Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=3)[C:13]([O:15][CH3:16])=[O:14])[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(C)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-2-methylbenzoate obtained in Example (172b) (26.3 mg, 0.09 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (15 mg, 0.09 mmol), WSC hydrochloride (49.4 mg, 0.26 mmol) and HOBt (11.6 mg, 0.09 mmol), to obtain 33.0 mg of the title compound as a pale yellow oily substance (88%).
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[ClH:24]>>[ClH:24].[CH2:20]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)O)cc1
Temperature: 0 °C
Yield: 85.7 %

Procedure:
A mixture of methyl 4-(3-dibutylaminopropoxy)benzoate [18a] (7.65 g, 23.8 mmol) and 32% hydrochloric acid (30 mL) was stirred for 5 hours under reflux conditions and for one hour at 0-5° C. (ice/water bath). The suspension was filtered. The precipitated crystals were washed on the filter with water and hexane and dried under reduced pressure at 50-60° C. (water bath) to give 6.90 g (85.7%) of 4-(3-dibutylaminopropoxy)benzoic acid hydrochloride [19a] as white crystals with mp 157-159° C.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([CH:7]=[CH:8][C:1]=1[O:9][CH3:10])[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: COc1ccccc1OC
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(-c3ccccc3)cc2)cc1OC
Temperature: 0 °C

Procedure:
300 g of veratrole was added dropwise over a period of 30 minutes to a suspension of 300 g of aluminum chloride in 300 ml of methylene chloride, taking care that the internal temperature did not exceed 30° C. Then, 450 g of biphenyl-4-carboxylic acid chloride were added in portions over a period of 30 minutes, while stirring and cooling (internal temperature 20°-25° C.). The resulting mixture was stirred for 4 hours at room temperature and was then poured into a mixture of 2 kg of ice/500 ml of concentrated hydrochloric acid. After the organic phase had been separated, the aqueous phase was extracted twice more with methylene chloride.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]([CH2:14][OH:15])[CH:11]([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[CH3:12][CH:11]([CH3:13])[C@H:10]([N:9]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:14][OH:15]
Reactant: CC(C)[C@H](N)CO
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)[C@@H](CO)N=Cc1ccccc1

