(=O)C1CCCCC1C(=O)OCC(O)CN(CCCC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 8 h

Procedure:
A mixture of 5 g of 4-butylamino-2,2,6,6-tetramethylpiperidine and 3 g of bis(2,3-epoxypropyl)1,2-cyclohexanedicarboxylate in 10 ml of t-butanol was refluxed, with stirring, for 8 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel eluted with a 20:1 by volume mixture of ethyl acetate and triethylamine. The desired compound was obtained in the form of a pale yellow, viscous oil having an Rf value of 0.53 on thin layer chromatography on silica gel developed with a 5:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10]/[C:9]/2=[CH:16]\[O:17][Si](C(C)C)(C(C)C)C(C)C)=[CH:4][CH:3]=1.Cl>C(OC(C)C)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CC(C)[Si](O/C=C1\CC(C)(C)CCC1(O)c1ccc(Cl)cc1)(C(C)C)C(C)C
Agent: Cl
Solvent: CC(=O)OC(C)C
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1

Procedure:
The solution from EXAMPLE 3 was slowly treated with 2N HCl (240 mL), maintaining an internal temperature below 20° C. The contents were mixed at 20° C. for 10-12 hours, and the mixture was monitored by GC analysis. Isopropyl acetate (130 mL) was charged to the reaction mixture, and the layers were mixed and separated. The organic layer was washed with water (45 mL), 1% aqueous NaHCO3 (45 mL), and 20% aqueous NaCl (2×45 mL). The product mixture was azeotropically dried through a solvent exchange with toluene (125 g) to obtain a 32% solution of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 0.95 (s, 6 H) 1.48 (t, J=6.45 Hz, 2 H) 2.03 (t, J=1.92 Hz, 2 H) 2.53-2.57 (m, J=6.38, 6.38, 2.20, 2.06 Hz, 2 H) 7.36 (ddd, J=8.75, 2.54, 2.30 Hz, 2 H) 7.47 (ddd, J=8.78, 2.54, 2.26 Hz, 2 H) 9.37 (s, 1 H) ppm. Mass Spec: DCI/NH3 M+1=248 amu; M+NH3=266 amu.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[C:13]=1[CH2:20][OH:21].C(N(CC)CC)C>ClCCl.ClCCl.CS(C)=O>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[C:13]=1[CH:20]=[O:21]
Reactant: OCc1cccc(F)c1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cccc(F)c1C=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72.3 %

Procedure:
To a solution of oxalyl chloride 2M in dichloromethane (DCM) (11 m1, 22 mmol, 2.2 molar equivalents) cooled to −78° C., was added dropwise a solution of dimethylsulfoxyde (DMSO) (3.10 ml, 44 mmol, 4.4 molar equivalents) in DCM (10 ml). The solution was then stirred at −78° C. for 5 minutes and 3-fluorobenzene-1,2-dimethanol (Compound 17) (1.55 g, 10 mmol, 1.0 molar equivalent) dissolved in a mixture of DCM-DMSO (1-2 ml) added dropwise. The solution was then stirred for 1 hour at −78° C. and triethylamine (25 ml) was slowly added at −78° C. The reaction mixture was then stirred for 10 minutes at −78° C. and slowly warmed up to room temperature. Ice-cold water (50 ml) was added to the reaction mixture and the aqueous layer extracted with DCM (3 times 50 mls). The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated in vacuum to give a brown oil. Purification by distillation gave the title compound as a light yellow solid (1.10 g, 73%). 1H NMR (300.13 MHz, CDCl3) δ(ppm) 7.36-7.50 (m, 1H) 7.69-7.79 (m, 2H) 10.51 (s, 1H) 10.57 (s, 1H). 19F NMR (282.38 MHz, CDCl3) δ(ppm) −118.90 (s).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:26]([CH3:39])=[C:27]([CH3:38])[C:28]4[O:32][C:31]([CH3:34])([CH3:33])[CH:30](O)[C:29]=4[C:36]=3[CH3:37])[CH2:21][CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH2:1]([NH:8][CH:30]1[C:29]2[C:36]([CH3:37])=[C:25]([N:22]3[CH2:21][CH2:20][CH:19]([C:13]4[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([O:10][CH3:9])[CH:12]=4)[CH2:24][CH2:23]3)[C:26]([CH3:39])=[C:27]([CH3:38])[C:28]=2[O:32][C:31]1([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1OC
Reactant: NCc1ccccc1
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(NCc3ccccc3)C(C)(C)O4)CC2)cc1OC
Yield: 80 %

