Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][CH:11](NC)[CH2:10]2)=[CH:5][CH:4]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]([CH2:32][C:33]([OH:35])=O)[CH:29]([CH3:31])[CH3:30])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH3:36][N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.OS([O-])(=O)=O.[K+]>ClCCl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]([CH:29]([CH3:31])[CH3:30])[CH2:32][C:33]([NH:37][CH2:36][CH:11]2[CH2:12][CH2:13][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=3)[CH2:10]2)=[O:35])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CC(C)N(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CNC1CCN(c2ccc(C(F)(F)F)cc2)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CC(=O)NCC1CCN(c2ccc(C(F)(F)F)cc2)C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of crude [1-(4-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-methylamine (26.6 mg, 0.11 mmol, crude) and [(4-fluoro-benzenesulfonyl)-isopropyl-amino]-acetic acid (30.0 mg, 0.11 mmol) in dichloromethane (5 mL) at 25° C. was treated with HATU (41.4 mg, 0.11 mmol). N,N-Diisopropylethylamine (28.2 mg, 0.22 mmol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2 M aqueous KHSO4 and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (50/50 hexanes/ethyl acetate) afforded 2-[(4-fluoro-benzenesulfonyl)-isopropyl-amino]-N-[1-(4-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-acetamide (24.2 mg, 44%) as a white solid. [MH]+=502.1.
Reaction SMILES: C([Li])CCC.[C:6]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH3:7].[CH:14]12[CH2:26][CH2:25][CH:21]([C:22](=[O:24])[CH2:23]1)[C:20]1[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=1>C1COCC1.C1(C)C=CC=CC=1>[C:10]([O:9][C:6](=[O:8])[CH2:7][C:22]1([OH:24])[CH2:23][CH:14]2[CH2:26][CH2:25][CH:21]1[C:20]1[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1CC2CCC1c1ccccc12
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(O)CC2CCC1c1ccccc12
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3.5 mL of DIPA in 6 mL THF were added dropwise 9.9 mL of n-butyllithium (2.5M in Hept) at −20° C. After 20 min, 12 mL of toluene were added and the solution was stirred for 30 min. The mixture was cooled to −50° C., 4.5 mL of tert.-butyl acetate were added and stirring was continued for 1 h at −50° C. Then, 2.5 g of rac-(1R*,8R*)-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-one dissolved in 6 mL of toluol were added and the solution was stirred at −50 to −20° C. over 2.5 h. The reaction mixture was poured on ice/aq. HCl, the organic phase was separated, washed with sat. aq. NaHCO3, dried over Na2SO4 and concentrated in vacuo. The crude reaction product was purified by CC with Hept/EtOAc (4:1) to yield 2.6 g of the major racemate, rac-(1R*,8R*,9R*)-(9-hydroxy-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-yl)-acetic acid tert-butyl ester as beige solid and 0.4 g of the minor racemate, rac-(1R*,8R*,9S*)-(9-hydroxy-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-yl)-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]2=[O:25])=[N:6][C:5]=1[CH3:26])(=[O:3])[CH3:2].CO[C:29](OC)([N:31]([CH3:33])[CH3:32])[CH3:30]>CN(C)C(=O)C>[CH3:32][N:31]([CH3:33])/[C:29](/[CH3:30])=[CH:2]/[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)[C:10]2=[O:25])=[N:6][C:5]=1[CH3:26])=[O:3]
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Reactant: COC(C)(OC)N(C)C
Solvent: CC(=O)N(C)C
Product: C/C(=C\C(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C)N(C)C
Temperature: 110 °C