Procedure:
2.64 ml (2.78 g, 26.16 mmol) of benzaldehyde were added to a stirred solution of 2.57 g (24.91 mmol) of L-valinol in 28 ml of toluene, and the mixture was heated under reflux with a water trap for one hour. Cooling was followed by concentration and recrystallization from heptane. The colorless solid was filtered off with suction and dried under reduced pressure (3.74 g).
Reaction SMILES: [Cl:1][CH:2](Cl)[B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1.[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>O1CCCC1>[Cl:1][CH:2]([B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1)[CH2:15][CH:14]=[CH2:13]
Reactant: C=CC[Mg]Br
Reactant: CC1(C)OB(C(Cl)Cl)OC1(C)C
Solvent: C1CCOC1
Product: C=CCC(Cl)B1OC(C)(C)C(C)(C)O1
Temperature: -78 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
2 g (9.48 mmol) of 2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were dissolved in 30 ml of tetrahydrofuran and the solution was cooled under a nitrogen atmosphere to -78° C. 9.5 ml (9.5 mmol) of 1M allylmagnesium bromide were added dropwise and the solution was stirred at room temperature for 18 hours. The solution was partitioned between ethyl acetate, saturated sodium chloride solution and 2M hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulphate. After filtration and evaporation the oil obtained was distilled to give 1.45 g of 2-(1(RS)-chloro-3-butenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; b.p. 53° C./0.4 mm Hg.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Cl:7].[Mg].II.BrCBr.[Br-].[Li+].[F:16][C@H:17]1[CH2:34][C@@:32]2([CH3:33])[C@@H:28]([CH2:29][CH2:30][C:31]2=[O:35])[C@H:27]2[C@H:18]1[C@@H:19]1[C:24]([CH:25]=[CH:26]2)=[CH:23][C:22](=[O:36])[CH2:21][CH2:20]1>C1COCC1.CN1CCCN(C)C1=O.C[Si](C)(C)Cl.[Cu]I.C(O)(=O)C>[Cl:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C@@H:26]1[CH2:25][C:24]2[C@H:19]([CH2:20][CH2:21][C:22](=[O:36])[CH:23]=2)[C@@H:18]2[C@@H:27]1[C@H:28]1[C@@:32]([CH2:34][C@@H:17]2[F:16])([CH3:33])[C:31](=[O:35])[CH2:30][CH2:29]1
Reactant: ClCCCCCBr
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: II
Solvent: CC(=O)O
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
First, 20% of a solution of 39 ml of 1-bromo-5-chloropentane in 300 ml of THF is added to a suspension of 7.2 g of magnesium chips in 100 ml of THF under nitrogen. After the reaction starts, which can be achieved by adding iodine and dibromomethane, the remaining solution is added in drops in such a way that the internal temperature does not exceed 35° C. In a second flask, 51.2 g of lithium bromide is added to a suspension of 28.1 g of copper(I) iodide in 130 ml of THF at 0° C., whereby the internal temperature climbs to 40° C. Without cooling, 49.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one is now added and stirred for 15 minutes at 40° C. A clear solution is obtained, which is added in drops to the Grignard solution that is cooled to -50° C. Then, it is stirred for 15 more minutes at -30° C. and mixed at -70° C. drop by drop with a solution of 25 g of 11β-fluoro-estra-4,6-diene-3,17-dione in 260 ml of THF, 26 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 59 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed -65° C. It is stirred for 30 minutes cold, then 34.7 ml of glacial acetic acid is added in drops, the cooling bath is removed, and it is stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.51 of water, diluted with the same amount of ethyl acetate, the precipitate is separated on Celite, rewashed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 22.1 g of 7α-(5-chloropentyl)-11β-fluoro-estr-4-ene-3,17-dione is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].C1OCCOCCOCCOCCOCCOC1.CC([O-])(C)C.[K+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CCOCC>[CH2:36]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(=O)c1ccc[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)C(=O)c1cccn1Cc1ccccc1
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
A suspension of 10 g (65 mmol) of methyl pyrrol-2-ylglyoxylate in 100 ml of ether is added to a solution of 1.7 g (6.5 mol) of 18-crown-6 with 7.3 g (65 mmol) of potassium tert-butylate in 100 ml of ether, stirring is carried out for 30 minutes and 11.1 g (65 mmol) of benzyl bromide in 50 ml of ether are then added dropwise. Stirring is carried out overnight at room temperature, the mixture is poured onto water and extracted with ether and the organic phase is dried and evaporated down. Chromatography over silica gel with hexane/ethyl acetate gives 6.7 g (42%) of the title compound as a reddish brown oi.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([Cl:20])[CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O>C(O)C.[OH-].[Na+]>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:2]([C:7]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([Cl:20])[CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Yield: 3.5 %

Procedure:
A mixture of 3.0 g of methyl 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoate in 75 ml of absolute ethanol and 2.0 ml of 10N sodium hydroxide is heated on a steam bath for 3 hours. Water is added to obtain a solution which is extracted with methylene chloride. The aqueous phase is acidified with acetic acid and the resulting solid collected and dried in vacuo at 80° C. to give 0.1 g of the desired product as a crystalline solid, m.p. 217°-219° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:46][CH2:45][C:44]3([CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[C:43]2=[O:52])=[C:38]([CH3:53])[CH:37]=1.CC(C)([O-])C.[Na+].[NH:60]1[CH2:65][CH2:64][CH:63]([OH:66])[CH2:62][CH2:61]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:66][CH:63]1[CH2:64][CH2:65][N:60]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:46][CH2:45][C:44]4([CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[C:43]3=[O:52])=[C:38]([CH3:53])[CH:37]=2)[CH2:61][CH2:62]1
Reactant: Cc1cc(Br)ccc1N1CCC2(CCOCC2)C1=O
Reactant: OC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: Cc1cc(N2CCC(O)CC2)ccc1N1CCC2(CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.2 %