Procedure:
Using benzylamine and 5-(4-(3,4-dimethoxyphenyl)piperidino)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 19, the title compound was synthesized in the same manner as in Example 57. Yield 80%. Amorphous state powder.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH2:15][CH2:16]/[C:17](/[C:24]1[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=1)=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[CH:8]2.Cl>CO>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH2:15][CH2:16]/[C:17](/[C:24]1[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=1)=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[CH:8]2
Reactant: CCOC(=O)/C=C(/CCc1ccc2cc(OCOC)ccc2c1)c1ccc2ccccc2c1
Agent: Cl
Solvent: CO
Product: CCOC(=O)/C=C(/CCc1ccc2cc(O)ccc2c1)c1ccc2ccccc2c1

Procedure:
A solution of ((Z)-ethyl 5-(6-(methoxymethoxy)naphthalen-2-yl)-3-(naphthalen-2-yl)pent-2-enoate (0.35 g, 0.80 mmol) in methanol (10 mL) was treated with 10% HCl (2 mL) and the resulting mixture was refluxed for 2 h. After cooling the solvent was removed, the residue was extracted with ethyl acetate (3×) and dried with MgSO4. Then the crude product was concentrated to obtain the product; yellow oil; yield: 0.32 g (quant, without further purification);
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[N+:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[CH:30]2)([O-:26])=[O:25]>CN(C=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:32]3[C:33]4[C:29](=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:35][CH:34]=4)[CH:30]=[N:31]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1ncc2cc([N+](=O)[O-])ccc21)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (0.834 g, 3.3 mmol) was taken in dry DMF (15 mL) and dry potassium carbonate (1.6 g, 11.6 mmol) was added to it and the reaction mixture stirred at room temperature for 1 h under nitrogen. 5-Nitro-1H-indazole (0.5 g, 2.9 mmol) in DMF (2 mL) was then added to the mixture through a syringe. The reaction was heated at 70° C. for 14 h, cooled and then quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded material that on purification on neutral alumina column (pet ether/ethyl acetate) gave title compound as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[Br:22]N1C(=O)CCC1=O.O>C(OCC)(=O)C>[Br:22][CH:5]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CC(=O)C1CC1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(Br)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 106.8 %

Procedure:
Methyl 3-cyclopropyl-3-oxopropanoate (2.0 g) and magnesium perchlorate (940 mg) were dissolved in ethyl acetate (20 ml), followed by stirring at room temperature for 5 minutes, and N-bromosuccinimide (2.76 g) was added thereto, followed by stirring at room temperature for 4 hours. Water was added thereto, followed by extraction with ethyl acetate, the organic layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain, as a colorless oily product, methyl 2-bromo-3-cyclopropyl-3-oxopropanoate (3.32 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].[C:13]1([C@H:19]2[N:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:22][CH:21]([CH2:28]OS(C3C=CC(C)=CC=3)(=O)=O)[O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH3:25][C:24]([N:23]1[CH2:22][CH:21]([CH2:28][O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)[O:20][C@H:19]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:26])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(C(C)(C)C)[C@H](c3ccccc3)O2)cc1
Reactant: OCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)N1CC(COc2ccc(CCO)cc2)O[C@H]1c1ccccc1

Procedure:
4-(2-Hydroxyethyl)phenol (2.5 g, 18 mmol) was dissolved in 37 ml DMF then NaH (60% in mineral oil) (0.72 g, 18 mmol) was added while stirring under N2 atmosphere. After the evolution of H2 ceased, (S)-2-phenyl-5-tosyloxymethyl-3-(1,1-dimethylethyl) oxazolidine (7.0 g, 18 mmol) in 25 ml DMF was added and the reaction mixture was heated at 115°-120° C. for 14 hours. The solvent was evaporated in vacuo. A sodium carbonate solution (100 ml, 20% saturated) was added to the residue and the mixture was extracted with CHCl3 (150 ml then 100 ml). The chloroform was removed in vacuo and the residue was used directly in the next step without further purification.