Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.[C:21]1([S:27]([C:30]2[S:34][C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([S:27]([C:30]2[S:34][C:33]([N:35]3[CH2:40][CH2:39][N:38]([C:7]([C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH2:3][C:2]([CH3:1])([CH3:19])[CH3:18])=[O:9])[CH2:37][CH2:36]3)=[N:32][CH:31]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(c1ccccc1)c1cnc(N2CCNCC2)s1
Reactant: CC(C)(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccccc3)s2)CC1
Yield: 57 %

Procedure:
Prepared in analogy to example 1 (b) from 2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoic acid (Example A11) and 1-(5-benzenesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 4(d)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 57%). MS (m/e): 578.2 (M+H+, 100%), 595.3 (M+NH4+, 92%).
Reaction SMILES: [O:1]1[CH2:15][C@H:2]1[CH2:3][N:4]1C(=O)C2=CC=CC=C2C1=O.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24].C1CCN2C(=NCCC2)CC1.NN>C1(C)C=CC=CC=1.C(O)(C)C>[NH2:4][CH2:3][C@@H:2]([OH:1])[CH2:15][O:24][C:18]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[CH3:16]
Reactant: Cc1ccc(O)c(C)c1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1CO1
Agent: NN
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(OC[C@H](O)CN)c(C)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a solution of (R)—N-(2,3-epoxypropyl)-phthalimide (3.0 g, 14.8 mmol) and 2,4-dimethylphenol (1.6 g, 13.0 mmol) in toluene (30 mL) was added DBU (1.3 mmol) and the resulting mixture was heated at 120° C. for 18 h. The reaction mixture was cooled to 75° C., diluted with isopropanol (50 mL) and treated with hydrazine (4 mL). After stirring the mixture at 80° C. for 4 h, cooled to room temperature and solvents were evaporated in vacuo. The residue was dissolved in aq. NaOH (100 mL, 5 N) and extracted with chloroform (2×100 mL). The combined organic layer was washed with brine (100 mL) and dried over Na2SO4. The solvent was filtered and evaporated in vacuo to afford the desired product as an off-white solid. Yield: 1.7 g, 59% LCMS [M+H]+ 196.1 The product can be recrystallized from isopropyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](I)[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C.O>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.44 mmol) in anhydrous DMF (3 ml) was added sodium carbonate (0.051 g, 0.484 mmol). After 10 minutes stirring at room temperature pentyl iodide (0.063 ml, 0.484 mmol) was added and stirring continued under nitrogen at room temperature for 18 hours. The reaction mixture was diluted with water (25 ml) and extracted with EtOAc (2×25 ml). The combined organic extracts were dried (MgSO4) filtered and evaporated. Purification by SPE (Si, 5 g) eluting with 4:1 EtOAc/cyclohexane afforded the title compound as a white solid (96 mg, 74%); m/z 297.2 [MH+].
Reaction SMILES: C([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([Br:15])[CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1)(=O)C.C1C=C(Cl)C=[C:19]([C:24]([O:26]O)=[O:25])C=1>ClCCl>[C:24]([O:26][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([Br:15])[CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1)(=[O:25])[CH3:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cn(C)c2c(Br)cccc2c1=O
Solvent: ClCCl
Product: CC(=O)Oc1cn(C)c2c(Br)cccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 3-acetyl-8-bromo-1-methylquinolin-4(1H)-one (3.4 g, 12.14 mmol) in dichloromethane (60 mL) at room temperature was added portionwise with stirring m-CPBA (4.08 g, 18.21 mmol). The resulting mixture was stirred at room temperature for 1 h. The excess m-CPBA was quenched via addition of 15% aqueous Na2SO3 (30 mL), and the resulting mixture was stirred at room temperature for 0.5 h. The layers were separated, and the organic layer was washed sequentially with water (100 mL), 5% aqueous NaHCO3 (100 mL), and brine (100 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford crude 8-bromo-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl acetate (3.68 g, 10.56 mmol, 87% yield) as brown solid, which was used in the next hydrolysis step without further purification. LCMS: (M+H)+: 295.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4](Br)[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:19]1([OH:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:29][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: Oc1cccc2ccccc12
Reactant: COC(=O)[C@H](Br)CCC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCC(=O)OCc1ccccc1)Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 92.1 %

