Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][C:41]([F:44])([F:43])[F:42])[CH:4]=1)#[N:2].[OH:45]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([O:40][C:41]([F:42])([F:43])[F:44])[CH:4]=1)(=[O:45])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2OC(F)(F)F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2OC(F)(F)F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-trifluoromethoxy-phenyl)-amide (40 mg, 0.06 mmol) prepared in Example 145 in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.1 g, 0.9 mmol), then aqueous solution (1N) of NaOH (0.3 mL, 0.3 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (0-100% EtOAc in dichlormethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-trifluoromethoxy-phenyl)-amide as a white solid (Yield 9 mg, 22%)
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][CH:10]=[N:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C1COCC1.CO>[C:1]1([N:7]2[CH:12]=[CH:11][CH2:10][NH:9][C:8]2=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1ncccn1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NCC=CN1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-phenylpyrimidin-2(1H)-one (250 mg, 1.45 mmol) in dry THF (20 mL) was added a solution of NaBH4 (58 mg, 1.5 mmol) in 20 mL MeOH by dropwise at 0° C. The reaction mixture was stirred at rt for 1 h. The mixture was concentrated to remove DCM, the residue was purified by SFC to give 1-phenyl-3,4-dihydropyrimidin-2(1H)-one and Compound 365 (74.8 mg, 30% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.41-7.33 (m, 4H), 7.23-7.21 (m, 1H), 6.53 (brs, 1H), 6.14-6.11 (m, 1H), 4.88-4.84 (m, 1H), 4.32-4.31 (m, 2H). MS (ESI) m/z [M+H]+ 174.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@@:12]([CH:24]([F:26])[F:25])([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[F:23])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[F:23])([CH:24]([F:26])[F:25])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc([N+](=O)[O-])ccc2F)(C(F)F)COC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)COC1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To a suspension of [(R)-5-difluoromethyl-5-(2-fluoro-5-nitro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (8 g, 19.23 mmol) in MeOH (56 mL) was added Pd(OH)2/C (20%, 50% water, 0.8 g). The atmosphere in the reactor was replaced by hydrogen (1 bar), then the reaction mixture was stirred at 20° C. for 5 h, filtered through Micro-crystals cellulose and concentrated. The crude product was recrystallized from MeOH and water to provide the title compound as a white solid: ESIMS: 360.1521; [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 6.83 (dd, 1H), 6.74 (m, 1H), 6.50 (m, 1H), 6.22 (t, 1H), 4.95 (s, 2H), 4.46 (dd, 2H), 4.03 (m, 1H), 3.84 (m, 1H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([OH:29])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37]([O:44][C:45](=[O:48])[CH2:46]Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:46][C:45]([O:44][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:48])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3ccccc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 g 4-{2-[(4-Hydroxy-quinoline-2-carbonyl)-amino]acetyl}-piperazine-1-carboxylic acid butyl ester in 41 ml of DMF, 8.6 g of cesium carbonate and 6.1 g of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 5.2 g.
Reaction SMILES: O[CH2:2][N:3]1[CH2:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][C:4]1=[O:21].S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:24][CH2:2][N:3]1[CH2:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][C:4]1=[O:21]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)CN1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C1CCC(c2ccccc2)(c2ccccc2)CN1CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a stirred suspension of 28 g (0.1 mol) of the product of step (a) in 150 mL of benzene at 10° C. was added dropwise a solution of 16 mL (1.63 mol) of thionyl chloride in 150 mL of benzene. The mixture was allowed to warm to ambient temperature, stirred overnight and concentrated to dryness. Fresh benzene was added and the solution reconcentrated several more times to give 27 g of crude 1-(chloromethyl)-5,5-diphenyl-2-piperidinone as a white solid.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16]C)[C:12](=[O:18])[C:11]([CH3:20])([CH3:19])[CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=CC=1>O>[CH2:1]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[C:12](=[O:18])[C:11]([CH3:19])([CH3:20])[CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc2c(cc1OC)C(=O)C(C)(C)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCc1cc2c(cc1O)C(=O)C(C)(C)C2

Procedure:
1.93 g (7 mmol) of 5-hexyl-6-methoxy-2,2-dimethylindan-1-one, 2.84 g (21 mmol) of aluminium chloride and 40 ml of toluene are heated for 15 minutes at reflux. The mixture is poured into water and extracted with ether. The organic phase is dried (Na2SO4) and the solvent evaporated off. The residue is purified by flash chromatography (dichloromethane, 2.8 g; 90%).
Reaction SMILES: C(O[CH:5]([O:10][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=1)[C:6](Cl)([Cl:8])[Cl:7])(=O)C.S(=O)(=O)(O)O.[OH-].[Na+]>CO>[Cl:7][C:6]([Cl:8])=[CH:5][O:10][C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)OC(Oc1cccc(C)c1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(OC=C(Cl)Cl)c1
Temperature: 15 °C