Yield: 90 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)-imidazolidin-2-one (1.00 g, 2.60 mmol) in N,N-dimethylacetamide (10 mL) was added N,N-dimethylacetamide dimethyl acetal (1.0 mL, 6.15 mmol). The reaction mixture was heated for 20 hours at 110° C. The solvent was removed in vacuo, and the residue was washed with water to afford the title compound as a colorless solid in 90% yield (1.07 g): 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 5.23 (s, 1H), 4.49 (s, 2H), 3.99-3.91 (m, 2H), 3.48-3.40 (m, 2H), 2.98 (s, 6H), 2.49-2.43 (m, 6H); MS (ES+) m/z 453.1 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH2:20][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC[C@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
tert-Butyl (2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-(tritylamino)propylcarbamate (6.19 g, 11.3 mmol) was dissolved in 115 mL of anhydrous CH2Cl2 and 18.2 mL of glacial acetic acid. The reaction mixture was cooled to 0° C. under an atmosphere of N2 and boron trifluoride diethyl etherate (1.51 mL, 11.9 mmol) was added dropwise over several minutes. After stirring for 5 hours, the reaction mixture was treated with 183 mL of cold, aqueous 10% NaOH solution. The reaction mixture was extracted into 200 mL of a 3:1 chloroform/2-propanol mixture and the layers were separated. The aqueous portion was extracted with two additional portions of the chloroform/2-propanol mixture. The organic phases were combined and dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 5%-10% methanol/CHCl3) gave tert-butyl (2S)-2-amino-3-{[tert-butyl(dimethyl)silyl]oxy}propylcarbamate (3.43 g) as a colorless syrup.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][C:12]=1[CH2:20][CH3:21])(C(C)(C)C)(C)C.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH2:28])=[O:27].O.[C:33]([OH:37])(=[O:36])[CH:34]=O>>[C:26]([C:25]1[CH:24]=[C:23]([NH:22][CH:34]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][OH:8])=[C:12]([CH2:20][CH3:21])[CH:13]=2)[C:33]([OH:37])=[O:36])[CH:31]=[CH:30][CH:29]=1)(=[O:27])[NH2:28]
Reactant: NC(=O)c1cccc(N)c1
Reactant: CCc1cc(B(O)O)ccc1CCO[Si](C)(C)C(C)(C)C
Reactant: O=CC(=O)O
Solvent: O
Product: CCc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1CCO
Yield: 88 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 46B (1.4 g, 4.1 mmol) was reacted with 3-aminobenzamide and glyoxylic acid monohydrate to afford 46C (1.25 g, 88%) as a yellow solid. MS (ESI) m/z 343.3 (M+H)+.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@:11]1(C=C=O)[C@H:14]([C@H:15]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[S:18])[CH3:16])[N:13](OC(C)(C)C)[C:12]1=[O:31])[CH3:10])(C(C)(C)C)(C)C.[C:35]1([O:41]C)[CH:40]=CC=CC=1.O.C(=O)(O)[O-:45].[Na+]>C(Cl)Cl>[OH:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[S:18])[CH3:16])[N:13]([CH2:40][C:35]([OH:41])=[O:45])[C:12]1=[O:31])[CH3:10]
Reactant: COc1ccccc1
Reactant: C[C@@H](C(=S)c1ccc(Cl)cc1)[C@@H]1N(OC(C)(C)C)C(=O)[C@]1(C=C=O)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N(CC(=O)O)[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
(3S,4S)-3-[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1R)-1-p-chlorophenylthiocarbonylethyl]-1-t-butoxy- carbonylmethyl-2-azetidinone (1.0 g) was dissolved in dry methylene chloride (10 ml), and anisole (497 mg) and boron trifluoride-diethyl ether complex (1.04 g) were added thereto, followed by stirring at 38° to 42° C. for 3 hours. The organic layer was shaken with water and aqueous sodium bicarbonate. The aqueous layer was separated, adjusted to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate (1 ml) was added to the residue, and the resultant mixture was warmed at 50° C. After dropwise addition of toluene (5 ml), the resultant mixture was stirred for 30 minutes and allowed to cool to room temperature. The precipitated crystals were collected by filtration and dried to give (3S,4S)-3-[(1R)-1-hydroxyethyl]-4-[(1R)- 1-p-chlorophenylthiocarbonylethyl]-1-(1-carboxymethyl)-2-azetidinone. m.p., 81°-83° C.
