Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH3:12][C:13]1[CH:21]=[CH:20]C(C(Cl)=O)=[CH:15][CH:14]=1>O.C1(C)C=CC=CC=1>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[C:7]1[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][CH:15]=1)[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1ccc(C)cc1
Yield: 34.9 %

Procedure:
Sodium hydroxide solution (33%, 32.5 ml) was added to ethyl acetoacetate (97.5 g, 750 mmol) in a mixture of water (250 ml) and toluene (12 ml) at 0–5° C. under stirring (pH 11). After 30 minutes 4-methylbenzoylchloride (127.46 g, 825 mmol) and sodium hydroxide solution (33%, 135 ml) was added simultaneously over a period two hours. The reaction mixture was stirred for 15 minutes at 0° C. and for 1 hour at 35° C. Aqueous layer was separated, ammonium chloride (40 g) was added and stirred slowly over night. The reaction mixture was saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulphate and concentrated to dryness in vacuum. The crude product thus obtained was purified by column chromatography to yield the title compound as viscous oil (54 g, 35%). MS m/z: 207.1 (M+). Preparation 2 Synthesis of ethyl(4-chloro)benzoylacetate
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:22][O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)NOCc1ccccc1
Yield: 67 %

Procedure:
Reaction with isatoic anhydride: A mixture of isatoic anhydride (3.3 g, 20 mmol), O-benzylhydroxylamine hydrochloride (4.4 g, 27 mmol) and K2CO3 (6.9 g, 50 mmol) in 20 mL of DMF was stirred at rt until all the anhydride was consumed (ca. 2 days) by thin layer chromatographic analysis. The mixture was diluted with MTBE and washed with water and brine. After removal of solvent, the crude product was recrystallized from EtOAc/heptane to give 2-amino-N-benzyloxylbenzamide as a white solid (3.25 g, 67% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10](I)[CH:9]=2)=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)cc(I)n1
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-iodo-6-trifluoromethyl-pyridine (example A.50) (9 g, ca. 35% pure, ca. 8.2 mmol) and commercially available 3-bromo-benzene-boronic acid (1.80 g, 9 mmol) according to the general procedure IVb. Obtained as a white solid (1.7 g, 50%). MS (ISP) 412.0 [(M+H)+], 414.1 [(M+2+H)+] and 416.1 [(M+4+H)+].
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][NH:21][C:22]([C:24]34[CH2:31][CH2:30][C:27]([NH:32]C(=O)OC(C)(C)C)([CH2:28][CH2:29]3)[CH2:26][CH2:25]4)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=S(Cl)Cl>O1CCOCC1>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:22]([C:24]45[CH2:29][CH2:28][C:27]([NH2:32])([CH2:30][CH2:31]4)[CH2:26][CH2:25]5)=[N:21][N:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)C45CCC(NC(=O)OC(C)(C)C)(CC4)CC5)cnc32)cc1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Temperature: 80 °C
Yield: 24.4 %

Procedure:
To a solution of tert-butyl 4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-bicyclo[2.2.2]octan-1-ylcarbamate (6.1 g, 11.0 mmol, Example #9, Step E), and TEA (6.1 mL, 44.0 mmol) in 1,4-dioxane (110 mL) was added SOCl2 (2.0 mL, 27.5 mmol). The reaction mixture was heated at about 80° C. for about 2 h then cooled to ambient temperature. The reaction mixture was washed with saturated aqueous NaHCO3 (3×50 mL). The layers were separated and the aqueous portion was filtered to give 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]-octan-1-amine as a brown solid (1.17 g, 24%): LC/MS (Table 1, Method a) Rt=1.28 min; MS m/z: 437 (M+H)+. The remaining filtrate was extracted with EtOAc (10 mL). The combined organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to afford crude tert-butyl 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate (3.5 g). The crude Boc-protected material was dissolved in 1,4-dioxane (38 mL) and HCl (4 N in 1,4-dioxane, 8 mL) was added. The reaction mixture was heated to about 50° C. for about 3 h. The precipitate formed was collected by filtration. The solid was dissolved in DCM (50 mL), and washed with saturated aqueous NaHCO3 (3×20 mL). The layers were separated and the organic portion was dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give additional 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine as a brown solid (2.3 g, 50% over 2 steps): LC/MS (Table 1, Method a) Rt=1.28 min; MS m/z: 437 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[CH3:12][Sn:13](Cl)([CH3:15])[CH3:14]>CCOCC>[CH3:1][N:2]1[C:6]([Sn:13]([CH3:15])([CH3:14])[CH3:12])=[CH:5][CH:4]=[N:3]1
Reactant: C[Sn](C)(C)Cl
Reactant: Cn1cccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cn1nccc1[Sn](C)(C)C
Reaction time: 1.5 h
Yield: 42.9 %