Procedure:
An 25-mL round bottom flask containing a stir bar was charged with Pd2(dba)3 (00.01 equiv., 0.0154 mmol, 14 mg.), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 1 (0.05 equiv., 0.077 mmol, 36.7 mg), 2-(4-bromo-2-methyl-phenyl)-8-oxa-aza-spiro[4.5]decan-1-one (0.50 g, 1.54 mmol, 1 equiv.), and sodium t-butoxide (2.5 equiv., 3.85 mmol, 370 mg.), and piperidin-4-ol (1.5 equiv., 2.3 mmol, 234 mg). The vial was capped with a rubber septum, evacuated and backfilled with N2. To this vial was introduced 8 mL of anhydrous toluene. The reaction was heated in an oil bath set at 90° C. for 2 h, allowed to cool down to room temperature and quenched with water (2 mL). The two layers were separated and the aqueous layer was extracted with DCM (3×10 mL). The combined DCM extracts were washed with sodium bicarbonate (50 mL), and brine (50 mL), dried (anhydrous potassium carbonate), filtered, and concentrated. The crude product was purified by a silica gel column to give 75.1 mg (14% yield) of the title compound as a light yellow solid after standing.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27]I>>[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[C:10]([OH:12])=[O:11]
Reactant: ClCCCCI
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: N#Cc1ccc(C(CCCCCl)C(=O)O)cc1
Yield: 71.6 %

Procedure:
Step AU (1): 2-(4-Cyanophenyl)acetic acid (5.0 g, 31.0 mmol) was deprotonated with NaHMDS (2.0 M in THF, 46.5 mL, 93 mmol) and reacted with 1-chloro-4-iodobutane (10.2 g, 46.5 mmol) using a procedure analogous to Step AC (1) to afford, after purification by silica gel column chromatography, 6-chloro-2-(4-cyanophenyl)hexanoic acid (5.59 g, 22.2 mmol, 72% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH2:13]([NH2:15])[CH3:14].CO.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:15][CH2:13][CH3:14]
Reactant: CCN
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCNCc1cccc([N+](=O)[O-])c1C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
A mixture of 2-methyl-3-nitrobenzylchloride (0.50 g, 2.7 mmol) and ethylamine (2.76 g, 61.2 mmol) in THF (10 ml)/MeOH (5 ml) was stirred at ambiend temperature for 48 h. The solvent was reduced and the recidue was dissolved in EtOAc/aq. K2CO3 solution. The aqueous phase was extracted with EtOAc (×2). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to give the title compound 0.46 g (86%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[N:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([O:31]C)=[O:30])[O:17][N:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[N:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([OH:31])=[O:30])[O:17][N:16]=1
Reactant: COC(=O)Cc1ccccc1OCc1nc(CCc2nc(-c3ccccc3)oc2C)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCc1noc(COc2ccccc2CC(=O)O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a mixture of methyl 2-[2-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]acetate (0.30 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.22 g, 76%) of 2-[2-[[3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-1,2,4-oxadiazol-5-yl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:23]2[CH:24]=[CH:25][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: CN(C)c1ccc(-c2ccc(S(=O)(=O)NCCCCCO)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 4-dimethylaminophenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 22.7, 28.9, 32.0, 39.9, 42.6, 60.5, 112.6, 125.5, 125.8, 127.1, 127.8, 137.5, 143.9 and 150.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[C:35]1[N:39]([CH3:40])[N:38]=[CH:37][CH:36]=1)[C:5]([NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:31])([F:30])[F:29])[CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)=[O:6].NN>CO.C1COCC1>[NH2:10][CH2:9][C@@H:8]([NH:7][C:5](=[O:6])[C:4]1[CH:32]=[CH:33][C:34]([C:35]2[N:39]([CH3:40])[N:38]=[CH:37][CH:36]=2)=[C:2]([Br:1])[CH:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:31])([F:30])[F:29]
Reactant: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1Br
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1ccc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.8 %