Procedure:
To a solution of (2R)-2-bromo-4-carbobenzyloxy-butyric acid methyl ester (1.00 g, 3.17 mmol) and 1-naphthol (0.500 g, 3.47 mmol) in dimethylformamide (4.0 mL) at room temperature under nitrogen was added powdered anhydrous K2CO3 (0.560 g, 4.7 mmol). After stirring at room temperature for 3.5 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO4 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to a yellow oil. The crude product was purified by flash chromatography on silica gel eluting with Et2O-hexane(1:4) to give the title compound (1.105 g, 92%) as a pale yellow oil. TLC(Et2O-hexane; 3:7; 2 developments) Rf=0.33 (bromide Rf=0.52; 1-naphthol Rf=0.41).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:19])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])[CH:3]=[CH2:4].[Cr](Cl)([O-])(=O)=[O:22].[NH+]1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>ClCCl.CCOCC>[CH3:17][O:16][CH2:15][O:14][CH2:13][C:12]([CH3:18])=[CH:11][CH2:10][CH2:9][C:8]([CH3:19])=[CH:7][CH2:6][CH2:5][C:2]([CH3:1])=[CH:3][CH:4]=[O:22]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: C=CC(C)(O)CCC=C(C)CCC=C(C)COCOC
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCOCC(C)=CCCC(C)=CCCC(C)=CC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A solution of 3,7,11-trimethyl-12-(methoxymethyl)oxy-1,6,10-dodecatrien-3-ol (460 mg, 1.6 mmol) in dichloromethane (30 ml) was added pyridinium chlorochromate (690 mg, 3.2 mmol), and the mixture was stirred at room temperature for 8 hours. After addition of a mixture of hexane, ethyl acetate, and ether (3:1:1) (100 ml), the mixture was stirred and insoluble materials were filtered. The filtrate was concentrated in vacuo, and the residue was purified with silica gel column chromatography to give 12-(methoxymethyl)oxy-3,7,11-trimethyl-2,6,10-dodecatrienal (233 mg, 52%). The physico-chemical properties of the product was the same as those described in Reference Example 1.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9](=O)[NH:10][C:11]([C:17]2([CH3:25])[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19][CH2:18]2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]1[CH2:37][CH2:36][N:35]2[C:30](=[N:31]CCC2)[CH2:29][CH2:28]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.NCC1C=CC=CN=1>CC#N>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:35][CH2:36][C:37]2[CH:27]=[CH:28][CH:29]=[CH:30][N:31]=2)=[N:10][C:11]([C:17]2([CH3:25])[CH2:18][O:19][C:20]([CH3:24])([CH3:23])[O:21][CH2:22]2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)OCC(C)(c2nc3cccc(-c4ccccc4)c3c(=O)[nH]2)CO1
Reactant: C1CCC2=NCCCN2CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CC#N
Product: CC1(C)OCC(C)(c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)CO1
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of 5-phenyl-2-(2,2,5-trimethyl-1,3-dioxan-5-yl)quinazolin-4(3H)-one (0.22 g, 0.62 mmol) in MeCN (10 mL) at room temperature was added DBU (0.24 g, 1.57 mmol) and BOP reagent (0.36 g, 0.81 mmol). Upon completion of addition, the reaction mixture was stirred for 30 min. Aminomethylpyridine (0.11 ml, 1.13 mmol) was added and the resulting mixture was stirred for an additional 16 h. After this time, the reaction mixture was concentrated and purified by silica gel column chromatography (2% MeOH in DCM) to provide 5-phenyl-N-(pyridin-2-ylmethyl)-2-(2,2,5-trimethyl-1,3-dioxan-5-yl)quinazolin-4-amine (0.18 g, 68% yield) as a white solid. LCMS Method V: retention time 2.21 min, [M+1]=531.2.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[Cl:30].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:30][C:24]1[CH:25]=[C:26]([NH2:27])[CH:28]=[CH:29][C:23]=1[C:10]1[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2cc(C(F)(F)F)ccc2OCc2ccccc2)c(Cl)c1