Procedure:
A solution of 1-methyl-1H-pyrazole (1.6 g, 20.0 mmole) in Et2O was treated with n-butyllithium (12.5 ml, 1.6 M in hexanes, 20.0 mmole) over a period of 10 minutes at room temperature. The yellow slurry was stirred for a further 90 minutes. Subsequently, trimethyltin chloride (4.0 g, 20.0 mmole) was added in one portion. The brown slurry was stirred for 30 minutes, filtered and the filtrate was concentrated, in vacuo, to a black oil (5.0 g). The product was isolated by distillation at 1.5 Torr (67–72° C.) as a clear oil (2.1 g, 42%): 1H-NMR (DMSO-d6, 400 MHz) δ 7.40 (1H, d, J=1.5 Hz), 6.27 (1H, d, J=1.7 Hz), 3.84 (3H, s), 0.34 (9H, s). ESIMS m/z 243–247 ion cluster (M+H)+.
Reaction SMILES: [Na+].[I-].C[Si](Cl)(C)C.[CH3:8][C:9]([S:11][C:12]1[C:23]2[O:22][C:21]([CH3:25])([CH3:24])[O:20][C:19]=2[C:18]([C:26]([C:48]2[C:58]3[O:59][C:60]([CH3:63])([CH3:62])[O:61][C:57]=3[C:56]([S:64][C:65]([CH3:67])=[O:66])=[C:50]3[O:51][C:52]([CH3:55])([CH3:54])[O:53][C:49]=23)([C:28]2[C:38]3[O:39][C:40]([CH3:43])([CH3:42])[O:41][C:37]=3[C:36]([S:44][C:45]([CH3:47])=[O:46])=[C:30]3[O:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=23)O)=[C:17]2[C:13]=1[O:14][C:15]([CH3:69])([CH3:68])[O:16]2)=[O:10]>C(#N)C>[CH3:67][C:65]([S:64][C:56]1[C:50]2[O:51][C:52]([CH3:54])([CH3:55])[O:53][C:49]=2[C:48]([CH:26]([C:18]2[C:19]3[O:20][C:21]([CH3:25])([CH3:24])[O:22][C:23]=3[C:12]([S:11][C:9]([CH3:8])=[O:10])=[C:13]3[O:14][C:15]([CH3:68])([CH3:69])[O:16][C:17]=23)[C:28]2[C:38]3[O:39][C:40]([CH3:42])([CH3:43])[O:41][C:37]=3[C:36]([S:44][C:45]([CH3:47])=[O:46])=[C:30]3[O:31][C:32]([CH3:34])([CH3:35])[O:33][C:29]=23)=[C:58]2[C:57]=1[O:61][C:60]([CH3:63])([CH3:62])[O:59]2)=[O:66]
Reactant: CC(=O)Sc1c2c(c(C(O)(c3c4c(c(SC(C)=O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SC(C)=O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Sc1c2c(c(C(c3c4c(c(SC(C)=O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SC(C)=O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Reaction time: 0.08 h
Yield: 83 %

Procedure:
NaI (0.15972 g, 1.1256 mmol) and trimethylsilyl chloride (0.142 mL, 1.1256 mmol) were stirred in acetonitrile (50 mL). Tris(8-methylcarbonylthio-2,2,6,6-tetramethylbenzo-[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)methanol (0.1286 g, 0.1407 mmol, Example 49) was added in solid form and the color of the solution became brownish. Na2S2 O4 (20 mL, sat.) was added after 60 minutes and the mixture was stirred 5 minutes before separation of the phases. The aqueous phase was extracted with diethyl ether (50 mL), and the combined organic phase was dried (MgSO4) and evaporated, yielding 0.105 g (0.1168 mmol, 83%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.Br[CH2:31][C:32]([NH:34][CH3:35])=[O:33]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:22])=[CH:11][C:12]([C@@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([CH2:31][C:32]([NH:34][CH3:35])=[O:33])[CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CNC(=O)CBr
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCCNC4)cc3C)ncc2Cl)n[nH]1
Solvent: CN(C)C=O
Product: CNC(=O)CN1CCC[C@@H](c2cc(C)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)C1