Reaction SMILES: COC[O:4][C:5]1[C:6]([CH3:36])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2.C(O)(=O)C.C1C=CC=CC=1.S(=O)(=O)(O)O>O>[OH:4][C:5]1[C:6]([CH3:36])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2
Reactant: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(OCOC)c(C)c(C)c2O1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
A mixture of 3.7 g of 6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman (prepared as described in Preparation 14), 10 ml of acetic acid, 30 ml of benzene and 0.75 ml of 10% w/v aqueous sulfuric acid was heated under reflux for 30 minutes. The reaction mixture was then poured into water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-])=O)=[C:13]([CH:18]=1)[C:14]([NH:16][CH3:17])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1.COCCO.[H][H]>CO.[Pd]>[NH2:19][C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][C:13]=1[C:14]([NH:16][CH3:17])=[O:15]
Reactant: [H][H]
Reactant: CNC(=O)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: c1ccsc1
Solvent: COCCO
Solvent: CO
Product: CNC(=O)c1cc(C(=O)c2ccccc2)ccc1N
Yield: 79.3 %

Procedure:
A mixture of 6.5 parts of intermediate 21, namely 5-benzoyl-N-methyl-2-nitrobenzamide, 2 parts of a solution of thiophene in methanol 4% and 97 parts of 2-methoxyethanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was recrystallized from 2-propanol, yielding 4.64 parts (79.3%) of 2-amino-5-benzoyl-N-methylbenzamide; mp. 140.5° C. (interm. 22).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[CH3:17][O:18][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH2:20][NH2:21].C(OCC)(=O)C>C1(C)C=CC=CC=1>[ClH:28].[ClH:28].[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:21][CH2:20][CH:19]([O:18][CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(CN)c1cccc(Cl)c1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(CC(C)NCC(OC)c2cccc(Cl)c2)cc1
Product: Cl

Procedure:
1-(4-carbomethoxymethoxyphenyl)propan-2-one (2.80 g) and 2-methoxy-2-(3-chlorophenyl)ethanamine (2.58 g) in dry toluene (200 ml) were boiled under reflux for 2 hours in an apparatus incorporating a water trap. The solution was cooled and the solvent removed under reduced pressure. The residue dissolved in methanol (100 ml) was hydrogenated in the presence of platinum (from platinum oxide, 50 mg) until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, and the solvent removed under reduced pressure. Chromatography of the residue on silica-gel in 3% methanol-dichloromethane gave an oil. Treatment of this oil with an ethereal solution of hydrogen chloride gave N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-methoxy-2-(3-chlorophenyl)ethanamine hydrochloride, mp 148°-50° C. (ethyl acetate), as an 85:15 mixture of diastereoisomers.
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1>C(O)C>[C:1]([CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([O:3][CH2:16][CH3:17])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CSCCCCC1=CCCC1=O
Solvent: CCO
Product: CCOC(=O)CSCCCCC1=CCCC1=O

Procedure:
In the manner described in Example 39, treatment of 2-(6-carboxy-5-thiahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol gives the subject ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][OH:17])[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:19].[C:27]([O:31][C:32](ONC(C1C=CC=CC=1)C#N)=[O:33])([CH3:30])([CH3:29])[CH3:28].O.CCOC(C)=O>C(N(CC)CC)C>[C:32](=[O:33])([O:17][CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[CH:5]=[CH:4][C:3]([C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[C:2]([Cl:1])[CH:7]=1)[O:31][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)ONC(C#N)c1ccccc1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CCO)cc1Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2CCOC(=O)OC(C)(C)C)cc1Cl
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Compound 102 (200 mg) was dissolved in dry triethylamine (3.0 mL) and {[(tert-butoxycarbonyl)oxy]amino}(phenyl)acetonitrile (148 mg) was added. The solution was stirred at 70° C. for 5 h. The reaction mixture was cooled to room temperature and then poured into a mixture of water and EtOAc. The aqueous phase was extracted with more EtOAc (×2). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using petroleum ether/diethyl ether 8:1 as the eluent to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](O)([C:28]4[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=4)[C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]([CH3:35])[C:10](=[O:36])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:39])=O>>[ClH:1].[Cl:39][C:18]([C:28]1[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=1)([C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:35])[C:10](=[O:36])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cncc1C(O)(c1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Product: Cl
