Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:34])[C:16](N2C3(CCCCC3)OC3C=CC=CC=3C2=O)=[O:17])[NH:13][C:12]1=[O:35])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].OO.[OH-].[Li+].S([O-])([O-])=[O:41].[Na+].[Na+]>O1CCCC1.O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@H:14]([C@@H:15]([CH3:34])[C:16]([OH:17])=[O:41])[NH:13][C:12]1=[O:35])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: O=S([O-])[O-]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@H]1[C@@H](C)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of 500 mg of 3-{(2R)-2-[(3S, 4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one in 20 ml of a mixture of tetrahydrofuran and water are added 0.9 ml of 30% aqueous hydrogen peroxide and 84 mg of lithium hydroxide in this order, and the mixture is stirred at the same temperature for one hour. The pH of the mixture is adjusted to about 10 by adding dropwise 5 ml of 1.5N aqueous sodium sulfite at the same temperature and tetrahydrofuran is removed under reduced pressure. The precipitated crystals are removed by filtration and the aqueous layer of the filtrate is washed with 20 ml of chloroform. 10 ml of 10% hydrochloric acid are added thereto and the pH of the mixture is adjusted to about one. The aqueous layer is extracted with 30 ml of ethyl acetate. The ethyl acetate layer is dried and then evaporated under reduced pressure to give the crude product. The product is recrystallized from a mixture of ethyl acetate and hexane to obtain 216 mg of (2R)-2-[(3S, 4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionic acid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1)=[N+]=[N-].C(N(CC)CC)C.[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>CO.[Pd]>[C:26]([O:25][C:23]([NH:1][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1)=[O:22])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])nc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)nc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a degassed solution of methyl 6-(azidomethyl)nicotinate from Example G2 (1.6 g, 8.30 mmol) in methanol (50 ml) was added 10% palladium-on-carbon (0.15 g). Hydrogen gas was bubbled through the mixture for 2 h at room temperature. The catalyst was removed by filtration through a pad of celite and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane and cooled to 0° C. To this solution were added triethylamine (1.67 g, 16.0 mmol) and (BOC)2O (2.17 g, 9.96 mmol). The mixture was allowed to warm to room temperature and stirred for 18 h, then concentrated in vacuo. The residue was dissolved in EtOAc and washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 50:50) to give a yellow solid; yield 1.57 g (71%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C[Al](C)C.C([O:24][C:25]([C:27]1[C:36]2[C:35]3[N:37]=[CH:38][CH:39]=[CH:40][C:34]=3[CH2:33][CH2:32][CH2:31][C:30]=2[NH:29][CH:28]=1)=O)C.O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([NH:17][C:25]([C:27]2[C:36]3[C:35]4[N:37]=[CH:38][CH:39]=[CH:40][C:34]=4[CH2:33][CH2:32][CH2:31][C:30]=3[NH:29][CH:28]=2)=[O:24])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Nc1cccnc1OCCOC1CCCCO1
Reactant: CCOC(=O)c1c[nH]c2c1-c1ncccc1CCC2
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccnc1OCCOC1CCCCO1)c1c[nH]c2c1-c1ncccc1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 2-[2-(tetrahydropyran-2-yloxy)-ethoxy]pyridin-3-ylamine (2.3 g, 9.7 mmol) in DCM (8 mL) is added AlMe3 (2M in toluene, 4.9 mL) at rt. After stirring at room temperature for 1 h, a solution of 3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid ethyl ester (500 mg, 1.95 mmol) in DCM (10 mL) is added. The mixture is refluxed overnight. On cooling, water (5 mL) is added, and the resulting mixture is extracted with DCM. The combined DCM extracts are dried and solvent removed. The residue is separated by column chromatography on silica gel (5% methanol in DCM) to give 850 mg of 3,4,5,6-tetrahydro-3,10-diaza-benzo[e]azulene-1-carboxylic acid {2-[2-(tetrahydropyran-2-yloxy)-ethoxy]-pyridin-3-yl}amide as an oil.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][C:14](=[O:20])[NH:15]2.[OH-].[Na+]>O1CCCC1.CN(C)C=O.N1C=CC=CC=1>[O:20]=[C:14]1[CH2:13][C:12]2[C:16](=[CH:17][CH:18]=[CH:19][C:11]=2[CH2:10][CH2:9][O:8][C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[NH:15]1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: CC(C)(C)N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)OCCc1cccc2c1CC(=O)N2
Temperature: 80 °C
Yield: 11.8 %