Procedure:
A solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-3-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (700 mg, 1.70 mmol), 2-bromo-N-methylacetamide (258 mg, 1.70 mmol) and TEA (1.2 mL, 8.5 mmol) in DMF (4 mL) was stirred at rt for 30 min. The reaction was purified by RP-HPLC to give the product as a racemate; ESMS m/z 483.2 (M+1). Chiral separation of the racemic mixture was conducted with chiral HPLC (ChiralCel OD-H, Hex:EtOH:MeOH/80:10:10, 15 min run time, 1 mL/min). The two purified enantiomer peaks were collected separately, both as white solids: (R)-2-(3-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)-N-methylacetamide and (S)-2-(3-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)-N-methylacetamide; both peaks: ESMS m/z 483.2 (M+H+). The earlier eluting peak (rt=5.63 min. vs. rt=7.62 min.) was arbitrarily assigned as the (R) enantiomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[F:19][C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>>[F:19][C@@H:20]1[CH2:24][CH2:23][N:22]([CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:21]1
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: F[C@@H]1CCNC1
Product: COc1cc(N2CCC(N3CC[C@@H](F)C3)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (INTERMEDIATE 18) and (R)-3-fluoropyrrolidine. m/z 324.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:17][C:18](=[O:39])[C:19](=[CH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)=[C:27]([O:37][CH3:38])[CH:26]=2)[CH2:20][CH2:21][CH2:22]Cl)[CH3:16])[CH:12]=[CH:13][CH:14]=1.O>C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]([C@H:15]([N:17]2[CH2:22][CH2:21][CH2:20]/[C:19](=[CH:24]\[C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]4)=[C:27]([O:37][CH3:38])[CH:26]=3)/[C:18]2=[O:39])[CH3:16])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cc(C=C(CCCCl)C(=O)N[C@@H](C)c2cccc(F)c2)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCCN([C@H](C)c3cccc(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a DMF (3 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetic acid salt (100 mg) obtained according to the method described in Example 418 and (S)-1-(3-fluorophenyl)ethylamine hydrochloric acid salt (31 mg), IPEA (0.2 mL) and HOBT (36 mg) and EDC (51 mg) were added, and the reaction solution was agitated at room temperature for 3 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was dried over magnesium sulfate and concentrated under reduced pressure. By purifying the residue with silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate 1:1->ethyl acetate), 79 mg of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid ((1S)-1-(3-fluorophenyl)ethyl)amide was obtained. Sodium hydride (40% mineral oil content, 8 mg) was added to the DMF (3 mL) solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid ((1S)-1-(3-fluorophenyl)ethyl)amide obtained, and the reaction solution was agitated at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate system 1:1->ethyl acetate) to obtain 48 mg of the racemic title compound. The physical properties of the compound are as follows.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][C@H:16]3[NH:27][CH2:26][CH2:25][C@@:22]4([C:23]=2[CH:24]=1)[C@H:17]3[CH2:18][CH2:19][CH2:20][CH2:21]4.C(N(CC)CC)C>>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][C@H:16]3[N:27]([C:1](=[O:3])[CH3:2])[CH2:26][CH2:25][C@@:22]4([C:23]=2[CH:24]=1)[C@H:17]3[CH2:18][CH2:19][CH2:20][CH2:21]4
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(C)=O)CC3
Temperature: 60 °C
Yield: 81.9 %

