Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C([C:19]1[C:20]([N:26]=[CH:27][N:28]([CH3:30])C)=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=1)#N>C(O)(=O)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[C:2]([NH:1][C:30]2[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[N:21][C:20]=3[N:26]=[CH:27][N:28]=2)[CH:7]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(Br)ccc1Sc1ccc(O)cc1
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc(Br)ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 130 °C
Yield: 35.4 %

Procedure:
A mixture of the product from Example 238B (0.158 g, 0.533 mmol) and the product from Example 10B (0.100 g, 0.533 mmol) in glacial acetic acid (2 mL) was heated in a 130° C. oil bath for 30 min. An additional amount of the product from Example 10B (0.060 g, 0.319 mmol) was added and the reaction mixture was heated for an additional 30 min at 130° C. The reaction mixture was then cooled to room temperature and the solvent evaporated under reduced pressure. The residue was triturated with 2-propanol, and the resulting solid isolated by vacuum filtration and dried to provide the title compound (0.083 g, 36% yield) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C@H:7]([C:25]([OH:27])=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])=[CH:11][CH:10]=1)=[O:5].C(Cl)(=O)C([Cl:36])=O.CN(C=O)C>C1COCC1>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C@H:7]([C:25]([Cl:36])=[O:27])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])=[CH:11][CH:10]=1)=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine (0.1 g) in THF (5 mL) at 0° C. under N2 was added oxalyl chloride (0.055 mL) followed by a drop of DMF. The solution was stirred at 0° C. for 2 h followed by stirring at room temperature for 2 h. THF was evaporated and fresh THF (5 mL) was added and the solution was evaporated again. This process was repeated one more time and the residue was dried under vacuum to yield N(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanyl chloride.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Cl)[CH:6]=1)=[O:3].C[C:13]([CH3:16])([O-])[CH3:14].[Na+]>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].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH2:5]([N:4]([CH2:2][CH2:14][CH2:13][CH3:16])[C:7]1[CH:6]=[C:5]([NH:4][C:2](=[O:3])[CH3:1])[CH:10]=[CH:9][CH:8]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)Nc1cccc(Cl)c1
Reactant: CC(C)(C)[O-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCCN(CCCC)c1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 161.6 %

Procedure:
An oven-dried resealable schlenk tube containing a stir bar was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (11.9 mg, 0.025 mmol), 3-chloroacetanilide (85 mg, 0.5 mmol) and sodium tbutoxide (120 mg, 1.25 mmol). The tube was capped with a rubber septum, evacuated and backfilled with argon. Dinbutylamine (126 μL, 0.75 mmol) and tbutanol (1 mL) were added through the septum via syringe. The septum was replaced with a Teflon screw cap. The schlenk tube was sealed and put into a pre-heated oil bath at 90° C. The reaction mixture was stirred for 18 h, allowed to cool down to room temperature and quenched with water. Extraction with ethyl acetate three times followed by chromatography on silica gel column with 4:1 hexane:ethyl acetate gave 106 mg (81%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=1)[C:9]([O:11]C)=[O:10].[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COCCCc1cc(CCCOC)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCCc1cc(CCCOC)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 3,5-bis(3-methoxypropyl)benzoate (1 eq.) from the previous step in THF/MeOH (2:1 v/v, 0.1 M) was added 2 M aqueous NaOH (2 eq.). After stirring at rt for 72 h, the reaction was diluted with EtOAc. The organic extract was washed with 10% aqueous HCl solution, brine, dried over MgSO4, and concentrated in vacuo to afford the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][CH2:14]O.N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:31])(=O)=O.[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][CH2:14][Cl:31]
Reactant: OCC=Cc1ccc2ccccc2c1Br
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: ClCC=Cc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.4 %

Procedure:
A solution of Example 3C (0.85 g, 3.24 mmol), collidine (0.94 mL, 7.13 mmol) and lithium chloride (0.21 g, 4.97 mmol) in DMF (10 mL) at 0° C. was treated with methanesulfonyl chloride (0.38 mL, 4.87 mmol), stirred 16 hours at room temperature, poured into aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate was washed with water, brine, dried (MgSO4), filtered, concentrated, and purified on silica gel with 3% ethyl acetate/hexanes to provide 0.35 g (38%) of the desired compound.
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]([CH3:23])([CH2:10][C:11](=[O:22])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][NH:7][CH:8]=[O:9]>[Pt]=S>[Cl-:1].[CH3:23][N+:3]([CH3:2])([CH2:10][C:11](=[O:22])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][NH:7][CH:8]=[O:9]
Reactant: C[N+](C)(CCCNC=O)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: S=[Pt]
Agent: [Cl-]
Product: C[N+](C)(CCCNC=O)CC(=O)Nc1ccc(N)cc1