Procedure:
The product from example 32 step (ii) (0.5 g) and 4-bromo-3-chloroaniline (0.38 g) were dissolved in toluene (4 ml). Ethanol (1 ml), 2M aqueous sodium carbonate (1 ml) and Pd(PPh3)4 (0.115 g) were added sequentially and the mixture heated at reflux for 4 h. The reaction was cooled, evaporated, dissolved in EtOAc, washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica eluting with 10% EtOAc/isohexane. Yield 0.23 g.
Reaction SMILES: C([O:3][C:4](=[O:27])/[CH:5]=[CH:6]/[CH:7]=[C:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)C.[OH-].[Na+]>O>[N+:15]([C:11]1[CH:10]=[C:9]([C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:27])=[O:3])[CH:14]=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: CCOC(=O)/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Yield: 97.6 %

Procedure:
A mixture of (E)-5,5-bis(3-nitrophenyl)-2,4-pentadienoic acid ethyl ester (6.1 g) methanol (25 mL) and 2N sodium hydroxide solution (12.5 mL) was stirred at reflux for 15 minutes, then was diluted with water (50 mL) and concentrated in vacuo to remove the methanol. The basic solution was poured into a mixture of ice and 2N hydrochloric acid (20 mL), and the resulting buff-colored solids were filtered and dried to afford 5,5 g of (E)-5,5-bis(3-nitrophenyl)-2,4-pentadienoic acid mp 234°-237° C. Recrystallization of a portion from chloroform-ethanol furnished the acid as its 0.25 molar hydrate, mp 237°-238° C. Anal. Calculated for C17H12N2O6.0.25H2O:C, 59.22; H, 3.65; N, 8.12 Found: C, 59.27; H, 3.63; N, 8.13.
Reaction SMILES: Br.C[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]3[C:17]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[CH:16][O:15][C:14]=3[CH:24]=2)[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+]>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:13]3[CH:12]=[CH:11][C:10]([C:6]4[CH:5]=[C:4]([OH:3])[CH:9]=[CH:8][CH:7]=4)=[CH:24][C:14]=3[O:15][CH:16]=2)[CH:19]=1
Reactant: COc1cccc(-c2ccc3c(-c4cccnc4)coc3c2)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Oc1cccc(-c2ccc3c(-c4cccnc4)coc3c2)c1
Yield: 76 %

Procedure:
47% hydrobromic acid solution (1.6 ml) was added to 3-[6-(3-methoxyphenyl)benzo[b]furan-3-yl]pyridine (80 mg, 0.2655 mmol) obtained in Example 5, and the mixture was refluxed for 24 hours. After neutralizing with 2N sodium hydroxide aqueous solution and a saturated aqueous solution of sodium bicarbonate, and extracting with ethyl acetate, the organic layer was washed with water, then with saturated brine, and dried with anhydrous magnesium sulfate, followed by evaporating the solvent under reduced pressure. The product was crystallized in ether-chloroform to obtain a white powder of 3-[3-(3-pyridyl)benzo [b]furan-6-yl]phenol (58 mg, 76%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[N:14]([CH3:38])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH3:37])[N:16]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CC(O)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:38])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH3:37])[N:16]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reaction time: 65 h
Yield: 99.8 %

Procedure:
To a solution of 3-[2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethylene]azetidine-1-carboxylic acid tert-butyl ester (205 mg, 0.40 mmol) in EtOH (10 mL) and AcOH (3 mL) was added 10% Pd/C (40 mg) and the resulting mixture stirred under an atmosphere of H2 for 65 h. The reaction mixture was filtered through Celite®, washing with MeOH, and the filtrate concentrated in vacuo affording the title compound (207 mg, quant.). LCMS (method H): RT 2.92 min [M+H]+ 519.4
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C.CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O>>[CH3:18][S:19]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCCOS(C)(=O)=O)CC1

