Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[CH:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[C:4]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:3]([CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:29])[N:7]([CH3:8])[N:6]=2)=[CH:10][CH:11]=1
Reactant: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1Br
Reactant: O=Cc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1C(O)c1ccccc1
Temperature: 40 °C
Yield: 12 %

Procedure:
To solid magnesium (60 mg, 5 mmol) under nitrogen was added a solution of 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (450 mg, 1.35 mmol) (prepared in accordance with Example A-214) in tetrahydrofuran (7 mL). The mixture was heated at 40° C. for 2 hours. Benzaldehyde (1 mL) was added. The mixture was heated to 45° C. for 2 hours. It was quenched with HCl (10 mL, 1N) and washed with ethyl acetate. The aqueous acid layer was basified and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MGSO4, filtered and concentrated to give a residue. The residue was purified with a silica gel column to give the title compound (59 mg, 12% yield). MS: m/z=360 (M+1); 1H NMR was consistent with the proposed structure. Anal. Calc'd for C22H18N2OF.0.6EtOAC: C, 71.1; H, 5.6; N, 10.2; Found: C, 70.9; H, 5.47; N, 10.2.
Reaction SMILES: [CH3:1][N:2]([CH2:32][C:33]([NH:35][C@H:36]1C[CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]1)=[O:34])[C:3]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=[N:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[N+:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][C:5]([N:4]=[C:3]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[N:2]([CH2:32][C:33]([NH:35][CH:36]2[CH2:37][NH:38][CH2:39]2)=[O:34])[CH3:1])=[O:6])=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: CN(CC(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1)C(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)NC1CNC1)C(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of the compound (1.22 g), which had been obtained in (1), in anhydrous dichloromethane (12 ml), trifluoroacetic acid (6 ml) was added dropwise under ice cooling. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(2), whereby the title compound was obtained. The product was provided for use in the subsequent reaction without isolation.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:21][CH:22]=1)[CH3:2]
Reactant: CC(=O)c1ccc(CCNS(=O)(=O)c2ccc(Br)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(O)c1ccc(CCNS(=O)(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.4 g. (29.8 mmole) 4-Bromobenzenesulphonic acid(4-acetylphenethylamide) are dissolved in a mixture of 40 ml. methanol and 100 ml. ethanol and 0.85 g. (22.4 mmole) sodium borohydride then added portionwise thereto at 0° C. Subsequently, the reaction mixture is stirred at ambient temperature for 2 hours and then evaporated in a vacuum. After the addition of dilute hydrochloric acid, the reaction mixture is shaken out with methylene chloride and the methylene chloride phase is dried with anhydrous sodium sulphate Thereafter, it is evaporated and the residue is recrystallised from toluene. Yield 10.4 g. (91% of theory): m.p. 125°-127° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[CH2:12]([O:11][CH2:10][C@@H:9]([C:19]([OH:21])=[O:20])[NH2:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](COCc1ccccc1)C(=O)O

Procedure:
Nα -t-Butoxycarbonyl-O-benzyl-L-serine, 5.0 g., is treated with 20 ml. of trifluoroacetic acid at 5° C. The solution is let stand at room temperature for 15 minutes and then the excess trifluoroacetic acid removed under reduced pressure. Benzene is added followed by evaporation. This process is repeated three times to remove excess trifluoroacetic acid. Finally the product is dried under reduced pressure and used without further treatment.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16](Cl)[C:15]3[C:10](=[CH:11][C:12]([Cl:19])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[C:10](=[CH:11][C:12]([Cl:19])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1ccc2c(Cl)nc(-c3ccc(Br)cc3)nc2c1
Solvent: C1CCOC1
Product: Clc1ccc2c(Nc3ccccc3)nc(-c3ccc(Br)cc3)nc2c1
Reaction time: 18 h

Procedure:
A solution of 2-(4-bromo-phenyl)-4,7-dichloro-quinazoline (0.085 mmol, 30 mg) in 2 ml THF is treated with aniline (0.01 ml, 0.11 mmol). The suspension is heated to 60° and stirred for 18 hrs. The reaction mixture is filtered and the crystals are washed with THF and dried. [2-(4-Bromo-phenyl)-7-chloro-quinazolin-4-yl]-phenyl-amine is obtained.
Reaction SMILES: C(N(CC)CC)C.I.CS[C:11]1[NH:12][CH2:13][CH2:14][N:15]=1.[NH2:16][C:17]1[C:38]([Cl:39])=[CH:37][C:20]([C:21]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH2:27][CH2:26]2)=[O:22])=[C:19]([O:40][CH3:41])[CH:18]=1.[OH-].[Na+]>CO>[NH2:16][C:17]1[C:38]([Cl:39])=[CH:37][C:20]([C:21]([NH:23][CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[CH2:29][CH2:30]2)=[O:22])=[C:19]([O:40][CH3:41])[CH:18]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: CSC1=NCCN1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC2=NCCN2)CC1
Yield: 47.5 %

