Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][NH:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:20].[Na+].[CH2:22]=O>C(O)C.O>[OH:20][CH2:22][N:11]1[CH2:12][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][C:10]1=[O:13]
Reactant: [OH-]
Reactant: C=O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)CN1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccccc2)(c2ccccc2)CN1CO

Procedure:
To a stirred mixture of 37 g (0.147 mol) of 5,5 diphenyl-2-piperidinone and 24 g of sodium hydroxide in 170 mL of ethanol at ambient temperature was added dropwise 165 mL of a 35-40% formaldehyde in water solution during 10 minutes. The mixture was heated at reflux temperature overnight, concentrated to near dryness and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried. Concentration at less than 30° C. under vacuum, trituration with hexanes and filtration gave 28 g of product, mp 140°-150° C.(decomp.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:18]O.O>C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N+:14]([O-:18])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: c1ccc(COCCCc2cccnc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: [O-][n+]1cccc(CCCOCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
3-(3-Benzyloxypropyl)pyridine (34.28 g) was dissolved in acetic acid (260 ml), followed by the addition of a 30% aqueous solution of hydrogen peroxide (52 ml), and the mixture was stirred at 50° C. overnight. After cooling as it was, water (52 ml) was added to the reaction solution, which was then evaporated. The resulting residue was dissolved in chloroform, washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound as a yellow oil (30.23 g, yield; 88%).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:13][C:12](=[O:14])[NH:11][CH:10]1[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])C1C=CC=CC=1.[H][H]>[Pd].O.CO>[ClH:1].[O:14]=[C:12]1[NH:11][CH:10]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[NH:9][CH2:13]1
Reactant: CC(C)COC(=O)CCC1NC(=O)CN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)COC(=O)CCC1NCC(=O)N1
Yield: 87.2 %

Procedure:
To a mixture of 10% palladium on charcoal (1 g) and 99% formic acid (1 ml) in methanol (25 ml), under nitrogen, was added a solution of isobutyl 3-benzyl-5-oxo-2-imidazolidinepropanoate hydrochloride (1 g, 2.93 mmol) and 99% formic acid (1.25 ml) in methanol (25 ml). The mixture was stirred under nitrogen for 6 hours. After addition of water (15 ml) and removal of the catalyst, the solvent was evaporated and the residue was triturated with ethanol to give 0.3 g (41%) of the title compound, m.p. 136°-140° C. The same compound was obtained also by the following procedure: into a mixture of isobutyl 3-benzyl-5-oxo-2-imidazolidinepropanoate hydrochloride (2.2 g, 6.4 mmol), and 10% palladium on charcoal (1.1 g) in water-methanol 2:1 (150 ml) hydrogen was bubbled at room temperature and at atmospheric pressure for 2 hours. Removal of the catalyst and evaporation of the solvent under reduced pressure gave a residue which was triturated with ethanol to afford 1.4 g (90%) of the title compound, m.p.136°-140° C. NMR (DMSO-d6): deltaH =11.1-9.50 (b.s., 2H, NH2+); 9.20 (b.s., 1H, CONH); 4.95 (t, J=6.2 Hz, 1H, NHCHNH); 3.84 (d, J=6.7 Hz, 2H, COOCH2); 3.65 (s, 2H, NCH2CO); 2.70-2.30 (c.a., 2H, CH2CH2COO); 2.25-1.60 (c.a., 3H, CH2CH2COO, CH(CH3)2); 0.87 (d, J=6.7 Hz, 6H, CH(CH3)2. MS (E.I., 70 eV, 1.5 mA) m/z=214 (M+), 141 (M-OC4H9)+, 85 (C3H5N2O)+.
Reaction SMILES: C(O)C.[C:4]([N:8]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH3:18])=[O:16])=[C:11](Cl)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5].[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1>C(N(CC)CC)C>[C:4]([N:8]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH3:18])=[O:16])=[C:11]([NH:27][CH2:26][C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: NCc1ccncc1
Reactant: COC(=O)c1c(Cl)cnn(C(C)(C)C)c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1c(NCc2ccncc2)cnn(C(C)(C)C)c1=O