Product: Cn1cncc1C(Cl)(c1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of (±)-4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)(4-nitrophenyl)methyl]-1-methyl-2(1H)-quinolinone (described in Example B4) (0.00107 mol) in thionyl chloride (6 ml) was stirred at room temperature for 2 hours. The mixture was evaporated. The residue was taken up in CH2Cl2 and evaporated. The product was used without further purification in the next step, yielding 0.6 g (100%) of (±)-6-[chloro(1-methyl-1H-imidazol-5-yl)(4-nitrophenyl)methyl]4(3-chlorophenyl)-1-methyl-2(1H)-quinolinone monohydrochloride.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[C:16]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[N:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)[CH2:4][CH2:3]1.[OH-].[Na+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].O>C1COCC1>[C:33]([O:32][C:30](=[O:31])[CH2:29][O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[C:16]([C:18]4[CH:25]=[CH:24][CH:23]=[C:20]([C:21]#[N:22])[CH:19]=4)[N:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)[CH2:4][CH2:3]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cccc(-c2nc(N3CCC(O)CC3)cc3cccnc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COC1CCN(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[6-(4-Hydroxy-piperidin-1-yl)-[1,7]naphthyridin-8-yl]-benzonitrile (570 mg, 1.73 mmol) THF (5 ml) is added to NaOH (60% dispersion in mineral oil) (166 mg, 6.9 mmol) suspended in THF (20 ml) at 0° C. Stirred at 0° C. for 30 minutes. tert-Butyl bromoacetate (0.51 ml, 3.45 mmol) is added and the reaction mixture is stirred at 0° C. for 5 minutes then at room temperature for 18 hours. Further tert-butyl bromoacetate (0.25 ml, 1.73 mmol) and NaOH (80 mg, 3.3 mmol) are added and the reaction mixture is stirred at room temperature for 2 hours. After cooling to 0° C. water (20 ml) is added and the mixture is extracted with ethyl acetate (×1). The ethyl acetate extract is dried (MgSO4), filtered and concentrated. Purification by chromatography on silica gel, eluting with 10-20% ethyl acetate in isohexane, gives the product. MS (ES+) Observed [M+H]+ 445.12
Reaction SMILES: [C:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Li+]>>[C:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]([OH:16])=[O:15])=[CH:27][CH:28]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCC(Oc1ccc(C(=O)CCCCC)cc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCCCC(Oc1ccc(C(=O)CCCCC)cc1)C(=O)O
Yield: 80.7 %

Procedure:
1-[4-Hydroxyphenyl]-1-hexanone (384 mg, 2.0 mmol) and ethyl (RS)-2-bromodecanoate (614 mg, 2.2 mmol) were reacted according to the procedure used for the preparation of I to give Ethyl (RS)-2-[4-Hexanoylphenoxy]decanoate (628 mg, 80%). 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J=9.0 Hz, 2H), 6.84 (d, J=9.0 Hz, 2H), 4.60-4.65 (m, 1H), 4.15 (q, J=7.0 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 1.86-1.97 (m, 2H), 1.61-1.70 (m, 2H), 1.38-1.52 (m, 2H), 1.20-1.34 (m, 14H), 1.18 (t, J=7.2 Hz, 3H), 0.78-0.87 (m, 6H); 13C NMR (101 MHz, CDCl3): δ 199.17, 171.36, 161.78, 130.95, 130.46 (2C), 114.72 (2C), 76.66, 61.51, 38.41, 32.84, 32.00, 31.76, 29.52, 29.35 (2C), 25.31, 24.41, 22.83, 22.74, 14.33, 14.26, 14.14. The resulting ester (628 mg, 1.6 mmol) was saponified with lithium hydroxide (193 mg, 8.0 mmol) according to the procedure used for the preparation of I to give (RS)-2-[4-Hexanoylphenoxy]decanoic Acid (468 mg, 80%). 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J=9.0 Hz, 2H), 6.91 (d, J=9.0 Hz, 2H), 5.77 (br s, 1H), 4.70 (dd, J=5.8, 6.6 Hz, 1H), 2.89 (t, J=7.4 Hz, 2H), 1.97-2.03 (m, 2H), 1.67-1.74 (m, 2H), 1.44-1.60 (m, 2H), 1.23-1.37 (m, 14H), 0.90 (t, J=6.8 Hz, 3H), 0.87 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.76, 176.29, 161.56, 131.20, 130.70 (2C), 114.81 (2C), 76.12, 38.56, 32.78, 32.03, 31.80, 29.53, 29.40, 29.36, 25.36, 24.51, 22.87, 22.76, 14.33, 14.20. The acid (468 mg, 1.3 mmol) was then converted to the sodium salt according to the procedure used for the preparation of I to give Sodium (RS)-2-[4-Hexanoylphenoxy]decanoate (459 mg, 93%) as a white solid. mp 275-280° C.; 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.44-4.48 (m, 1H), 2.89-2.96 (m, 2H), 1.88-1.96 (m, 2H), 1.63-1.71 (m, 2H), 1.44-1.61 (m, 2H), 1.24-1.38 (m, 14H), 0.84-0.93 (m, 6H); 13C NMR (101 MHz, CD3OD): δ 200.89, 177.86, 163.36, 130.27 (2C), 129.60, 114.75 (2C), 79.54, 37.94, 33.18, 31.86, 31.49, 29.44, 29.38, 29.21, 25.73, 24.55, 22.58, 22.45, 13.36, 13.23; LRMS (ESI): m/z 769.8 (M2H+), 747.8 (2M−Na++2H+), 363.2 (M−Na++2H+); HPLC: 3.min.