Procedure:
Tert-butyl isocyanate (0.685 mL, 6 mmol) was added dropwise to a stirred mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (709 mg, 4 mmol) in tetrahydrofuran (8 mL), dimethylforamide (2 mL) and pyridine (3 drops). The mixture was heated at 70° C. for 15 hours and 80° C. for 39 hours. 0.457 mL of tert-butyl isocyanate was added to the reaction and continued to heat at 90° C. for 24 hours. More tert-butyl isocyanate (0.457 mL) was added and continued to heat at 90° C. for 37 hours. The reaction was cooled, poured into 1 N sodium hydroxide solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with 1 N hydrochloric acid (100 mL) and brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from methanol/ethyl acetate/hexane to give 130 mg (12%) of tert-butyl-carbamic acid 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)-ethyl ester.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.FC(F)(F)C(O)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:3][NH:4][CH2:5][C@@H:6]1[CH2:7][NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 1,1-dimethylethyl (3S,4S)-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (for a synthesis see WO2006002047 preparation 24(c), (±)-1,1-dimethylethyl cis-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate E1 isomer) (1 g, 2.85 mmol) in DCM (50 ml) was added trifluoracetic acid (50 ml) and stirred for 2 h. The reaction mixture was concentrated and placed under high vacuum for 3 h. To the TFA salt dissolved in DCM (50 ml) was added MP-carbonate resin (4 g; 11.4 mmol) and stirred overnight. The reaction mixture was filtered and concentrated to provide the title compound as a pale yellow oil (840 mg, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]([OH:5])[C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccc(Cl)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a stirred solution of 2,4′-dichlorobenzophenone (239 mmol) in methanol (400 mL) was added sodium borohydride (119 mmol) portionwise at 0° C. Reaction mixture was warmed to room temperature and stirred for 1 hour, then quenched with water and the methanol was removed under reduced pressure. The residue was diluted with dichloromethane (400 mL) and washed with water and brine, dried (MgSO4) and concentrated in vacuo to yield the product as an orange oil (47.1 g, 78%).
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[C:12](=[O:13])[C:3]=12.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[CH3:9][N:6]1[C:7](=[O:8])[C:2]([C:30]2[CH:31]=[N:26][CH:27]=[N:28][CH:29]=2)=[C:3]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:10][C:4]2=[CH:5]1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Reactant: OB(O)c1cncnc1
Product: Cn1cc2c(c(-c3cncnc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2

Procedure:
The title compound was prepared in analogy to the process of Example 13 starting from 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (see Example c4)) and pyrimidin-5-ylboronic acid.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:17])=O>>[CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCCc1ccc(C(=O)O)cc1
Product: CCCCCc1ccc(C(=O)Cl)cc1

Procedure:
15 g. of p-n-pentylbenzoic acid are dissolved in 100 ml. of thionyl chloride and boiled at reflux for 1 hour. The excess thionyl chloride is then removed by distillation and the acid chloride is distilled under high vacuum. The p-n-pentylbenzoic acid chloride which is obtained has a boiling point of 104°C/2 mm.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[N:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1>>[CH3:22][C:19]1[N:18]=[N:17][C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[CH:21][CH:20]=1
Reactant: Cc1ccc(I)nn1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1ccc(C#Cc2c(-c3ccccc3)noc2C)nn1
Yield: 80 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (70 mg, 0.38 mmol) was converted (using 3-iodo-6-methyl-pyridazine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 84 mg, 80%) which was obtained as a light brown solid. MS: m/e=276.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>O1CCCC1>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])[CH2:2][CH2:3]1
Reactant: C=C1CC(=O)O1
Reactant: OCC1CCNCC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 25 g (0.22 mol) of 4-piperidine methanol in 200 ml tetrahydrofuran was added dropwise to a solution of 18 g of diketene (0.2 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 35.40 g (0.18 mol, 83% yield) of a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1c2n(c3c(-c4ccc(F)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (71 mg, 86%), MS (ISP) m/z=329.4 [(M+H)+], mp 227.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1[C:29]([F:30])=[CH:28][C:10]([O:11][C:12]2[CH:26]=[CH:25][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][C:20](=[O:24])[CH2:19]3)=[O:17])=[CH:14][C:13]=2[F:27])=[C:9]([O:31]C)[CH:8]=1)[CH3:6].O>ClCCl>[CH2:5]([C:7]1[C:29]([F:30])=[CH:28][C:10]([O:11][C:12]2[CH:26]=[CH:25][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][C:20](=[O:24])[CH2:19]3)=[O:17])=[CH:14][C:13]=2[F:27])=[C:9]([OH:31])[CH:8]=1)[CH3:6]
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCc1cc(O)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A commercial solution of boron tribromide (1N in DCM, 3.5 mL, 3.46 mmol) was added to a solution of 4-[4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoy]piperazin-2-one (which may be prepared in accordance with the experimental described in Example 5, step 1; 500 mg, 1.28 mmol) in dichloromethane (4.3 mL) placed under argon at −30° C. The reaction mixture was stirred at room temperature for 36 hours then diluted by addition of dichloromethane (20 mL) and water (20 mL). After separation, the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/acetone (80:20) as eluent. The title product was obtained as a beige solid (440 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O-:12])=[O:11])[CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16](S([O-])(=O)=O)=[CH:15][CH:14]=1.[NH+]1C=CC=CC=1.C(O)C1C=CC=CC=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH2:23][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=C([O-])c1cc(Cl)c(Cl)c(Cl)n1
Agent: c1cc[nH+]cc1
Solvent: OCc1ccccc1
Product: O=C(OCc1ccccc1)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 142.5 °C