Procedure:
7 ml of an absolute ethanol solution of 170 mg of 2-tert-butyl-5-chloro-4-methoxycarbonylpyridazin-3-(2H)-one, 76 mg of 4-picolylamine and 80 mg of triethylamine, was reacted for 4 hours under heating and refluxing and then left to cool. Ethanol was distilled off under reduced pressure, and 0.3 g of the obtained oil was subjected to column chromatography. Using an eluent (ethyl acetate:methanol=20:1), 0.13 g of the desired product (Compound No. 22) having a melting point of from 99° to 100° C., was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10](OC)[CH:9]=[C:8](Cl)[C:5]=1[CH:6]=O)([O-])=O.C(O)C.Cl.Cl.[NH2:20][C:21](N)=N>C1C=CC=CC=1.[Fe]>[N:1]1[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:20][CH:21]=1
Reactant: N=C(N)N
Reactant: COc1cc(Cl)c(C=O)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: c1ccc2ncncc2c1

Procedure:
The nitro group of 2-nitro-4-methoxy-6-chlorobenzaldehyde (1 equivalent) is reduced to the amine by refluxing in benzene or ethanol with iron powder (the powder having been pretreated with concentrated hydrochloric acid). This amine is then treated with guanidine hydrochloride as described above (step k) to yield the quinazoline (COMPOUND XXIII) which is purified by column chromatography and/or crystallization. Benzoylation of this product is performed as described above (step d), to yield COMPOUND XXII.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.Cl.Cl.[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([NH2:25])=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH:13]=[C:12]([N:26]2[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]2)[N:11]=1.O1CCCC1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O.CCOC(C)=O>[NH2:9][C:10]1[N:11]=[C:12]([N:26]2[CH2:31][CH2:30][CH2:29][CH:28]([NH:32][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:27]2)[CH:13]=[C:14]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([NH2:25])=[N:21][NH:22]3)=[CH:18][CH:17]=2)[N:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCC(N)C2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCC(NC(=O)c3ccccc3)C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
Sodium bicarbonate (145 mg, 1.73 mmol) was added to a solution of 6-[2-amino-6-(3-amino-1-piperidinyl)-4-pyrimidinyl]-1H-indazol-3-amine trihydrochloride (150 mg, 0.346 mmol) in water (1.5 mL) with stirring. Tetrahydrofuran (THF) (1.5 mL) was added, the mixture was cooled in an ice bath, and benzoyl chloride (0.044 mL, 0.380 mmol) was added dropwise with stirring. The mixture was then warmed to room temperature and stirred for 2 hours. LCMS showed starting material remaining, product, and bis-benzoylation. An additional 40 uL of benzoyl chloride and 145 mg of NaHCO3 were added, and the mixture was stirred for 1 hour. HPLC showed complete conversion to multi-benzoylated product. The reaction was diluted with EtOAc, washed with water, dried (Na2SO4), filtered and evaporated. The crude was suspended in CH3OH (8 mL), 1 mL of concentrated aqueous HCL was added, and the mixture was stirred 3 days at 65° C. HPLC showed conversion to the desired product. The mixture was concentrated to ˜2 mL, then diluted with CH3CN (˜8 mL) and heated. Additional CH3CN was added to the hot solution until turbid. The mixture was allowed to cool slowly to room temperature with strring over 2 hours. The precipitate was collected by filtration, washed with CH3CN, then Et2O and finally hexanes. Drying afforded the title compound (156 mg) dihydrochloride as an off-white solid. A 100 mg portion was purified further by Gilson automated reverse phase HPLC (Gemini Phenomenex C18 5u, 100×300 mm), eluting with 5-90% CH3CN-water+0.1% NH4OH) to give the title compound (55 mg) as a white solid. LC-MS (ES) m/z=429 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.43-1.60 (m, 1H), 1.60-1.74 (m, 1H), 1.76-1.86 (m, 1H), 1.92-2.03 (m, 1H), 2.87-3.00 (m, 2H), 3.83-3.95 (m, 1H), 4.27-4.39 (m, 1H), 4.49 (bs, 1H), 5.38 (s, 2H), 6.12 (s, 2H), 6.64 (s, 1H), 7.46 (t, J=7.3 Hz, 2H), 7.50-7.54 (m, 1H), 7.54-7.61 (m, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.87 (d, J=7.1 Hz, 2H), 7.94 (s, 1H), 8.39 (d, J=7.6 Hz, 1H), 11.52 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:12]3[NH:13][CH:14]=[CH:15][N:16]=3)=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][N:10]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: c1ccc(-c2nnc(-c3ncc[nH]3)s2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2-c2nnc(-c3ccccc3)s2)cc1
Temperature: 120 °C
Yield: 87 %