Procedure:
To a solution of 3-bromo-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)benzamide (172 mg, 0.28 mmol) in MeOH/THF (4 mL, 1:1) at RT was added hydrazine (0.17 mL, 5.5 mmol). After stirring for 18 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound (60.4 mg, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(CC)CC)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: O=S(=O)(CCCCCCBr)NC1CC1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Solvent: CCN(CC)CC
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 94.1 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (458.6 mg, 1.60 mmol) and N-cyclopropyl-6-bromohexanesulfonamide (500 mg, 1.76 mmol) were refluxed in triethylamine (2 ml) for 4 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (737.8 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 94.1%).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][C:26](=O)[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1>C(O)(=O)C>[F:1][C:2]1([F:30])[CH2:3][CH2:4][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][CH:26]([N:32]5[CH2:35][CH2:34][CH2:33]5)[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:6][CH2:7]1
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Reactant: C1CNC1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCC(N4CCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 133 using 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexyl methyl)-amide, and azetidine hydrochloride in glacial acetic acid. 1H NMR (400 MHz, DMSO-d6): δ 8.76 (t, J=6.0 Hz, 1H), 8.11-8.06 (m, 1H), 7.97-7.94 (m, 1H), 7.76-7.73 (m, 1H), 7.64-7.54 (m, 1H), 4.71 (s, 1H), 3.47-3.16 (m, 1H), 3.07-2.49 (m, 4H), 2.23-2.02 (m, 1H), 2.01-1.95 (m, 6H), 1.90 (s, 6H), 1.64-1.59 (m, 8H. m/z: 478.3 [M+H]+
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:29])=[C:5]([C:20]([O:27]C)=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][C:17](=[O:19])[CH3:18])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:24][O:23][C:22]1[C:3](=[O:2])[C:4]([CH3:29])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][C:17](=[O:19])[CH3:18])=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:20](=[O:27])[C:21]=1[O:25][CH3:26]
Reactant: COc1c(C)c(Cc2ccc(OC(C)=O)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Yield: 85.9 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-acetoxybenzoic acid (0.200 g, 0.495 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (0.678 g, 1.24 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.160 g, 0.425 mmol, 86%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:26])([C:21]1[N:25]=[CH:24][O:23][N:22]=1)[CH3:20]>>[CH3:18][C:19]([NH:26][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[N:25]=[CH:24][O:23][N:22]=1)[CH3:20]
Reactant: CC(C)(N)c1ncon1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ncon1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 1-methyl-1-[1,2,4]oxadiazol-3-yl-ethylamine (CAN 1153757-41-5) as starting materials, MS (LC/MS): 343.1 (M+H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9](O)(=[O:11])[CH3:10]>Br>[OH:2][C:1]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cccc(O)c1
Reactant: CC(=O)O
Agent: Br
Product: CC(=O)c1ccc(O)cc1O
Temperature: 80 °C

Procedure:
In a procedure similar to Example 1, resorcinol (0.55 g, 5.0 mmol) was dissolved in 20% hydrogen bromide in glacial acetic acid (40 g, 99 mmol of HBr, made by bubbling hydrogen bromide gas through glacial acetic acid) and the mixture was heated to 80° C. for 5.5 hours. Isolation of the product as in Example 1 yielded the title product, with the same n.m.r. data as in Example 1.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:10]=[C:9]([CH2:11][N:12]2[CH2:16][CH2:15][N:14]([C@@H:17]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([O:20]C(C)(C)C)=[O:19])[C:13]2=[O:29])[CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].FC(F)(F)C(O)=O>O>[OH:1][C:2]([C:5]1[N:10]=[C:9]([CH2:11][N:12]2[CH2:16][CH2:15][N:14]([C@@H:17]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([OH:20])=[O:19])[C:13]2=[O:29])[CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2cccc(C(C)(C)O)n2)C1=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(O)c1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 224.2 %

Procedure:
The product of Example 50-5 (61 g, 150.6 mmol) at 25° C. was treated with 90% trifluoroacetic acid in water (300 mL). The reaction was stirred at 25° C. for 5 hours and concentrated to give 118 g of residue. The residue was loaded on 600 g of silica gel, eluted with 4 L of 5% methanol in dichloromethane, then with 4 L of 10% methanol in dichloromethane. The desired fractions were combined and concentrated to give 100 g of crude material. The crude material was crystallized from diethyl ether (350 mL) to afford 54 g of the trifluoroacetic acid salt of the title compound, 77% yield. 1H NMR (CDCl3): δ ppm 1.10 (s, 9 H,) 1.63 (s, 6 H), 3.48 (m, 2 H), 3.65 (m, 1 H), 3.87 (m, 1H), 4.33 (s, 1 H), 4.78 (q, 2 H), 7.54 (d, 1 H), 7.61 (d, 1 H), 8.12 (t, 1 H), 9.2(w, 3H).