Procedure:
tert-Butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (Intermediate 121, 2.38 g, 9.8 mmol) was reacted with methanesulfonyl chloride (0.91 mL, 11.7 mmol) in the presence of triethylamine (1.9 mL, 13.7 mmol) as described for Intermediate 6. The crude product was used without further purification for the next step.
Reaction SMILES: BrC1C=CC(S([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14](=[O:26])[CH:13]=2)(=O)=O)=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]O.[OH-].[Na+].Cl>CN(C=O)C>[CH2:19]([N:15]1[C:16]([CH3:18])=[CH:17][C:12]([O:11][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([Cl:27])[CH:29]=2)=[CH:13][C:14]1=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(OS(=O)(=O)c2ccc(Br)cc2)cc(=O)n1Cc1ccccc1
Reactant: OCc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2cccc(Cl)c2)cc(=O)n1Cc1ccccc1

Procedure:
1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate (3.0 mmol, 1.3 g), N,N′-dimethylformamide (30 mL), 3-chlorobenzyl alcohol (3.0 mmol, 0.43 g), and sodium hydroxide (60%, 3.3 mmol, 0.13 g) were stirred at room temperature under nitrogen for 4 hours. Hydrochloric acid (1 N, 10 mL) was added and the mixture extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate and concentrating, the mixture was purified by flash column chromatography eluting with ethyl acetate:hexanes (1:1) to obtain a light yellow oil. (14.3 g, 64%): 1H NMR (DMSO-d6/300 MHz) δ: 7.4-7.0 (m, 10H), 6.0-5.8 (m, 2H), 5.2 (s, 2H), 5.0 (s, 2H), 2.1 (s, 3H). ES HRMS m/z 340.110 (M+H, C20H18NO2Cl requires 340.110).
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[C:23](OCCCC)(=[O:28])[CH2:24][C:25]([CH3:27])=O>>[OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:23](=[O:28])[CH2:24][C:25]([CH3:27])=[N:10][CH2:9][CH2:8]1
Reactant: CCCCCCCCCCCCC(O)CNCCNCCN
Reactant: CCCCOC(=O)CC(C)=O
Product: CCCCCCCCCCCCC(O)CNCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 313.5 g (1 mole) of N-(2-hydroxy)tetradecyldiethylenetriamine and 158.1 g (1 mole) of butyl acetoacetate. At 150° to 160° C. and under a reduced pressure of 50 mmHg, 18 g of water and 74 g of butanol were distilled off to obtain 4-(2-hydroxytetradecyl)aminoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: O1CC[CH2:3][CH2:2]1.C([Li])CCC.[CH3:11][C@H:12]([CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13][CH:14]=O>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)CC)C=CC=CC=1.O>[CH3:11][C@H:12]([CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13][CH:14]=[CH:2][CH3:3]
Reactant: C1CCOC1
Reactant: C[C@@H](CC=O)CCO[Si](C)(C)C(C)(C)C
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Product: CC=CC[C@H](C)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a slurry of 80 g. (0.2155 m) of triphenyl-ethyl phosphonium bromide in 800 ml. of dry tetrahydrofuran cooled to 0° C. was added 165.7 ml. of 1.3M solution of n-butyl lithium (0.2155 m) in the same solvent. After 2 hours, 45 g. (0.196 m) 3-(R)-methyl-5-(t-butyldimethylsilyloxy)-1-pentanal in 200 ml. of dry tetrahydrofuran was added dropwise to the reaction mixture. The reaction was allowed to stir 2 hours at room temperature and was then poured into water and extracted with ether. The combined extracts were washed with water and a brine solution and dried over magnesium sulfate. Removal of the solvent in vacuo gave a yellow oil which, on distillation gave 37.4 g. of product, b.p. 74°-79° C./0.2-0.1 torr.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:26][O:25][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=3)[N:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:6]2=[O:24])[O:4][CH2:3]1.Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1([CH3:27])[CH2:3][O:4][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N:14]([CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=3)[N:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:6]2=[O:24])[O:25][CH2:26]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc(NS(C)(=O)=O)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc(N(CCN3CCOCC3)S(C)(=O)=O)ccc21
Temperature: 70 °C
Yield: 88.1 %