Procedure:
Triethylamine (0.59 g) and 2-methylthio-2-imidazoline hydroiodide (1.4 g) were added to a solution of 4-amino-N-((1-(5-aminopentyl)-piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (1.5 g) in methanol (20 ml), and the mixture was stirred at refluxing temperature for 4 hr. A 10% aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with brine and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 0.84 g of 4-amino-5-chloro-N-((1-(5-(imidazolin-2-ylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:13]1[N:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1.C1(C)C=CC=CC=1.CC([O-])(C)C.[Na+]>CCOC(C)=O.O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:13]2[N:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(OC)nn2)CC1
Temperature: 95 °C
Yield: 40.2 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid ethyl ester (5.66 g, 36.0 mmol) and 3-chloro-6-methoxy-pyridazine (4.34 g, 30 mmol) in toluene (60 mol) was added NaOtBu (3.46 g, 36 mol), BINAP (560 mg, 0.90 mmol) and tris(dibenilideneacetone)dipalladium(0) (549 mg, 0.60 mmol). The reaction mixture was heated at 95° C. for 1 hours, cooled down to RT, and diluted with AcOEt (500 mL) and H2O (50 mL). The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/heptane, 1:9 to 1:1) yielded 3.20 g (34%) of 1-(6-methoxy-pyridazin-3-yl)-piperidine-4-carboxylic acid ethyl ester as a yellow oil. ES-MS m/e: 266.3 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Clc1ccccc1CBr
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccccc4Cl)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 1-bromomethyl-2-chloro-benzene. MS (ESI) m/z 503.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.CO.[Pd]>[C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15]([OH:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2CCCCC(C(=O)O)C2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butylester (2.28 g, 4.5 mmol) are dissolved in 40 ml Dioxane/Methanol (3:1). Palladium on charcoal (10%) (170 mg, 0.16 mmol) are added under an Argon flow. The flask is evacuated and flushed three times with Hydrogen. The reaction is stirred for 6 h at room temperature. Filtration through Celite and evaporation of the solvents afforded the product: 1H NMR (DMSO, 400 MHz), ppm: 7.81 (d, 2H), 6.95 (d, 2H), 5.40 (d, 1H), 3.68 (s, 3H), 3.65 (m, 1H), 3.25 (m, 1H), 2.92 (m, 1H), 2.15 (m, 1H), 1.95 (m, 1H), 1.78 (m, 2H) 1.25 (s, 9H).
Reaction SMILES: [F-].[K+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O.Br[C:15]1[CH:16]=[N:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])[CH:28]=3)[C:23]([S:38]([CH3:40])=[O:39])=[CH:22]2)=[N:19][CH:20]=1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:15]1[CH:20]=[N:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])[CH:28]=3)[C:23]([S:38]([CH3:40])=[O:39])=[CH:22]2)=[N:17][CH:16]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: CS(=O)c1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CS(=O)c1cn(-c2ncc(-c3cccc(F)c3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 70 °C

Procedure:
Potassium fluoride (0.048 g, 0.83 mmol), 2,3-difluoro phenyl boronic acid (0.10 g, 0.67 mmol), and bis(tri-tert-butylphosphine)palladium(0) (0.026 g, 0.05 mmol) were added at room temperature under an argon atmosphere to a solution of [1-(5-bromo-pyrimidin-2-yl)-3-methanesulfinyl-1H-indol-6-yl]-morpholin-4-yl-methanone (0.15 g, 0.33 mmol) in dry THF (12 mL). The reaction mixture was heated at 70° C. for 16 h, then filtered through a plug of celite and concentrated. The residue was purified by flash column chromatography [methanol/dichloromethane=1:40]. White solid. Yield: 100 mg (63% of theory).
Reaction SMILES: Cl.[CH2:2]([N:5]1[C:10](=[O:11])[C:9]([NH2:12])=[CH:8][N:7]=[C:6]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]=[CH2:4].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:26]([NH:12][C:9]1[C:10](=[O:11])[N:5]([CH2:2][CH:3]=[CH2:4])[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:8]=1)(=[O:28])[CH3:27]
Reactant: C=CCn1c(-c2ccccc2)ncc(N)c1=O
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCn1c(-c2ccccc2)ncc(NC(C)=O)c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-Allyl-5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidine hydrochloride was dissolved in tetrahydrofuran (27 ml) and triethylamine (1.16 ml, 8.33 mmol), and acetyl chloride (0.284 ml, 3.99 mmol) was added to it under cooling on ice, and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. After saturated aqueous sodium bicarbonate was added, the reaction solution was extracted with ethyl acetate, and it was washed with saturated saline. After dried over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) whereby the title compound (617 mg, 69%) was obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:19][CH:18]([F:20])[CH2:17]3)[C:4]=2[N:3]=1.[F:21][C:22]1[CH:23]=[C:24]([C:29]2[NH:30][CH:31]=[CH:32][N:33]=2)[CH:25]=[CH:26][C:27]=1[F:28]>>[F:21][C:22]1[CH:23]=[C:24]([C:29]2[N:33]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]5[CH2:19][CH:18]([F:20])[CH2:17]5)[C:4]=4[N:3]=3)[CH:32]=[CH:31][N:30]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CC(F)C1
Reactant: Fc1ccc(-c2ncc[nH]2)cc1F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(F)c(F)c3)nc2N1C1CC(F)C1