Procedure:
Acetic anhydride (3.14 g, 30.76 mmol) was added to a solution of (+)-3-methoxy-morphinan hydrochloride (1.5 g, 5.1 mmol) in TI-IF (30 ml) and triethylamine (8.7 g, 85.98 mmol) in the presence of nitrogen. The resulting solution was heated at 60° C. for 15 hr. The reaction mixture was cooled to room temperature and evaporated under vacuum. The residue was dissolved in methylene chloride (50 ml), washed with water (40 ml×2) and dried (MgSO4). Evaporation of the dried solution gave a tan viscous oil (1.25 g, 81% yield); ms (ESI+): m/z 300 (M+1).
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]([O:18][CH3:19])=[O:17]>C(O)(=O)C>[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH:9]2[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)Cc1c[nH]c2ccc(F)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC1CNc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere 910 mg (14.5 mmol) sodium cyanoborohydride was added batchwise to 1.0 g (4.83 mmol) methyl (5-fluoro-1H-indol-3-yl)-acetate in 12.5 g acetic acid while cooling slightly. After 2 h stirring at RT another 910 mg (14.5 mmol) sodium cyanoborohydride was added batchwise while cooling slightly. After 3 h stirring at RT the solvent was evaporated down using the rotary evaporator. The residue was taken up in 4M hydrochloric acid and stirred for 30 min. Then the reaction solution was made alkaline with solid potassium carbonate and extracted with dichloromethane (3×). The combined organic phases were dried on sodium sulphate, filtered and evaporated down using the rotary evaporator. The product thus obtained was reacted directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:24])[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[C:9]([CH3:25])[S:8][C:7]=2[C:26]=1[O:27]S(C1C=CC(C)=CC=1)(=O)=O.CO>C1COCC1.[OH-].[Na+]>[OH:27][C:26]1[C:7]2[S:8][C:9]([CH3:25])=[C:10]([C:11](=[O:24])[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)c2c(C)sc3c(OS(=O)(=O)c4ccc(C)cc4)c(OC)ccc23)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)c2c(C)sc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 30 °C
Reaction time: 8 h
Yield: 279.4 %

Procedure:
A mixture of the product of Example 41 (0.035 g; 0.00645 mmol) in THF (0.5 ml) and 1% NaOH in MeOH (0.52 ml; 0.0129 mmol) was stirred overnight at 30° C. under N2 and acidified with the drop of CF3 CO2H. This was evaporated to dryness and diluted to 15 ml with diethyl ether, washed with 0.1 M HCl (2 ml), 5% NaHCO3 (2 ml), brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, CH2Cl2) to give pure title compound (0.007 g; 28%), as a colourless crystals. 1H-NMR (CDCl3) 2.47 (s, 3H); 3.83 (s, 6H); 3.92 (s, 6H); 5.94 (s, 1H); 6.93 (d, 1H, J=8.69 Hz); 7.05 (d, 1H, J=8.69 Hz); 7.1 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[F:30].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CCOC(C)=O>[F:30][C:21]1[CH:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[CH:28]=[CH:29][C:20]=1[C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(Br)c(F)c1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(OC)cc2F)c(F)c1

Procedure:
2-(2-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (600 mg, 2.38 mmol), methyl 4-bromo-3-fluorobenzoate (665 mg, 2.856 mmol), 1,1′-bis(diphenylphosphino) ferrocene-palladium dichloride dichloromethane adduct (292 mg, 0.358 mmol), potassium carbonate (2.38 ml, aq., 2M, 4.76 mmol) and 1,4-dioxane (10 ml) were sealed and subject to microwave irradiation at 145° C. for 15 min. Aliquot indicated formation of the desired cpd. TLC (20% EtOAc/hex) indicated a bright purple spot @ Rf=0.4. Crude mixture was dried/Na2SO4 then purified by flash chromatography (SiO2, Biotage 40+M cartridge). The column was eluted by a 0% to 20% EtOAc/hexanes mixture. Related fractions were pooled and concentrated in vacuo to afford the title compound. LCMS (ESI) calc.=278.08; found=279.09 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][C:13]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[CH:14][C:7]2=[N:6][CH:5]=1.CC[O-].[Na+]>CCO.O>[F:23][C:19]1[CH:18]=[C:17]([C:16]#[C:15][C:13]2[CH:12]=[CH:11][N:8]3[C:9](=[O:10])[C:4]([CH:3]=[CH2:2])=[CH:5][N:6]=[C:7]3[CH:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=c1c(CCBr)cnc2cc(C#Cc3cccc(F)c3)ccn12
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=Cc1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O

