Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH:11]([OH:27])[CH2:10]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].[C:33](=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:28][S:29]([O:27][CH:11]1[CH2:12][N:13]2[C:14](=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[C:17]=32)[N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:10][CH2:33]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: O=C([O-])O
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(O)CN3c1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc3n(c12)CC(OS(C)(=O)=O)CCN3c1ccc(Cl)cc1Cl
Yield: 99 %

Procedure:
To a solution of 1-(2,4-dichlorophenyl)-6-(diethylamino)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-3-ol (235 mg, 0.563 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.436 mL, 5.63 mmol) at room temperature. The resultant mixture was stirred at room temperature for 30 min. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as an orange amorphous solid (279 mg, 0.560 mmol, 99%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6](Br)[CH:7]=[CH:8][CH:9]=1.[Mg].[B:14](OC)(OC)OC.S(=O)(=O)(O)O.[OH:26][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(OCC)C>[CH3:28][C:27]1([CH3:29])[C:30]([CH3:32])([CH3:31])[O:33][B:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:12])([F:11])[F:1])[CH:5]=2)[O:26]1
Reactant: COB(OC)OC
Reactant: CC(C)(O)C(C)(C)O
Reactant: FC(F)(F)Oc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: CC1(C)OB(c2cccc(OC(F)(F)F)c2)OC1(C)C
Reaction time: 0.5 h

Procedure:
2.41 g of 3-(trifluoromethoxy)brombenzene are dissolved in 25 ml of diethyl ether and added dropwise to a suspension of 0.28 g of magnesium in 25 ml of diethyl ether such that the solution remains at the boil. After addition is complete, the mixture is stirred under reflux for 2 h. The cooled solution is added dropwise to a solution of 1.16 ml of trimethyl borate in 25 ml of diethyl ether at a temperature of <−50° C. and then stirred at room temperature for 2 h. 5 ml of 40% strength sulfuric acid and 1.21 g of pinacol are successively added to this solution. After 30 minutes, the solvent is removed on a Rotavapor, the residue is neutralized using saturated sodium hydrogencarbonate solution and the mixture is extracted three times with methyl tert-butyl ether. The organic phase is dried over magnesium sulfate and concentrated in vacuo. 4,4,5,5-Tetramethyl-2-(3-trifluoromethoxyphenyl)-[1,3,2]dioxaborolane is obtained, which is reacted further without further purification.
Reaction SMILES: S(Cl)(Cl)=O.ClC1C(C(O)=O)=C(C2C=CC=CC=2)C=CN=1.[CH2:21]([NH2:24])[CH2:22][NH2:23].CS(O[CH2:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=1)(=O)=O>C1COCC1.CN(C=O)C>[F:38][C:37]([F:39])([F:40])[C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([C:41]([F:44])([F:42])[F:43])[CH:34]=1)[CH2:30][NH:23][CH2:22][CH2:21][NH2:24]
Reactant: CS(=O)(=O)OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCCN
Agent: O=C(O)c1c(-c2ccccc2)ccnc1Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (0.15 ml) and DMF (catalytic amount) were added to a THF (5 ml) solution of 2-chloro-4-phenyl-3-pyridinecarboxylic acid (145 mg) and heated under reflux for 2 hours. The solvent was removed by distillation, and the residue was dissolved in THF (5 ml). The resulting solution was added to a mixture of N-[3,5-bis(trifluoromethyl)benzyl]-N′-tert-butoxycarbonylethylenediamine (240 mg), triethylamine (0.26 ml) and THF (10 ml), while cooling with ice, and stirred for 3 hours at room temperature. The N-(3,5-bis(trifluoromethyl)benzyl]-N′-tert-butoxycarbonylethylenediamine used herein was prepared as an oily compound, by reacting ethylenediamine with 3,5-bis(trifluoromethyl)benzyl methanesulfonate in THF to give an oily compound of N-[3,5-bis(trifluoromethyl)benzyl]ethylenediamine, followed by further reacting the compound with di-tert-butyl dicarbonate in the presence of triethylamine in THF.
Reaction SMILES: BrC1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4]C=1OC.[Mg].[C:12]([CH:14]1[CH2:16][CH:15]1[C:17](N(OC)C)=[O:18])#[N:13].[CH2:23]([O:25][CH2:26][CH3:27])C>BrC(Br)C.C1COCC1.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:27]([C:17]([CH:15]2[CH2:16][CH:14]2[C:12]#[N:13])=[O:18])=[C:26]([O:25][CH3:23])[CH:7]=1
Reactant: COc1ccc(Cl)cc1Br
Reactant: CCOCC
Reactant: CON(C)C(=O)C1CC1C#N
Agent: CC(Br)Br
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1C(=O)C1CC1C#N