Procedure:
The title compound was prepared similarly to the methods described in Example 77, with Intermediate W instead of Intermediate C and with 2-(3,4-difluorophenyl)-1H-imidazole instead of 2-phenyl-1H-imidazole. LCMS: 443.1 m/z (M+H)+; ret. Time: 6.85 min (Analytical Method C).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C:13]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[N:15]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])(=[O:25])=[O:24])[C:14]1=[O:36].O>C(Cl)Cl>[C:8]([NH:12][C:13]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[N:15]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])(=[O:25])=[O:24])[C:14]1=[O:36])(=[O:10])[CH3:9]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3)c3cc(Cl)ccc32)c(OC)c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2C(=O)C(NC(C)=O)(c3ccccc3)c3cc(Cl)ccc32)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.051 g of triethylamine and then 0.04 g of acetyl chloride are added to a solution of 0.234 g of the compound obtained in EXAMPLE 1 in 2 ml of DCM and the reaction mixture is stirred for two hours at RT. It is poured into water, extracted with DCM, washed with water, dried over sodium sulfate and evaporated under vacuum to give the expected product after crystallization and recrystallization from a DCM/iso ether/ MeOH mixture. m=0.146 g. M.p.=253° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[CH3:19][CH:20]([CH3:26])[CH2:21][CH2:22][C:23](Cl)=[O:24].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[O:24]=[C:23]([N:3]1[C@@H:2]([CH3:1])[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4]1=[O:13])[CH2:22][CH2:21][CH:20]([CH3:26])[CH3:19]
Reactant: CC(C)CCC(=O)Cl
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Temperature: 0 °C
Yield: 96.2 %

Procedure:
To a solution of (4S,5R)-4-methyl-5-phenyl-2-oxazolidinone (9.7 g) [prepared according to the procedures in Evans, D. A.; Mathre, D. J.; Scott, W. L. J. Org. Chem. 1985, 50, 1830-1835] in 100 mL of THF cooled to -78° C. with stirring, was added 35.6 mL of n-butyllithium (1.6M in hexane) until the orange-red color of the di-anion just persisted. The reaction mixture was then treated with 7.0 mL (7.7 g) of distilled 4-methylpentanoyl chloride, warmed to 0° C. and stirred for 30 min. Then 20 mL of 1M aqueous K2CO3 was added and the resultant two-phase mixture was stirred at 25° C. for 1 h. The organic solvents were evaporated in vacuo and the residue was extracted twice with CH2Cl2. The combined organic extract was washed with water and brine, then was dried over Na2SO4 and evaporated. The residue was subjected to flash chromatography on silica gel (hexane-EtOAc) to give 14.5 g (97% yield) of (4S,5R)-3-(1-oxo-4-methylpentyl)-4-methyl-5-phenyl-2-oxazolidinone as a solid. Characteristic analytical data are as follows: mp 76°-77° C. (hexane/EtOAc); 1H NMR (300 MHz, CDCl3) δ7.30-7.46 (m, 5H), 5.67 (d, J=8 Hz, 1H), 4.77 (p, J=7 Hz, 1H), 2.88-3.05 (m, 2H), 1.53-1.69 (m, 3H), 0.94 (d, J=7 Hz, 6H), 0.90 (d, J=7 Hz, 3H); [α]25D -33° (c=1.07, CH2Cl2).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])[C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:22]1([N:25]2[CH2:30][C:29]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[O:28][CH2:27][C:26]2=[O:36])[CH2:24][CH2:23]1>CN(C)C=O.O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH:2]([N:33]2[CH2:34][CH2:35][C:29]3([O:28][CH2:27][C:26](=[O:36])[N:25]([CH:22]4[CH2:23][CH2:24]4)[CH2:30]3)[CH2:31][CH2:32]2)[C:3]([O:5][CH3:6])=[O:4])=[C:8]([F:14])[CH:9]=1
Reactant: COC(=O)C(Br)c1ccc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.9 %