Reaction SMILES: [F:1][CH2:2][CH:3]([N:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1)[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1.FCC(N1CCN(C(OCC2C=CC=CC=2)=O)CC1)CN1C=C(C2C3C=CN(COCC[Si](C)(C)C)C=3N=CN=2)C=N1.[H][H]>CO.[Pd]>[F:1][CH2:2][CH:3]([N:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1)[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CF)CN4CCN(C(=O)OCc5ccccc5)CC4)c3)ncnc21
Agent: [Pd]
Agent: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(CC(CF)N4CCN(C(=O)OCc5ccccc5)CC4)c3)ncnc21
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CF)CN4CCNCC4)c3)ncnc21

Procedure:
A mixture of (±)-benzyl 4-{3-fluoro-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazine-1-carboxylate (0.064 g, 0.11 mmol) and (±)-benzyl 4-(2-fluoro-1-{[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]methyl}ethyl)piperazine-1-carboxylate (0.064 g, 0.11 mmol) in 5 mL of methanol was hydrogenated in the presence of 5% Pd/C, under balloon pressure of hydrogen, for 2 h. After filtering off the catalyst, the filtrate was concentrated and used directly in next step. LCMS calculated for C22H35FN7OSi(M+H)+: m/z=460.3; Found: 460.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:7][C:6]=12.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][NH2:34])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][NH:34][C:10]1[N:5]2[N:4]=[CH:3][C:2]([Br:1])=[C:6]2[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:9]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: Clc1ccccc1-c1cc(Cl)n2ncc(Br)c2n1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCCC1CCNc1cc(-c2ccccc2Cl)nc2c(Br)cnn12
Temperature: 75 °C
Yield: 78.7 %

Procedure:
3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (400 mg, 1.166 mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (5.7 mL). 2-Aminoethylpiperidine-1-carboxylic acid tert-butyl ester (266 mg, 1.166 mmoles) and diisopropyl ethylamine (0.409 mL, 2.33 mmoles) were added and the mixture was heated at 75° C. for 48 h. Additional diisopropyl ethylamine (0.204 mL, 1.166 mmoles) was added and the heating was continued for a total of 58 h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column (15×5 cm) using dichloromethane followed by 0.3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 2-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]ethyl}piperidine-1-carboxylic acid tert-butyl ester (491.1 mg, 79%): FABMS: m/z 534.1 (MH+); HRESIMS: m/z 534.12797 (MH+). Calcd. for C24H30N5O2BrCl: m/z 534.12714; δH (CDCl3) 1.50 (1H, m, CH2), 1.51 (9H, s, COOC(CH3)3), 1.57 (2H, m, CH2), 1.68 (2H, m, CH2), 1.76 (2H, m, CH2), 2.24 (1H, bm, CH2), 2.82/3.40/3.54/4.08/4.51 (5H, m, CH/CH2), 6.34 (1H, s, H6), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.08 ppm (1H, s, H2); δC (CDCl3) CH3, 28.5, 28.5, 28.5; CH2, 19.2, 25.5, 29.2, 29.2, 39.2, 67.1; CH, ˜47.4, 87.1, 127.1, 130.1, 130.1, 131.6, 143.9; C, 80.0, 83.0, 132.1, 138.9, 145.7, 146.2, 158.0.