Procedure:
A solution of 500 mg (2.26 mmol) of 2-bromo-4-chloroanisole in 5 ml of diethyl ether was added dropwise to 57.6 mg (2.37 mmol) of magnesium turnings in 10 ml of diethyl ether, activated by adding a few drops of dibromoethane, and the reaction mixture was heated under reflux overnight. The reaction solution was added dropwise under argon to a solution of 316 mg (2.05 mmol) of the compound from Example 73A in 10 ml of THF, and the reaction mixture was heated under reflux for 2 h. It was diluted with ethyl acetate, and the organic phase was washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 9/1) to result in 278 mg (58% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:26]N1C(=O)CCC1=O>CN(C)C=O>[Br:26][C:10]1[N:9]=[C:8]([C@H:11]2[CH2:12][CH2:13][C@H:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22]3)[CH2:15][CH2:16]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: CC(=O)N1CCN([C@H]2CC[C@H](c3ncc4c(C)nccn43)CC2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(=O)N1CCN([C@H]2CC[C@H](c3nc(Br)c4c(C)nccn43)CC2)CC1

Procedure:
To a stirred solution of 1-(4-((trans)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)piperazin-1-yl)ethanone (0.422 mmol, 144 mg) in N,N-dimethylformamide (2 mL) was added N-bromosuccinimide (0.422 mmol, 75 mg). After two hours at 60° C. the reaction was quenched with a saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The organic extracts were washed twice with water and brine, dried (sodium sulfate) and concentrated under reduced pressure. The crude product was purified with column chromatography on silica gel (dichloromethane/methanol) to afford 176 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[H][H].[NH3:15]>>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:12])[CH2:9][CH2:10][NH2:15])[CH2:4][CH:3]=1
Reactant: [H][H]
Reactant: CC1=CCC(C(C)CC=O)CC1
Reactant: N
Product: CC1=CCC(C(C)CCN)CC1
Yield: 86 %

Procedure:
830 g of 3-[1-methylcyclohexen-4-yl]-butyraldehyde were dissolved in 800 ml of liquid ammonia in a stirrer autoclave and hydrogenated over 50 g of Raney nickel iron at 90° C. and a hydrogen pressure of 100 bar. After evaporation of the solvent, the mixture was filtered from the catalyst and distilled under vacuum. 720 g (86%) of 3-(1-methylcyclohexen-4-yl)-butylamine, b.p.10 120° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][Sn](C)(C)C>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Br)c2nccn2c1
Reactant: C[Sn](C)(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)c2nccn2c1

Procedure:
Microwave a mixture of 6-methyl-8-bromoimidazo[1,2-a]pyridine (1.0 g, 4.76 mmol), tetramethyl tin (2.0 g, 11.2 mmol), and palladium tetrakis(triphenylphosphine) (0.28 g, 024 mmol) at 120° C. for 10 minutes at 300 watts. Subject the reaction mixture to gel chromatography to provide a quantitative yield of the title compound as a tan oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)#[N:12].[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>>[C:11]([C:13]1[CH:14]=[C:15]([CH:16]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:21][C:22]3=[CH:26][CH:25]=[N:24][N:23]23)[CH:18]=[CH:19][CH:20]=1)#[N:12]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: N#Cc1cccc(C=O)c1
Reactant: Nc1cc[nH]n1
Product: CC1(C)CCC2=C(C1=O)C(c1cccc(C#N)c1)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 3-cyanobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.[O:11]=[N+:12]=[O:13].F[B-](F)(F)F.CCCCCC>ClCCl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[C:4]([N+:12]([O-:13])=[O:11])[CH:3]=1
Reactant: O=[N+]=O
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: F[B-](F)(F)F
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1c([N+](=O)[O-])cc(Cl)c(O)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A solution of 6-chloro-2-fluoro-3-methylphenol (9.00 g, 56.1 mmol) in dichloromethane (100 ml) was added dropwise to a suspension of 85% nitronium•tetrafluoroborate (9.50 g, 60.8 mmol) in dichloromethane (150 ml) at 0 to 5° C. under ice-cooling. The resulting mixture was warmed up to room temperature and stirred for 2 hours while maintaining the temperature. The mixture was poured into ice water and then partitioned and extracted with chloroform, and the organic layer was washed with water, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. After the crude product was dissolved in toluene (57 ml) by heating to 80° C., the solution was allowed to cool to 60° C. and maintained at this temperature. Hexane (171 ml) was added dropwise thereto and the resulting mixture was allowed to cool to room temperature and then it was ice-cooled while maintaining temperature. Thereafter, the crystals formed were collected by filtration and dried to obtain 6-chloro-2-fluoro-3-methyl-4-nitrophenol (7.05 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-:12].[K+].[OH2:14].CC(O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:14])=[O:12])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: [OH-]
Reactant: Cc1cc(Cl)cc(CC#N)c1
Reactant: O
Agent: [K+]
Solvent: CC(C)O
Product: Cc1cc(Cl)cc(CC(=O)O)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture 3-chloro-5-methylphenylacetonitrile (13.3 g; from step (ii) above) and KOH (17 g; 0.3 mol) in 150 mL of water:i-PrOH (2:1) was heated while stirring in an autoclave at 120° C. overnight and then at room temperature for 2 days. The i-PrOH was evaporated and the remainder was acidified (6M HCl) to pH 2 and extracted 3 times with ether. The combined organic layers were washed twice with water, dried (Na2SO4), and evaporated to yield the sub-title compound (10.4 g; 70%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C[Sn](C)(C)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[BH4-].[Na+]>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: Brc1cccc2cnccc12
Reactant: C[Sn](C)(C)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Product: c1ccc(-c2cccc3c2CCNC3)nc1