Procedure:
Following the procedure described in 1c above, N,N-dimethyl-N-(4-nitrophenyl)carbamylmethyl-N-3-formamidopropylammonium chloride was catalytically hydrogenated in aqueous solution at 70°-75°C. and at 600 pounds per square inch in the presence of a 5 per cent platinum sulfide on charcoal mixture to obtain N,N-dimethyl-N-(4-aminophenyl)carbamylmethyl-N-3-formamidopropylammonium chloride.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH3:13]I>CS(C)=O>[OH:10][C:9]1[C:2]([O:1][CH3:13])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(O)cccc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3-dihydroxybenzaldehyde (20.0 g) in dimethylsulfoxide (80 ml) was added sodium hydride (5.79 g), and the mixture was stirred at room temperature for 1 hr. Methyl iodide (9.0 ml) was added, and the mixture was further stirred at room temperature for 20 hrs. The obtained reaction mixture was partitioned between ethyl acetate (1000 ml) and water (500 ml). The aqueous layer was further extracted with ethyl acetate (1000 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and crystallized from diisopropyl ether and hexane to give 3-hydroxy-2-methoxybenzaldehyde (11.5 g) as pale-brown crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1CC1C=CC=CC=1.[ClH:18]>CO>[ClH:18].[CH3:1][N:2]([CH3:17])[CH2:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1
Reactant: CN(C)C[C@@H]1CCCCN1Cc1ccccc1
Agent: Cl
Solvent: CO
Product: CN(C)C[C@@H]1CCCCN1
Yield: 93.7 %

Procedure:
N,N-Dimethyl-1-[(2S)-1-(phenylmethyl)-2-piperidinyl]methanamine (590 mg, 2.539 mmol) was dissolved in a mixture of MeOH (20 mL) and 1N HCl (5.5 mL, 5.5 mmol), degassed and placed under argon. 10% Pd/C (117 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for 2 h. The contents were then degassed, and the Pd/C was removed by filtration through a fiberglass filter, washing with MeOH. The filtrate was concentrated in vacuo to provide pure N,N-dimethyl-1-[(2S)-2-piperidinyl]methanamine hydrochloride (425 mg, 78%). LCMS: (M+H)+: not detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH:18]2[O:33][CH2:34][C:35]#[CH:36])=[CH:13][CH:12]=1.I[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH:48][S:49]([CH3:52])(=[O:51])=[O:50].O>CN(C)C=O.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:52][S:49]([N:48]1[C:43]2[C:42](=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:36]=[C:35]1[CH2:34][O:33][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:37]=[CH:38][CH:39]=[CH:40][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19]1)(=[O:51])=[O:50]
Reactant: C#CCOC1CN(C(=O)OCc2ccccc2)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Reactant: CS(=O)(=O)Nc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cc3ccccc3n2S(C)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
The solution of 0.108 g of benzyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-prop-2-ynyloxypiperidine-1-carboxylate, 0.098 g of N-(2-iodophenyl)methanesulphonamide in 0.5 ml of N,N-dimethylformamide and 1.0 ml of triethylamine are admixed with stirring with 0.011 g of bis(triphenylphosphine)palladium(II) chloride and 0.005 g of copper(I) iodide. The reaction mixture is stirred at 80° C. over 20 hours, then cooled, admixed with water (5 ml) and extracted with ethyl acetate (3×5 ml). The organic phases are washed with brine (1×5 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.13 (1:2 EtOAc-heptane); Rt=6.07.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8][C:7]=1[O:17][CH:18]([CH2:21][CH2:22][N:23]=[N+]=[N-])[CH2:19][CH3:20])=[O:5])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][CH2:8][C:7]=1[O:17][CH:18]([CH2:21][CH2:22][NH2:23])[CH2:19][CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(OC(CC)CCN=[N+]=[N-])CCC(OS(C)(=O)=O)C1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1=C(OC(CC)CCN)CCC(OS(C)(=O)=O)C1
Reaction time: 24 h