Procedure:
By an electrochemical reductive dehydrohalogenation method 1(3-tolyloxy)-2,2,2-trichloroethyl acetate (15.8 g), concentrated sulphuric acid (98% w/v, 9.8 g) and methanol (220 ml) was charged into an electrolytic cell, which was surrounded by a cooling bath set to maintain the temperature at about 15°C, and fitted with a cylindrical diaphragm, stirrer, reference electrode (SCE) and a working electrode. The cathode was a lead plate (surface area about 40 cm2). Using a current density in the range 5 to 10 mA/cm2 the reaction was conducted in the potential range -1100 to 1700 mV (SCE). When reduction was completed the cathodic electrolyte was neutralised with caustic soda and extracted with methylene chloride, the extracts dried over anhydrous sodium sulphate and evaporated to yield a residue of crude 3-tolyl 2,2-dichlorovinyl ether.
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:15](=[O:16])[N:14]3[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][OH:18]>>[CH3:17][O:18][C:15]([CH:8]([CH:9]1[NH:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: CO
Reactant: O=C1C(c2ccccc2)C2CCCCN12
Agent: Cl
Product: COC(=O)C(c1ccccc1)C1CCCCN1
Temperature: 50 °C
Yield: 76.9 %

Procedure:
Hydrogen chloride (gas) was passed through a stirred solution of 7-phenyl-1-azabicyclo[4.2.0]octan-8-one with R*R*/S*R* 3.3:1 by GC (2.61 Kg, 13.0 mol) in methanol (13 L) under reflux conditions for 60 hour until TLC indicated that all starting material had been consumed. The mixture was evaporated under reduced pressure. The residue was treated with hot water (8 L) for 0.5 h. The hot mixture was filtered, cooled to 50° C., washed with toluene (2×1.2 L), cooled to the room temperature, basified with sodium carbonate to pH 10-11 and extracted with dichloromethane (3×2.5 L). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure to give 2.33 Kg (76.9%) of methylphenidate with threolerythro 3.5:1 by GC.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35]C(=O)OC(C)(C)C)[CH2:31][CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC(N)CC5)n4)n[nH]c3cn2)cn1
Yield: 36.8 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl piperidin-4-ylcarbamate were reacted and the product was deprotected to give 174 as a white solid (36.8% over two steps). 1H NMR (400 MHz, DMSO) δ 1H NMR (400 MHz, DMSO) δ 9.03 (d, J=1.2 Hz, 1H), 8.54 (d, J=1.3 Hz, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 7.63 (dd, J=8.4, 7.5 Hz, 1H), 7.41 (d, J=7.3 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 4.37 (d, J=13.1 Hz, 2H), 3.91 (s, 3H), 3.51-3.20 (m, 3H), 3.14-3.04 (m, 2H), 2.96-2.83 (m, 1H), 1.87 (d, J=9.9 Hz, 2H), 1.45-1.27 (m, 2H). LC/MS: m/z 375.1 [M+1]
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][O:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=3)[C:19](=[O:22])[CH2:20]Cl)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:39][NH:40][CH3:41]>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][N:18]([CH2:17][CH2:16][CH2:15][N:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:35][O:36][CH2:37][CH3:38])[C:19](=[O:22])[CH2:20][N:40]([CH3:41])[CH3:39])[CH:25]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCl
Reactant: CNC
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CN(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from step (vi) (30 mg) was dissolved in DMF (2 mL) then a solution of dimethylamine (2M in THF, 0.279 mL) was added at rt under nitrogen. The resulting solution was stirred at rt for 16 h. The mixture was purified by RPHPLC to give the title compound, yield 4.5 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[CH2:29][S:30][CH2:31][C:32]([F:35])([F:34])[F:33])[CH:6]=1.[CH3:37]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:37])=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[CH2:29][S:30][CH2:31][C:32]([F:35])([F:33])[F:34])[CH:6]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1ccc(C)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
{3-[4-Nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-trifluoromethanesulfonyloxy-phenyl}-acetic acid methyl ester (0.20 g, 0.35 mmol), trimethylboroxine (0.07 mL, 0.53 mmol), potassium carbonate (0.123 g, 0.89 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.041 g, 0.035 mmol) were combined in DME:H2O (2:1; 4 mL) and degassed with N2 for 8 minutes. The reaction was stirred at 90° C. for 2 hours, and then worked up with EtOAc and 10% aqueous HCl. The residue was purified by silica gel chromatography to give {4-methyl-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13].Cl[CH2:16][S:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH2:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCCl
Reaction time: 5 h
Yield: 75 %

Procedure:
A mixture of 1-(3-chloro-propoxy)-2-nitrobenzene (1.2 g, 6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmoles) was stirred in THF (50 mL) at −78° C., in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (18 mL, 18 mmoles) over a half hour period. Temperature was allowed to rise to 40° C., and the reaction mixture was stirred at this temperature for 5 hours. The reaction mixture was poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (1.9 g, 4.5 mmoles).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25].[H-].[Na+].[CH3:32][O:33][CH2:34]Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[N:23]([CH2:32][O:33][CH3:34])[C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: COCCl
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)N(COC)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18 %