Procedure:
In close analogy to the procedure described above, 5-Bromo-isoquinoline is reacted with 2-trimethylstannyl-pyridine and sodium borohydride to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[C:26](Cl)(=[O:28])[CH3:27]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:26](=[O:28])[CH3:27])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5](/[C:8](=[N:10]/[S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])=[CH:4][CH:3]=1.[CH3:17][Mg]Br.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])([CH3:17])[CH3:9])=[CH:4][CH:3]=1
Reactant: C/C(=N\S(=O)C(C)(C)C)c1ccc(Cl)nn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(NS(=O)C(C)(C)C)c1ccc(Cl)nn1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 24.7 %

Procedure:
Crude 2-methyl-propane-2-sulfinic acid[1-(6-chloro-pyridazin-3-yl)-eth-(E)-ylidene]-amide (56 mg, 0.22 mmol) was dissolved in dry THF (2.2 mL) and cooled to −20° C. under an atmosphere of inert gas. Methylmagnesium bromide (1.0 M in MePh/THF, 0.26 mL, 0.26 mmol) was added in one portion via syringe and the reaction was stirred −20° C. for 1.5 h. To the reaction mixture was added saturated aqueous NH4Cl (4 mL) and EtOAc (7 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4, concentrated and then purified by flash chromatography (silica, 0→4% MeOH/CH2Cl2). 15 mg of impure 2-methyl-propane-2-sulfinic acid[1-(6-chloro-pyridazin-3-yl)-1-methyl-ethyl]-amide was isolated as a light brown solid. This material was used without further purification.
Reaction SMILES: [CH2:1]([C:4]1([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15])[CH:2]=[CH2:3].C1(=O)C=CC(=[O:26])C=C1>CN(C=O)C.O.[Pd](Cl)Cl>[CH2:16]([C:4]1([CH2:1][C:2](=[O:26])[CH3:3])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15])[CH2:17][CH2:18][CH3:19]
Reactant: O=C1C=CC(=O)C=C1
Reactant: C=CCC1(CCCC)Cc2cc(OC)ccc2C1=O
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1(CC(C)=O)Cc2cc(OC)ccc2C1=O
Temperature: 65 °C
Reaction time: 3.83 h

Procedure:
A solution of 2-allyl-2-butyl-5-methoxy-1-indanone (253 mg, 0.98 mmol) in DMF (1.2 mL) was treated with benzoquinone (108 mg, 0.98 mmol), water (0.026 mL, 1.44 mmol), and palladium(II) chloride (36 mg, 0.2 mmol). The mixture was stirred and heated in an oil bath at 65° C. Additional water was added in 0.026 mL portions after 15, 45, and 130 minutes. After 230 minutes, the mixture was treated with more benzoquinone (10.9 mg, 0.1 mmol) and, after 285 minutes, with more water (0.026 mL). After heating at 65° C. for a total of 345 minutes, the mixture was diluted with water (50 ml) and extracted with Et2O (40 mL) followed by CH2Cl2 (2×50 mL). The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 12M (12 mm×15 cm) silica gel column, eluting with 10:1 hexane-EtOAc. The product-containing fractions were evaporated under vacuum to afford 2-butyl-5-methoxy-(2-oxopropyl)-1-indanone as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].[OH-:21].[K+].[OH-:23].C([N+:28]([CH2:37]CCC)([CH2:33][CH2:34]CC)CCCC)CCC>BrCCBr>[C:5]([O:21][C:37]([NH:28][CH2:33][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20])=[O:23])([CH3:8])([CH3:6])[CH3:4]
Reactant: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1O
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: [OH-]
Agent: [K+]
Solvent: BrCCBr
Product: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1OCCNC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A mixture of Intermediate 1 (8.4 g), 1,2-dibromethane (160 ml), 40% aqueous potassium hydroxide solution (45 ml) and 40% aqueous tetrabutylammonium hydroxide solution (4.5 ml) is heated with stirring at 40° C. for 18 hours. The reaction solution is washed with water, and the organic layer is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is dissolved in dimethylformamide (45 ml), and thereto is added potassium phthalimide (1.9 g). The mixture is stirred at 50° C. for 18 hours. The reaction solution is poured into ice-water, and the mixture is extracted with chloroform. The extract is washed with water, and the solvent is evaporated under reduced pressure. The residue is dissolved in ethanol (50 ml), and thereto is added hydrazine monohydrate (600 mg), and heated under reflux for 3 hours. The insoluble materials are removed by filtration, and the filtrate is concentrated, extracted with chloroform, washed with water, and the solvent is evaporated under reduced pressure. The residue is dissolved in chloroform (50 ml) and thereto is added di-tert-butyl dicarbonate (4.3 g). The mixture is stirred at 25° C. for 18 hours, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (5.2 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:36])[C@@H:10]([NH:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[C:27]=1[CH3:35])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[N:14][N:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)Cl.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[O:12][C:11]([C@H:10]([NH:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[C:27]=3[CH3:35])[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH3:36])=[N:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc([N+](=O)[O-])cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: [Pd]
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Yield: 92.8 %