Procedure:
A 22 L round bottom flask was fitted with a thermocouple, mechanical stirrer and a Dean-Stark trap which was connected to a nitrogen bubbler. The vessel was purged with nitrogen and then 4,5,6-trichloropicolinate (2547 g, 10.07 mol), pyridinium p-toluene sulfonate (PPTS; 130 g, 0.52 mol), benzyl alcohol (2249 g, 20.8 mol) and xylenes (10278 g) were added. Stirring was started, and the pot was heated to 140 to 145° C. The xylenes/water azeotrope was collected in the Dean-Stark trap over about 5 h. The total amount of distillate collected was 4750 g (415 g was water). After the water stopped distilling overhead, a reactor sample was taken and analyzed by high-performance liquid chromatography (HPLC) to ensure less than 1.5 area % of starting carboxylic acid remained. The reaction was allowed to cool to room temperature and stirred overnight. Xylenes (4000 g) were removed by vacuum distillation. The solution was cooled to 85-100° C. and then vacuum transferred to a 30 L jacketed crystallization vessel that had been fitted with a mechanical stirrer and thermocouple. The vacuum was released with nitrogen and a nitrogen bubbler was placed on the crystallization vessel. To the xylene solution was added isopropyl alcohol (IPA; 6200 g) over about 15 minutes (min). The resulting slurry was allowed to cool slowly to room temperature and then cooled further to 5° C. The solid was collected by filtration, and the cake was washed with cold (5-10° C.) IPA (3731 g). The solid was dried in air to a constant weight providing white crystals (2765 g, gas chromatography (GC) internal standard purity 96.5%, 84.3%).
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:22])[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:8][C:9]1([CH3:22])[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(c2nccc(Cl)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(N)CCN(c2nccc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.22 g (0.0068 mol) of 4-t-butoxycarbonylamino-1-(4-chloropyrimidin-2-yl)-4-methylpiperidine (step c) in 25 ml of anhydrous methylene chloride is cooled under a nitrogen atmosphere and 5 ml of anisole and 25 ml of trifluoroacetic acid are added slowly. The mixture is stirred for 1 hour at room temperature and 25 ml of a 30% solution of NaOH are added slowly. The reaction medium is extracted with methylene chloride and dried over Na2SO4 and the solvent and the anisole are evaporated off under reduced pressure. The residue is purified by chromatography using CH2Cl2 /MeOH=9/1 as the eluent to give 4-amino-1-(4-chloropyrimidin-2-yl)-4-methylpiperidine as the base, which is treated with maleic acid in an ethanol/isopropyl ether mixture. The maleate obtained in this way is isolated by filtration (m.p. 154°-155° C.).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[CH:24]=4)=[C:19]([N+:31]([O-])=O)[CH:18]=3)=[O:16])=[CH:11][C:10]=2[N+:34]([O-])=O)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1.C(OCC)(=O)C.C([O-])=O.[NH4+].[K+].[Br-]>[Pd].CO>[C:23]1([C:20]2[CH:21]=[CH:22][C:17]([C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:1]4[C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[CH:2]=4)=[C:10]([NH2:34])[CH:11]=3)=[O:16])=[CH:18][C:19]=2[NH2:31])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=1
Reactant: O=C(c1ccc(C2=Cc3ccccc32)c([N+](=O)[O-])c1)c1ccc(C2=Cc3ccccc32)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(C(=O)c2ccc(C3=Cc4ccccc43)c(N)c2)ccc1C1=Cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-benzocyclobutenyl-3-nitrophenyl ketone (11.0 g, 43.4 mmol) was partially dissolved in a mixed solvent (30 ml of ethyl acetate and 70 ml of methanol in a 300 ml round-bottomed flask). To the suspension was added 0.95 g of 10% Pd/C followed by the addition of 13.0 g (206 mmol) of ammonium formate. The black reaction mixture was then stirred magnetically under an atmosphere of nitrogen at room temperature for about 3 hrs. The reaction mixture was then filtered through a bed of Celite and the solid residue was washed with methanol until the filtrate was colorless. The yellow-green filtrate was subsequently subjected to rotary evaporation. The resultant viscous amber liquid was mixed with about 50 ml of methylene chloride and the solution formed was washed with 2 portions (100 ml) of H2O. Finally, the methylene chloride extract was dried over anhydrous magnesium sulfate. After the removal of the drying agent and the solvent, a very viscous and amber liquid was isolated. Despite drying in the vacuum (70° C.) for more than 24 hours, it never solidified. Yield: 8.0 g. It was used in the subsequent synthesis without further purification. Mass Spectroscopy: M+, m/e= 223, 100%. IR(KBr pellet). ν(NH2) at 3365 vs and 3460s; ν(CO) at 1646 vs. Proton NMR (CDCl3, δ in ppm): 3.21 (singlet, 4H, alicyclic protons); 3.83 (singlet, 2H, NH2); 6.73-7.77 (multiplet, 7H, aromatic protons).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[C:9](F)[C:8]([C:12]#[N:13])=[CH:7][C:6]=1[Cl:14].[C:16](=O)([O-])[O-:17].[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[C:9]([O:17][CH3:16])[C:8]([C:12]#[N:13])=[CH:7][C:6]=1[Cl:14]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1cc(F)c(C#N)cc1Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)Cc1cc(OC)c(C#N)cc1Cl
Temperature: 130 °C