Procedure:
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-phenyl}-N′-propylurea (100 mg) was dissolved in anhydrous tetrahydrofuran (30 ml), and sodium hydride (60 wt %, 88 mg) was added to the solution. The mixture was stirred at room temperature for 15 min. Next, chloromethyl methyl ether (67 μl) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. The solvent was removed by distillation under the reduced pressure, and water was added to the residue. The mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 18 mg (yield 18%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:36])[CH2:22][CH2:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])[O:16][C:15]2=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C1C=C(Cl)C=C(C(OO)=[O:46])C=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@@H:17]([CH2:19][NH+:20]([O-:46])[C:21](=[O:36])[CH2:22][CH2:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])[O:16][C:15]2=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CCC(=O)c1ccc2ccccc2c1)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Product: O=C(CCC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
To a cooled solution (0-5° C.) of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]-4-(2-naphthyl)-4-oxobutanamide (0.950 gm, 0.0019 moles) in dichloromethane (150 ml) was added 60% m-CPBA (0.550 g, 0.0032 moles) and the resulting solution stirred at room temperature for 12 hr. The solvent was evaporated under reduced pressure and the residue chromatographed over silica gel (100-200 mesh, 40 g). The column was eluted with ethyl acetate (200 ml), followed by a mixture of chloroform:methanol (4:1, 600 ml). Concentration the combined fractions gave the title N-oxide (0.891 g, 82%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26]>>[CH3:21][O:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:24]=1[C:25]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:26]
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Product: COc1ccc(C(=O)N2CC3CN(c4nccc(-c5ccccc5)n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2,4-dimethoxybenzoic acid. MS (ESI) mass calcd. for C26H26N4O3, 430.51; m/z found, 431.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)cc1Br
Reaction time: 3 h

Procedure:
2-Bromo-4-fluorobenzoic acid (1.533 g, 7 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Fluorochem) in dichloromethane (DCM) (40 mL) was cooled to 0° C., before oxalyl chloride (0.674 mL, 7.70 mmol) and a few drops of DMF (cat.) were added. The solution was then stirred under argon for 3 hours. The solvent was then evaporated in vacuo and the remaining residue was azeotroped with toluene (2×20 mL) to yield the product in 1.645 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH2:9]([O:11][CH2:12][C:13](O)=O)[CH3:10].[OH-].[Na+]>>[CH2:9]([O:11][CH2:12][C:13]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:10]
Reactant: Nc1ccccc1S
Reactant: CCOCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1nc2ccccc2s1
Yield: 63 %

Procedure:
2-Aminothiophenol was reacted with an equimolar amount of ethoxyacetic acid at 110° C. for 15 hours in a sealed tube. After cooling the reaction mixture, it was neutralized with a 20% aqueous solution of sodium hydroxide, followed by an extraction with ether. Ether was driven off and the residue was then subjected to distillation under reduced pressures, thereby obtaining 2-ethoxymethylbenzothiazole (boiling point: 126°-128° C./4 mmHg; yield: 63%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([O:11][C@H:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:15]=3[C@H:14]([CH3:28])[CH2:13]2)=[O:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:31]([O:35][C:36]([N:38]([CH:51]([CH3:53])[CH3:52])[CH2:39][CH:40]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:41](O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][C@H:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:27][CH2:26][CH2:25][N:24]([C:41](=[O:42])[C@@H:40]([C:44]5[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=5)[CH2:39][N:38]([C:36]([O:35][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:37])[CH:51]([CH3:52])[CH3:53])[CH2:23][CH2:22]4)[C:15]=3[C@H:14]([CH3:28])[CH2:13]2)=[O:10])=[CH:29][CH:30]=1)([O-:4])=[O:3]
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CCCNCC3)c21
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCCN(c2ncnc3c2[C@H](C)C[C@H]3OC(=O)c2ccc([N+](=O)[O-])cc2)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Yield: 49.5 %

Procedure:
(5R,7R)-4-(1,4-Diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate hydrochloride (61 mg, 0.140 mmol) and 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (48 mg, 0.140 mmol) were suspended in dichloromethane (5 mL). N,N-Diisopropylethylamine (54 mg, 0.420 mmol) was then added. HBTU (53 mg, 0.140 mmol) was added, and the resultant solution was stirred at ambient for 16 hours. After this time, the reaction mixture was quenched by the addition of saturated sodium carbonate solution and then extracted twice with dichloromethane. The combined organic portions were dried over sodium sulfate, filtered, and concentrated. The residue thus obtained was purified by silica gel chromatography to give (5R,7R)-4-(4-((S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoyl)-1,4-diazepan-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (50 mg, 50%). LCMS (APCI+) M+=721.1, Rt=4.51 min.