Procedure:
A mixture of methyl 2-(5,5-dimethyl-5′-(methylsulfonamido)-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (0.400 g, 1.004 mmol), 4-(2-chloroethyl)morpholine hydrochloride (0.224 g, 1.204 mmol) (prepared in an analogous manner as described in Example 17, Scheme 17, Steps 1, 2, 3, 4) and K2CO3 (0.306 g, 2.208 mmol) in DMF (8 ml) was heated at 70° C. for 3 hours. The mixture was partitioned between ethyl acetate and water, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed several times with brine and dried over sodium sulfate; the solvent was removed and the crude was purified by chromatography on silica gel cartridge (DCM:MeOH=99:1 to 97:3) affording methyl 2-(5,5-dimethyl-5′-(N-(2-morpholinoethyl)-methylsulfonamido)-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (0.453 g, 0.885 mmol, 88% yield, MS/ESI+ 512.1 [MH]+).
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([C:19](=[N:21][OH:22])[NH2:20])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[S:28].C1CCN2C(=NCCC2)CC1>CC#N>[O:26]=[S:2]1(=[O:1])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([C:19]4[NH:20][C:27](=[S:28])[O:22][N:21]=4)[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1
Reactant: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=S1(=O)N=C2CCCN2c2ccc(Oc3cccc(-c4noc(=S)[nH]4)c3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of the product obtained in Step A of Example 13 (300 mg, 0.81 mmol) in 6 ml of CH3CN there are added 239 mg (1.21 mmol) of thiocarbonyldiimidazole and then 481 μl (3.22 mmol) of DBU. The reaction solution is stirred at ambient temperature for 1 hour. Evaporation to dryness and chromatography on silica (CH2Cl2/MeOH 95/5) are carried out. After evaporating the fractions containing the product formed, the residue is triturated in MeOH and the title product is recovered by filtration.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:8][CH2:7][NH:6][C:5](=[O:9])[C@H:4]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)(=[O:13])=[O:12])[CH2:3]1.[F:22][CH:23]([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:22][CH:23]([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:10]([C@@H:4]2[CH2:3][C:2]([F:1])([F:21])[CH2:8][CH2:7][NH:6][C:5]2=[O:9])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)(=[O:12])=[O:13])=[CH:27][CH:26]=1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cn1
Reactant: FC(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCC(F)(F)C[C@H]1N(Cc1ccc(OC(F)F)cc1)S(=O)(=O)c1ccc(Cl)cn1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
5-Chloro-pyridine-2-sulfonic acid ((R)-5,5-difluoro-2-oxo-azepan-3-yl)-amide (0.21 g, 0.61 mmol), 4-(difluoromethoxy)benzyl bromide (0.23 g, 0.91 mmol), K2CO3 (0.85 g, 6.08 mmol), KI (0.02 g, 0.12 mmol) were added to dry DMF (10 ml) and the resultant reaction mixture was stirred for 1.5 h at 65° C. and for additional 3 h at room temperature under an argon atmosphere. The solvent was removed under reduced pressure and the residue was purified over silica gel (first: ethyl acetate/n-heptane 1:2 v/v; second: dichloromethane/MeOH, 100:0-95:5): brownish oil, 0.23 g;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[CH2:21][OH:22]>C1(C)C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[CH:21]=[O:22]
Reactant: O=C(Nc1ccc(Cl)c(CO)c1)c1cccc(C(F)(F)F)c1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: O=Cc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1Cl
Yield: 43.6 %

Procedure:
The solution of intermediate 7 (Example 13) (700 mg, 2.1 mmol) and MnO2 (1.8 g, 21 mmol) in anhydrous toluene (30 mL) was refluxed for 2 h. After cooling down, the MnO2 was removed by filtration. The solvent was removed by reduced pressure. The solid was re-crystallized from chloroform to yield an off-white solid (300 mg, 43%).