Procedure:
A suspension of 4-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (1.6 g, 3.03 mmol), 5 wt. % Pd on activated carbon (700 mg) in CH2Cl2 (50 mL) was pressurized with 30 psi of H2 and reacted on a Parr shaker for 5 h. The reaction was filtered through Celite® under N2 and rinsed with CH2Cl2 (3×40 mL). The filtrate was concentrated under reduced pressure to provide a colourless solid (1.40 g, 93%): 1H NMR (400 MHz, CDCl3, δ in ppm) 7.76 (dm, J=8.8 Hz, 2H), 7.34 (d, J=8.6 Hz, 1H), 6.70 (dm, J=8.8 Hz, 2H), 6.62 (d, J=8.6 Hz, 1H), 5.11 (d, J=9.0 Hz, 1H), 4.79 (dd, J=3.9, 8.8 Hz, 1H), 4.41 (dq, J=3.9, 6.3 Hz, 1H), 4.05 (s, 2H), 2.32 (s, 3H), 1.28 (d, J=6.3 Hz, 3H), 0.93 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:13])=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(Nc2ccncc2)c1
Reactant: C1CCNCC1
Product: O=C(c1cccc(Nc2ccncc2)c1)N1CCCCC1

Procedure:
1-[3-(4-Pyridinylamino)benzoyl]piperidine was prepared from 3-(4-pyridinylamino)benzoic acid and piperidine according to a procedure analogous to that of Example 48(b), and was obtained in the form of its hydrochloride salt, colorless powder, m.p. 224°-226° C. when recrystallized from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[N:23]1[CH2:32][C:31]2[C:26](=[N:27][C:28](S(C)(=O)=O)=[N:29][CH:30]=2)[N:25]([CH3:37])[C:24]1=[O:38].[NH3:39]>O1CCCC1>[NH2:39][C:28]1[N:27]=[C:26]2[N:25]([CH3:37])[C:24](=[O:38])[N:23]([C:3]3[CH:4]=[C:5]([NH:8][C:9]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:13][CH:12]=4)=[O:10])[CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:32][C:31]2=[CH:30][N:29]=1
Reactant: N
Reactant: CN1C(=O)N(c2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2Cl)Cc2cnc(N)nc21
Reaction time: 2 h
Yield: 31 %

Procedure:
0.079 g Biphenyl-4-carboxylic acid[4-chloro-3-(7-methanesulfonyl-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-amide were dissolved in 10 mL tetrahydrofuran. 10 mL of liquid ammonia were added in an autoclave and the reaction mixture was stirred for 2 h. The organic solvent was evaporated, and the crude product was purified by reverse phase chromatography (acetonitrile/water with 1% acetic acid) to give the title product in 31% yield.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3]1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[Na+].C(=O)(O)[O-].[Na+]>CCOCC.CO.C(Cl)Cl>[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3]1
Reactant: CCOC(=O)CCCCCCC1=CC(O)CC1=O
Reactant: C1=COCCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCCCCCC1=CC(OC2CCCCO2)CC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 674 mg. (2.64 mmoles) of 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 29) and 2.22 g. (26.4 mmoles) of dihydropyran in 2.6 ml. of methylene chloride is added 5.0 mg. (0.026 mmoles) of p-toluenesulonic acid monohydrate. After stirring for 20 minutes at room temperature the solution is diluted with ether and poured into saturated sodium chloride solution containing a little sodium bicarbonate. The organic phase is separated and washed with saturated sodium chloride solution. The extract is dried over magnesium sulfate, and volatile matter is evaporated at reduced pressure to give an oil, λmax.MeOH = 224 mμ (7950); θmax. = 1735 (ester carbonyl group), 1710 (ketone carbonyl group), and 1030 cm-1 (tetrahydropyranyloxy group).