Procedure:
A mixture of 2-[2-(phenyl)-1,3,4-thiadiazol-5-yl]-1H-imidazole (0.285 g, 1.25 mmol), 1-fluoro-4-nitrobenzene (0.176 g, 1.25 mmol) and sodium carbonate (0.265 g, 2.50 mmol) in DMF (10 mL) was heated at 120° C. for 24 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and washed with water and brine. The combined organic fraction was dried (Na2SO4) and evaporated to dryness. The crude product was purified by chromatography on silica gel using hexane/ethyl acetate as an eluant to give the product (0.38 g, 87%) as a white solid; 1H NMR δ (DMSO-d6) 8.38 (2H, d, J=8.9 Hz), 7.98 (2H, dd, J=7.7, 1.6 Hz), 7.86 (2H, dd, J=8.8, 1.6 Hz), 7.81 (1H, s), 7.55 (3H, m), 7.43 (1H, dd, J=1.3 Hz); 13C NMR δ (DMSO-d6) 167.8, 159.1, 147.3, 142.6, 136.6, 131.6, 131.0, 129.5, 129.0, 128.1, 127.7, 126.2, 124.3; MS (m/z): 350.4 (M+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClS(O)(=O)=O.Cl>O>[CH:6]1[C:5]([S:8]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)(=[O:10])=[O:11])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Reactant: Clc1ccccc1
Agent: Cl
Agent: O=S(=O)(O)Cl
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 60 %

Procedure:
A 211 g (1.1 moles) quantity of 4-chlorobenzenesulfonic acid was added to 112 g (1 mole) of chlorobenzene and the mixture was cooled with water while 123 g (1.1 moles) of chlorosulfonic acid was added to the mixture at about 10° to about 20° C. over a period of 1 hour. After the addition, the reaction mixture was stirred for 3 hours while being maintained at 20° to 30° C. The hydrochloric acid gas evolved during the reaction was continuously removed from the reaction system. After the termination of the reaction, about 400 ml of water was added to the reaction mixture and 11.2 g (0.1 mole) of the unreacted chlorobenzene was recovered by distillation. The separation of the precipitate formed gave 77 g of 4,4'-dichlorodiphenylsulfone in a yield of 60% (based on the amount of the aromatic hydrocarbon as consumed, the same hereinafter). M.P. 148.5° to 149.5° C. Purity of 99.8% (according to liquid chromatography, the same hereinafter).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:17]1([N:21]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[S:22]([C:25]2[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:20][CH2:19][CH2:18]1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:28]2[CH:29]=[CH:30][C:25]([S:22](=[O:23])(=[O:24])[N:21]([CH:17]3[CH2:18][CH2:19][CH2:20]3)[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=S(=O)(c1ccc(F)cc1)N(c1cccc(F)c1)C1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(S(=O)(=O)N(c3cccc(F)c3)C3CCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 105.6 %

Procedure:
To a solution of tert-butyl-4-hydroxy-1-piperidinecarboxylate (137 mg, 681 mmol) in anhydrous THF (5 mL) was added NaH (60% dispersion in mineral oil, 30 mg, 743 mmol) and the reaction was stirred at room temperature for 15 minutes. N-Cyclobutyl-4-fluoro-N-(3-fluoro-phenyl)-benzenesulfonamide (200 mg, 619 μmol) was added and the reaction was heated at 90° C. for 4 hours. The reaction was left to cool to room temperature, water added and extracted with EtOAc, washed with brine, dried with Na2SO4 then concentrated and purified by silica gel column chromatography (0-50% EtOAc in cyclohexane) to give 4-{4-[cyclobutyl-(3-fluoro-phenyl)-sulfamoyl]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (330 mg). LCMS (m/z, Method A) ES+ 527 [M+23]+.
Reaction SMILES: [CH2:1]1[CH:12]2[C:13]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[CH2:9][CH2:10][CH2:11]2)[CH2:3][C:2]1=O.[NH2:15][OH:16].Cl>N1C=CC=CC=1.C(O)C.O>[CH2:1]1[CH:12]2[C:13]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[CH2:9][CH2:10][CH2:11]2)[CH2:3][C:2]1=[N:15][OH:16]
Reactant: NO
Reactant: O=C1Cc2cccc3c2C(CCC3)C1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: ON=C1Cc2cccc3c2C(CCC3)C1
Reaction time: 1 h