Procedure:
A solution of 3-(2-bromoethyl)-8-((3-fluorophenyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one (289 mg, 0.78 mmol) and EtONa (208 mg, 3.05 mmol) in EtOH (absolute) was stirred at 50° C. for 3 hr. After the suspension was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL), the combined organic layers were dried over Na2SO4 and concentrated to give the desired product, which was purified by column chromatography. MS (ESI): 291 (MH+); 1H NMR (300 MHz, CDCl3) δ 9.10-9.07 (d, J=7.44 Hz, 1H), 8.44 (s, 1H), 7.76 (s, 1H), 7.42-7.39 (m, 2H), 7.32-7.31 (m, 1H), 7.20-7.17 (m, 2H), 6.86-6.76 (m, 1H), 6.36-6.29 (dd, J=17.65, 1.38 Hz, 1H), 5.50-5.46 (dd, J=11.41, 1.32 Hz, 1H).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]=1[CH:14]=[O:15].[NH4+].[Cl-]>CCOCC>[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:12])([CH3:13])[C:7]=1[CH:14]([OH:15])[CH2:3][CH:2]=[CH2:1]
Reactant: CC1=C(C=O)C(C)(C)CCC1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC(O)C1=C(C)CCCC1(C)C
Temperature: 0 °C
Yield: 57 %

Procedure:
In a typical experiment 10.7 g. of Mg turnings and 5 g. of allyl bromide were allowed to react in 70 ml. of dry ether. The reaction was exothermic and the temperature of the reaction mixture increased up to the boiling point of the solvent. To this solution allyl bromide (46 g.) and β-cyclocitral (61 g.) in 160 ml. of ether were added with vigorous stirring at such a rate as to maintain the ether at the boiling temperature. The reaction mixture was then kept at reflux during 6 hours and after cooling it was poured into a ice-cold concentrated aqueous solution of NH4Cl. The ethereal layer after the usual treatments gave 2,6,6-trimethyl-1-[1-hydroxy-3-butenyl]-1-cyclohexene (44.5 g.; 57 % yield): B.p. 60°-2°/0.001 Torr; nD20 = 1.4964; d420 = 0.9398; NMR spectrum (CCl4): 0.98 (3 H, s); 1.10 (3 H, s); 1.82 (3 H, s); 1.20-2.80 (9 H, m); 4.22 (1 H, m); 5.04 (2 H, d, J = 15 cps); 5.88 (1 H, m) δ ppm.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][N:14]1[CH2:18][CH2:17][CH:16]([OH:19])[C:15]1=[O:20].[C:22](N1C=CN=C1)(=[O:24])[CH3:23]>C1(C)C=CC=CC=1>[CH3:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[N:3]1[CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][N:14]1[CH2:18][CH2:17][CH:16]([O:19][C:22](=[O:24])[CH3:23])[C:15]1=[O:20]
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O
Reactant: CC(=O)n1ccnc1
Solvent: Cc1ccccc1
Product: CC(=O)OC1CCN(CC(=O)NCCN2[C@H](C)CCC[C@@H]2C)C1=O

Procedure:
0.594 g of (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide is boiled at reflux for 4 hours with 0.222 g of N-acetylimidazole in 10 ml of toluene. The mixture is chromatographed over 21 g of aluminum oxide (activity grade III, neutral). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with methylene chloride has a melting point of 120°-121° after crystallization from diethyl ether.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]([CH3:28])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([CH3:27])[CH:20]=2)=[N:15]1.O.NN>>[NH2:3][C@H:12]([CH3:28])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([CH3:27])[CH:20]=2)=[N:15]1
Reactant: Cc1cc(-c2ccn(C[C@@H](C)N3C(=O)c4ccccc4C3=O)n2)ccc1C#N
Agent: NN
Solvent: O
Product: Cc1cc(-c2ccn(C[C@@H](C)N)n2)ccc1C#N
Yield: 17.1 %

Procedure:
(R)-4-(1-(2-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (753 mg, 2.0 mmol) was treated with hydrazine hydrate using the method of Example 27(b). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-20% MeOH/DCM) to obtain 82 mg (17%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 0.96 (d, 3H), 2.52 (s, 3H), 3.22 (m, 1H), 3.99 (m, 2H), 6.84 (d, 1H), 7.77 (m, 2H), 7.81 (d, 1H), 7.89 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([F:11])[CH:5]=1)(=[O:3])[CH3:2].FC(F)(F)OC1C=CC(C(=O)C[Br:21])=CC=1>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH2:2][Br:21])=[CH:5][C:6]=1[F:11]
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)c1ccc(Cl)c(F)c1
Product: O=C(CBr)c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from 4-acetyl-1-chloro-2-fluorobenzene according to the procedure for preparing 4-(trifluoromethoxy)phenacyl bromide described in Example 189.