Procedure:
A solution of methyl 2-bromo-2-(4-bromo-2-fluorophenyl)acetate (7.29 mmol) in N,N-dimethylformamide (30 mL) was treated with potassium carbonate (19.90 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (8.31 mmol). The reaction was stirred at room temperature for two days. The reaction solution was diluted with water (200 mL) and was extracted three times with ethyl acetate. The combined organic layers were washed five times with water and three times with brine. The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting semi-solid was diluted with dichloromethane (10 mL) and was concentrated to dryness in vacuo. This was repeated twice, at which point the resulting solid was dried under high vacuum overnight, affording the title compound as a white solid (3.05 g, 87% yield). MS(ES)+ m/e 454.8/456.9 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[CH:14]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[N+:10]([O-:34])[CH:11]=[CH:12][C:13]=2[CH:14]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][CH:25]=1
Reactant: CCCCC(c1ccncc1OCc1ccc(Cl)cc1)n1ccnc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCCC(c1cc[n+]([O-])cc1OCc1ccc(Cl)cc1)n1ccnc1

Procedure:
0.624 g of 3-(4-chlorobenzyloxy)-4-[1-(1-imidazolyl)-pentyl]-pyridine is reacted analogously to example 15 with 0.410 g of m-chloroperbenzoic acid to the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH:8]([OH:9])[C:7]2([CH3:11])[O:10][C:3]1([CH3:13])[CH2:4][C:5](=[O:12])[CH2:6]2.N1C=CN=C1.[C:19]([Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])(Cl)Cl)([CH3:22])([CH3:21])[CH3:20]>ClCCCl>[C:19]([Si:23]1([C:26]([CH3:29])([CH3:28])[CH3:27])[O:1][CH:2]2[CH:8]([C:7]3([CH3:11])[O:10][C:3]2([CH3:13])[CH2:4][C:5](=[O:12])[CH2:6]3)[O:9]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](Cl)(Cl)C(C)(C)C
Reactant: CC12CC(=O)CC(C)(O1)C(O)C2O
Agent: c1c[nH]cn1
Solvent: ClCCCl
Product: CC12CC(=O)CC(C)(O1)C1O[Si](C(C)(C)C)(C(C)(C)C)OC12
Reaction time: 48 h
Yield: 90 %

Procedure:
To a solution of 6,7-dihydroxy-1,5-dimethyl-8-oxa-bicyclo[3.2.1]octan-3-one (Bulletin of the Chemical Society of Japan (1983), 56(9), 2680-99, 550 mg, 2.95 mmol) in DCE (20 mL) was added imidazole (2.0 g, 29 mmol) and di-tert-butyldichlorosilane (1.2 mL, 5.9 mmol). The resulting mixture was stirred under Ar for 48 h. The reaction mixture was treated with satd. NaHCO3 (20 mL) and the DCE layer was separated, dried (Na2SO4) and concentrated and the residue obtained was purified on silica gel (5-20% EtOAc/hexane) to obtain the title compound (869 mg, 90%). 1H-NMR (CDCl3; 400 MHz): δ 4.23 (s, 2H), 2.43 (d, 1H, J=15.6 Hz), 2.31 (d, 1H, J=15.6 Hz), 1.45 (s, 6H), 1.12 (s, 9H), 1.04 (s, 9H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27]Cl)[CH2:22][CH2:21]3)[C:5]=2[CH:4]=1.[OH:29][C:30]1[CH:44]=[CH:43][C:33]([O:34][CH2:35][C@@H:36]([OH:42])[CH2:37][NH:38][CH:39]([CH3:41])[CH3:40])=[CH:32][CH:31]=1>CS(C)=O.O.[OH-].[Na+]>[CH3:41][CH:39]([NH:38][CH2:37][C@H:36]([OH:42])[CH2:35][O:34][C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][N:6]3[C:5]4[CH:4]=[C:3]([Cl:2])[CH:16]=[CH:15][C:14]=4[S:13][C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:25][CH2:24]2)=[CH:44][CH:43]=1)[CH3:40]
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CC(C)NC[C@H](O)COc1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)NC[C@H](O)COc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of the chloride of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (9.4 g) in 75 ml dimethylsulfoxide was added (S)-1-(4-hydroxyphenoxy)-3-(1-methylethyl)amino-2-propanol (6.0 g) followed by 6.25 ml 4N sodium hydroxide solution. The mixture was stirred under argon at 55° for 2 hours then was cooled and diluted with 500 ml water and 35 ml 1N sodium hydroxide, and extracted with dichloromethane (3×). The extracts were backwashed with water (2×), dried over potassium carbonate and the solvent was removed in vacuo to give 12.8 g of crude (S)-1-(1-methylethylamino)-3-[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]piperazin-1-yl]ethoxy]phenoxy]-2-propanol as an oil.