Procedure:
A solution of methyl(2-chloro-4-cyano-5-fluorophenyl)acetate (1.40 g, 6.15 mmol) in methanol (30 mL) was divided into two 20 mL microwave vials. Potassium carbonate (2×850 mg) was added to each vial. Each was heated in a microwave at 130° C. for 60 minutes at which time HPLC/MS indicated no starting material was left and the product was all hydrolyzed to the acid. Most of the methanol was removed in vacuo and the residue was diluted with water, acidified with 2M HCl and the mixture was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was taken up in 1:1 methanol:dichloromethane (50 mL) and 2M trimethylsilyldiazomethane in ether was added until the yellow color persisted to re-esterify the acid. The excess diazomethane was quenched with acetic acid and the mixture was concentrated. Flash chromatography (40% DCM/hexanes to 100% DCM) gave the methyl(2-chloro-4-cyano-5-methoxyphenyl)acetate. 1H-NMR (400 MHz, CDCl3) δ ppm 3.73 (s, 3H), 3.83 (s, 2H), 4.07 (s, 3H), 7.139 (d, J=8.1 Hz, 1H), 7.468 (d, J=8.0, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[OH:19].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:16][C:13]([F:14])([F:15])[C:8]([C:6]1[CH:5]=[C:4]([CH3:18])[C:3]([O:19][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:2]([CH3:1])[CH:7]=1)([OH:17])[C:9]([F:10])([F:11])[F:12]
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Reaction time: 5 h

Procedure:
To 2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)phenol [Farah, et al, J. Org. Chem., 30, 1003 (1965)], (10.0 g=35 mmol) in 100 ml acetonitrile add ethyl bromoacetate (6.9 g=42 mmol) and potassium carbonate (9.7 g=69 mmol). Stir 5 hours, filter and concentrate. Partition between ether and 1.0 N HCl. Dry and concentrate the ether extract. Recrystallize from ether-hexane to obtain, as white crystals, m.p. 99°-101° C., ethyl 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetate.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]([OH:16])=O)[CH:7]=1.[O:20]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14](=[O:16])[NH:33][C:30]2[CH:29]=[CH:28][C:27]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:32][CH:31]=2)[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: COC(=O)C(Cc1cccc(OCC(=O)O)c1)OC
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCC(=O)Nc2ccc(Oc3ccccc3)cc2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-(3-carboxymethoxy-phenyl)-2-methoxy-propionic acid methyl ester (PREPARATION 4, step 2) and 4-phenoxy-phenylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H23NO6 [M+H]+: 322.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3][CH:2]=1.[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:13]=[C:14]([NH:18][NH2:19])[CH:15]=[CH:16][CH:17]=1>>[N:3]1[CH:4]=[C:5](/[CH:7]=[N:19]/[NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:10]([F:9])([F:21])[F:20])[CH:13]=2)[CH:6]=[N:1][CH:2]=1
Reactant: O=Cc1cncnc1
Reactant: NNc1cccc(OC(F)(F)F)c1
Product: FC(F)(F)Oc1cccc(N/N=C/c2cncnc2)c1
Yield: 12 %

Procedure:
In analogy to the procedure described in Example 167A], pyrimidine-5-carbaldehyde and (3-trifluoromethoxy-phenyl)-hydrazine gave the title compound as an orange solid (12%). MS: 281.5 (M−H−).