Procedure:
9.86 g Of 2,3,7,8,9,9a-hexahydro-1H-phenalen-2-on was dissolved in 15 ml pyridine. A solution of 3.8 g hydroxylamine.HCl in 12 ml ethanol/H2O (1:1) was added to this solution and the mixture was stirred for one hour. The resultant deposit was filtered off, washed off H2O and dried.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2].[ClH:35]>O1CCOCC1>[ClH:35].[ClH:35].[CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl [(1R,3S)-3 -isopropyl-3-(4- [6-(trifluoromethyl)pyridin-2-yl]piperazin- 1-ylcarbonyl)cyclopentyl]carbamate (300 mg, 0.62mmol) was dissoved in a 4.0 M solution of HCl in 1,4-dioxane (10 mL). After being stirred at room temperature for 1 h, the solution was concentrated to give 260 mg of desired product. MS calculated for C19H27F3N4O:(M+H) 385.2; found 385.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].[CH3:30][O:31][CH:32]([O:42][CH3:43])[CH2:33][NH:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1>O1CCCC1>[CH2:11]([NH:10][C:8]([C:4]1[S:3][C:2]([NH:1][C:18]([N:34]([CH2:33][CH:32]([O:31][CH3:30])[O:42][CH3:43])[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[O:19])=[N:6][C:5]=1[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(CNc1ccc(F)cc1)OC
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(CN(C(=O)Nc1nc(C)c(C(=O)NCc2ccccc2)s1)c1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 11 h
Yield: 68 %

Procedure:
To a solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (0.37 g, 1.50 mmol) in tetrahydrofuran (20 mL) was added 1,1′-carbonyldiimidazole (0.31 g, 1.91 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 11 hours, followed by the addition of N-(2,2-dimethoxyethyl)-4-fluoroaniline (0.40 g, 2.00 mmol). The reaction mixture was kept stirring for 17 hour at ambient temperature. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound in 68% yield (0.48 g): 1H NMR (300 MHz, CDCl3) δ 7.36-7.12 (m, 10H), 5.89 (t, J=5.7 Hz, 1H), 4.61 (t, J=5.4 Hz, 1H), 4.53 (d, J=5.4 Hz, 2H), 3.76 (t, J=5.7 Hz, 2H), 3.31 (s, 6H), 2.51 (s, 3H); MS (ES+) m/z 473.4 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH:14]([Li])(CC)C.C1CCCCC1.IC>COCCOC>[CH3:14][C:10]1[C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=[CH:8][C:9]=1[C:11]([OH:13])=[O:12]
Reactant: [Li]C(C)CC
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Solvent: COCCOC
Solvent: C1CCCCC1
Solvent: CI
Product: Cc1c(C(=O)O)ccc2c1OCCO2
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 34 %

Procedure:
To a round bottom flask equipped with magnetic stirring, an addition funnel and a nitrogen inlet, was added benzo(1,4)dioxan-6-carboxylic acid (18.00 g, 99.91 mmol) and 1,2-dimethoxyethane (667 mL). This mixture was cooled to −75° C. in a dry ice-acetone bath. To this was added 1.3 M sec-butyl lithium in cyclohexane (230.6 mL, 299.7 mmol) over 1 hour, maintaining reaction temperature below −60° C. The reaction was removed from the cooling bath, allowed to warm to −20° C., and subsequently stirred at −20° C. for 45 min. The reaction was cooled to −50° C., and iodomethane (15.6 mL, 249.8 mmol) was added. The reaction was again removed from the cooling bath, allowed to warm to −20° C., and stirred at this temperature for 45 min. All cooling was removed and the reaction stirred at room temperature for 16 hours. The reaction was quenched by addition of a few mls of 1N HCl (aq) and the solvent removed by evaporation. The residue was made substantially acidic by the addition of aqueous 1N HCl. The resultant precipitate was filtered and washed with water to give a light brown solid, 5-methyl-benzo(1,4)dioxan-6-carboxylic acid, (6.60 g, 33.9 mmol) in 34% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.62 (d, 114), 6.8 (d, 1H), 4.30 (br s, 4H), 2.52 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([SH:11])[CH:5]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([S:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: COC(=O)c1ccc(Br)c(S)c1
Product: COC(=O)c1ccc(Br)c(SCc2ccccc2[N+](=O)[O-])c1