Procedure:
(3R,4S,5R)-4-(diethoxy-phosphorylamino)-3-({1-(2-azido-ethyl}-propoxy)-5-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester (46) and Lindlar catalyst in ethanol was added. The flask was charged with hydrogen gas (1 atm) at room temperature. The resulting suspension was vigorously stirred for 24 hours. The reaction mixture was diluted with dichloro methane and the combined organic layers were filtered through a Celite pad. The combined organic phases were dried over Na2SO4 and the combined organic phases were evaporated in a rotary evaporator to yield the (3R,4S,5R)-4-(diethoxy-phosphorylamino)-3-({1-(2-amino-ethyl}-propoxy)-5-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester as a pale yellow liquid, which was used without further purification in the next step. (3R,4S,5R)-4-(diethoxy-phosphorylamino)-3-({1-(2-amino-ethyl}-propoxy)-5-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester was coupled with Fmoc-PEG-acid (16 atoms) in the presence of EDC, HOBT plus DIPEA in dichloro methane. The solution was stirred over a period of 18 hours the room temperature. The crude product was purified by a silica column chromatography using a 8:2 mixture of dichloro methane and hexane. The combined fractions were evaporated and dried over Na2SO4 and the combined organic phases were evaporated on a rotary evaporator to obtain as (3R,4S,5R)-4-(diethoxy-phosphorylamino)-3-({1-(2-Fmoc-Peg-amide-ethyl}-propoxy)-5-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester (47).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@H:6]([O:13][C:14]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48]>O1CCCC1.C(O)C>[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48].[NH2:1][CH2:4][CH2:5][C@@H:6]([O:13][C:14]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1O[C@H](CCN=[N+]=[N-])c1ccccc1
Agent: O=C(O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(F)(F)F)cc1O[C@H](CCN)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
A solution of 2-[[(1R)-3-azido-1-phenylpropyl]oxy]-4-(trifluoromethyl)benzonitrile (7.70 mg, 2.2 mmol) in tetrahydrofuran (50 ml) was treated with triphenylphosphine (1.5 eq.) and water (0.5 ml). The mixture was stirred at ambient temperature for 24 h then concentrated to an oil. The crude amine was purified on silica gel eluting with ethyl acetate, then 10% 7N ammonia in methanol/dichloromethane. The oil obtained was converted into an oxalate salt using 1 equivalent of oxalic acid in ethanol to afford the title compound as a colourless solid (510 mg, 56%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][C:9]([CH3:17])=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].[N+:19]([O-])([OH:21])=[O:20].O>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][C:9]([CH3:17])=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)[nH]c(=O)c1C(=O)OCC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)c1c([N+](=O)[O-])c(C)[nH]c(=O)c1C(=O)OCC
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
In 13 ml of acetic anhydride was suspended 5.0 g of 3,4-diethyoxycarbonyl-6-methyl-2-pyridone, and the suspension was cooled to -10° C., whereto 1.22 ml (2.1 eq.) of fuming nitric acid was added dropwise over 30 minutes. The mixture was stirred for 30 minutes. After 40 ml of water was added, the mixture was stirred overnight at room temperature. The resulting crystals were collected by filtration and dried.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O-]CC.[Na+].[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)=[CH2:15]>C(O)C>[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:18][CH:17]=1)=[CH2:15]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C=Cc1ccc(CC(C(C)=O)C(=O)OCC)cc1
Yield: 95 %

Procedure:
Ethyl acetoacetate (27.61 g, 0.21 mol) was dissolved in ethanol (100 ml) which was cooled in an ice-water bath, and sodium ethoxide (15.59 g, 0.22 mol) was added. 4-Vinylbenzyl chloride (33.92 g, 0.2 mole) was added. The mixture was refluxed for 16 hours, then the resulting slurry was filtered to remove any salt, and the solution collected. The solvent was removed under reduced pressure to give ethyl 2-(4-vinylbenzyl)-3-oxobutanoate in the form of a light red liquid (49 g) in 95% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[OH:12].[CH2:13]([O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([C:34](Cl)=[O:35])[CH:28]=[CH:27]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O1CCOCC1.N1C=CC=CC=1>O>[CH2:13]([O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([C:34]([NH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[OH:12])=[O:35])[CH:28]=[CH:27]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)Cl)ccc2c1
Reactant: CCCCc1ccc(O)c(N)c1
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCOc1ccc2cc(C(=O)Nc3cc(CCCC)ccc3O)ccc2c1
Temperature: 75 °C
Yield: 86.8 %

Procedure:
In a 50 ml three-neck flask, 0.40 g (2.42 m mole) of 2-amino-4-butylphenol, 0.85 g (2.74 m mole) of 6-decyloxy-2-naphthoic acid chloride and 10 ml of dioxane were placed. To the mixture, 0.81 ml of pyridine was added dropwise under stirring at ca. 75° C. of mixture temperature. After the reaction, the reaction mixture was poured into 80 ml of water to precipitate a crystal. The crystal was filtered, washed with water and recrystallized from acetone to obtain 1.00 g of 2-(6-decyloxy-2-naphthoylamino)-4-butylphenol (Yield: 86.5%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C@@H:13]12[C:21](=[O:22])[O:20][CH2:19][C@@H:18]1[CH2:17][CH2:16][CH2:15][CH2:14]2.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([C@@:13]12[C:21](=[O:22])[O:20][CH2:19][C@@H:18]1[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1OC[C@@H]2CCCC[C@H]12
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1OC[C@@H]2CCCC[C@]12Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Under argon, a solution of diisopropylamine (3.85 ml, 27.5 mmol) in 20 ml of dry THF is cooled to 0° C. and slowly admixed with butyllithium (11 ml, 27.5 mmol, 2.5M in hexane). With ice-cooling. This solution is stirred for 15 min and then cooled to −78° C. and a solution of cis-8-oxabicyclo[4.3.0]nonan-9-one (3.5 g, 25 mmol) in 10 ml of THF is added dropwise. The mixture is stirred at −78° C. for another 30 min and then mixed with benzyl bromide (3.27 ml, 27 mmol). The mixture is then slowly warmed to room temperature and stirred for another 16 h. The solvent is removed and the residue is taken up in 20 ml of dichloromethane and washed 2× with in each case 20 ml of 2 M HCl. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is purified by column chromatography (mobile phase: cyclohexane:ethyl acetate 10:1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([CH2:15][O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC2CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CC(OCC2CC2)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.6 %