Procedure:
4-Bromo-3-mercapto-benzoic acid methyl ester was reacted with 1-bromomethyl-2-nitro-benzene as described in the synthesis of Example 1f to obtain the title compound. Yield: (64%); 1H NMR (CDCl3): δ 3.90 (s, 3H, OCH3), 4.55 (s, 2H, CH2), 7.40-7.55 (m, 3H, Ar), 7.60 (d, 1H, Ar), 7.70 (d, 1H, Ar), 7.90 (d, 1H, Ar), 8.10 (d, 1H, Ar).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:9]=2[CH:10]=1)=[O:5].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:2]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:3]([CH:17]=1)[C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:9]=2[CH:10]=1)=[O:5]
Reactant: C1COCCN1
Reactant: COc1ccc2oc(C(=O)c3cc(F)ccc3F)cc2c1
Solvent: Cc1ccccc1
Product: COc1ccc2oc(C(=O)c3cc(F)ccc3N3CCOCC3)cc2c1

Procedure:
A mixture of 2-(2,5-difluorobenzoyl)-5-methoxybenzofuran (100 mg, 0.28 mmol) and morpholine (100 mg, 1.12 mmol) in toluene (10 ml) is heated at reflux for 24 hours. Evaporation and chromatography on silicagel gives the title compound, m.p. 85-88° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[NH2:5].C[Al](C)C.[NH:20](/[C:24](/[CH3:30])=[CH:25]\[C:26](OC)=[O:27])[C:21]([CH3:23])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:26](=[O:27])[CH:25]=[C:24]([CH3:30])[N:20]=[C:21]2[CH3:23])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(CN2CCOCC2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(CN3CCOCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.1 %

Procedure:
A mixture of 3-fluoro-4-(morpholinomethyl)aniline (0.21 g, 1.00 mmol), anhydrous CH2Cl2 (10 mL) and trimethylaluminum (4.5 mL, 4.5 mmol, 1.0 M in heptane) was stirred at rt for 20 min under N2, followed by the addition of a solution of methyl 3-acetaminocrotonate (0.19 g, 1.20 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at rt for 10 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2. The combined organic phases were washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (0.105 g, 30%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[N+:17]([O-:19])=[O:18].Br[CH2:21][CH2:22][CH3:23]>C(#N)C>[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:21][CH2:22][CH3:23])[CH:12]=[C:11]2[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1c[nH]c2ccc(F)cc12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1cc([N+](=O)[O-])c2cc(F)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
Potassium carbonate (1.5 g, 11.1 mmol) was added to a solution of 5-fluoro-3-nitro-indole (1.0 g, 5.6 mmol) and 1-bromo-propane (820 mg, 6.7 mmol) in ACN (20 mL) at rt. The reaction was heated to 80° C. and stirred overnight. The solution was filtered and concentrated, and the residue was purified by silica gel chromatography to give 520 mg (42%) of the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (3H, t, J=7.2 Hz), 1.81-1.87 (2H, m), 4.30 (2H, t, J=7.2 Hz), 7.28 (1H, td, J=2.4, 9.2 Hz), 7.77-7.86 (2H, m), 8.84 (1H, s).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:27]([O:12][C:10](=[O:11])[C@@H:9]([NH2:8])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:18][CH:19]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-(3′-chloro-biphenyl-4-yl)-propionic acid (12.9 g, 34.3 mmol) in DMF (130 mL) were added benzyl bromide (8.16 mL, 68.6 mmol) and NaHCO3 (5.77 g, 68.6 mmol). After stirred at room temperature overnight, the reaction mixture was diluted with EtOAc. The mixture was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was treated with 4M HCl in dioxane (30 mL) and stirred for 2 hours. The reaction mixture was concentrated and the resulted residue was rinsed with iPr2O to give (S)-2-amino-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (11.2 g). 1H NMR (400 MHz, DMSO-d6) δ 3.14 (dd, 1H, J=7.7, 12.0 Hz), 3.27 (dd, 1H, J=5.9, 12.0 Hz), 4.38 (dd, 1H, J=5.9, 7.7 Hz), 5.15 (s, 2H), 7.23-7.27 (m, 2H), 7.30-7.34 (m, 5H), 7.42-7.45 (m, 1H), 7.51 (dd, 1H, J=7.6, 7.6 Hz), 7.61-7.66 (m, 3H), 7.69 (dd, 1H, J=1.8, 1.8 Hz), 8.64 (bs, 2H); MS: m/z (MH+) 366.