Procedure:
A reaction flask was charged with 4-cyclopropylmethoxypiperidine-1-carboxylic acid t-butyl ester (6.80 g, 26.6 mmol) in DCM (15 mL). TFA (7 mL) was added and the reaction was stirred at rt for 4 h. The reaction mixture was quenched with 1 M NaOH and the product extracted into diethyl ether. The combined organic phases were dried over Na2SO4, filtered, and concentrated to give the title compound (3.949 g, 95%). 1H NMR (CD3CD) d 3.34-3.24 (m, 1H), 3.15 (d, 2H), 2.88-2.82 (m, 2H), 2.44-2.37 (m, 2H), 1.78-1.70 (m, 2H), 1.31-1.21 (m, 2H), 0.89-0.79 (m, 1H), 0.37-0.32 (m, 2H), 0.04-0.00 (m, 2H); 13C NMR (CD3OD) d 76.2, 73.6, 44.7, 33.2, 11.7, 3.5.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>[Cl-].[Cl-].[Cl-].[Ti+3]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]([C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[CH3:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2CCN(C(C)c3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Cc1ccc(N2CCN(C(C)c3ccc(N)cc3)CC2)cc1

Procedure:
In the manner given in Example 1B, 1-(4-methylphenyl)-4-[1-(4-nitrophenyl)ethyl]piperazine is reduced with aqueous titanium trichloride to give 1-(4-methylphenyl)-4-[1-(p-aminophenyl)ethyl]piperazine.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>N1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][N:11]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(-c3ccccc3)cn2)cc1OC
Temperature: 25 °C
Reaction time: 19 h
Yield: 69 %

Procedure:
To a solution of 5-phenylpyridin-2-amine (340 mg, 2 mmol) in 10 mL of dry pyridine was added 3,4-dimethoxybenzenesulfonyl chloride (529 mg, 2.23 mmol). The solution was stirred at room temperature under Argon. After 19 h, the pyridine was removed in vacuo and flashed off with toluene, the solid residue was partitioned between EtOAc and 1M NaOH. The alkaline phase was made acidic and the solid was collected by filtration and dried in vacuo to give 511 mg of a solid. This was taken up in 5 mL of HOAc, diluted with 3 mL of water; crystallization took place to give 447 mg of a white crystalline product with mp 202-204° C.
Reaction SMILES: C(OC1C(C(O)=O)=NC=CC=1OC)C1C=CC=CC=1.C([O:27][C:28]1[C:29]([C:38]([OH:40])=O)=[N:30][C:31]([O:36][CH3:37])=[CH:32][C:33]=1[O:34][CH3:35])C1C=CC=CC=1.CO[C:43]1[CH:56]=[CH:55][C:46]([O:47][C:48]2[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=2)=[CH:45][CH:44]=1.O(C1C=CC(N)=CC=1)C1C=CC=CC=1>>[OH:27][C:28]1[C:29]([C:38]([NH:52][C:51]2[CH:50]=[CH:49][C:48]([O:47][C:46]3[CH:55]=[CH:56][CH:43]=[CH:44][CH:45]=3)=[CH:54][CH:53]=2)=[O:40])=[N:30][C:31]([O:36][CH3:37])=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(Oc2ccc(N)cc2)cc1
Reactant: COc1cc(OC)c(OCc2ccccc2)c(C(=O)O)n1
Agent: COc1ccnc(C(=O)O)c1OCc1ccccc1
Agent: Nc1ccc(Oc2ccccc2)cc1
Product: COc1cc(OC)c(O)c(C(=O)Nc2ccc(Oc3ccccc3)cc2)n1

Procedure:
The procedure of Example 29 was repeated, except that 3-benzyloxy-4-methoxypicolinic acid was changed to 3-benzyloxy-4,6-dimethoxypicolinic acid and 4-(4′-methoxyphenoxy)aniline was changed to 4-phenoxyaniline. Thus, the title compound was prepared.