Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:14])[O:13][CH2:12]2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Cl-].[Mg+2].[Cl-]>ClCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C2(C)CO2)cc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(C)C=O)cc1
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 38.0 g (0.2 mole) of 2-(4-isobutylphenyl)-1,2-epoxypropane in 130 ml of dichloromethane was added 2.67 g (0.028 mole) of anhydrous powdered (100 mesh, Tyler) magnesium chloride and 5.0 g (0.04 mole) of thionisole, and the mixture was refluxed with stirring for 3 hours. After cooling the reaction mixture, insoluble materials were filtered off and washed with small amount of dichloromethane and the washings were combined with the filtrate. The combined solution was washed with aqueous sodium chloride and subjected to distillation under atmospheric pressure to remove dichloromethane. The remaining residue was subjected to distillation under reduced pressure to obtain 36.8 g of 2-(4-isobutylphenyl)propionaldehyde distilled at 127°-129° C. (8 mmHg) as colorless oil. Yield; 96.8%, purity; above 99%.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].COC1CCCC1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C(=O)(O)[O-].[Na+]>[C:37]([O:39][CH:40]([N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:19][CH2:20][CH3:21])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:38])[CH3:36]
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC1CCCC1
Product: CCCN(CCC)CCCCN(Cc1ccc(C#N)cc1)C(OC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 18.3 %

Procedure:
In a 50 ml recovery flask, 0.462 g (1.61 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a) and 9.2 ml of cyclopentyl methyl ether were charged and dissolved under a nitrogen stream. After the addition of 0.666 g (4.82 mmol, 3.0 equivalents) of potassium carbonate and 0.736 g (3.21 mmol, 2.0 equivalents) of benzyl bromoacetate at room temperature, the mixture was stirred at room temperature for 19 hours. After confirming the disappearance of the raw material by TLC, the reaction solution was added to 100 ml of a saturated sodium bicarbonate aqueous solution, and was extracted twice with 100 ml of chloroform. The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (Chromatorex NH, n-hexane:ethyl acetate=4:1), thereby obtaining 0.128 g of [(4-cyanobenzyl)-(4-dipropylaminobutyl)amino]benzyl acetate (20) as a light yellow oily substance (yield: 18.3%). [HPLC: 97.8% (HPLC measurement conditions A)]
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]#[CH:5].[CH2:14](I)[CH3:15]>CN(C=O)C.O.C(OCC)C>[CH2:14]([N:6]([CH2:3][C:4]#[CH:5])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH3:15]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: C#CCN(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A suspension of sodium hydride (354 mg, 14.2 mmol) in DMF (33 mL) at room temperature was treated with a solution of Example 516A (2.0 g, 12.9 mmol) in DMF (10 mL) and stirred for one hour at room temperature. The solution was cooled to 0° C., treated with ethyl iodide (1.24 mL, 15.5 mmol), stirred for one hour at 0° and overnight at room temperature. The solution was diluted with water (25 mL),extracted with diethyl ether (2×50 mL) and the combined organic layers were washed with brine (30 mL0, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using 5–10% ethyl acetate/hexanes to give the 1.1 g (47% yield) of the desired product. MS (ESI(+)) m/e 184 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C=O)C.Cl>[ClH:1].[NH2:3][C:4]([CH:15]1[CH2:16][CH2:17][N:18]([C:28](=[O:30])[CH3:29])[CH2:19][CH2:20]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6]
Reactant: NC(CCCCB(O)O)(C(=O)O)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(N)(CCCCB(O)O)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52.9 %

Procedure:
To a stirring solution of crude 2-amino-6-borono-2-(piperidin-4-yl)hexanoic acid dihydrochloride (Example 26-A, Step 1, 250 mg, 0.618 mmol) in dry DMF (13 mL) under nitrogen was added triethylamine (0.69 mL, 4.95 mmol) to give a white slurry. The resultant slurry was treated with acetic anhydride (0.131 mL, 1.39 mmol), added dropwise, and the reaction mixture was stirred at room temperature for 2.5 h. The mixture was then diluted with ice water (10 mL) and 3 N HCl (5 mL) prior to extraction with ethyl acetate (2×25 mL). The aqueous layer was concentrated under reduced pressure to give the crude product which was purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column. 40 mL/min flow rate. Gradient: solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water; 2% A for 2 min, 2% to 20% A over 23 min, then 20% to 100% A over 1 min.] Product fractions were pooled and concentrated, and the residue was taken up in 0.25N HCl (3 mL)/acetonitrile (8 mL) and concentrated. The residue was once again treated with 0.25N HCl (3 mL)/acetonitrile (8 mL) and concentrated and dried under high vacuum overnight to give 2-amino-6-borono-2-[1-acetylpiperidin-4-yl]hexanoic acid hydrochloride (110 mg, 53%) as a white solid. 1H NMR (D2O, 400 MHz) δ 4.38 (bt, J=12 Hz, 1H), 3.92 (bt, J=12 Hz, 1H), 3.03 (m, 1H), 2.55 (m, 1H), 2.11 (m, 1H), 2.00 (s, 3H), 1.87-1.78 (m, 3H), 1.55 (m, 1H), 1.50-1.00 (m, 6H), 0.68 (t, J=7.2 Hz, 2H). ESI+ MS found for C13H25BN2O5 m/z 583.3 (2M−18+H), 565.6 (2M−2×18+H), 283.4 (M−18+H), 265.3 (M−2×18+H); ESI− MS m/z 581.6 (2M−18−H), 299.4 (M−H), 281.4 (M−18−H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:11]([CH2:12][C:13]=1[C:14]1[O:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][OH:22])[N:18]=1)[CH2:10][N:9]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:8]2)=[O:5])C.[OH-].[Na+].N1C=CN=C1.[CH3:45][C:46]([Si:49](Cl)([CH3:51])[CH3:50])([CH3:48])[CH3:47].[NH4+].[Cl-]>CCO.CN(C=O)C>[C:34]([O:33][C:31]([N:9]1[CH2:8][CH:7]2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:11]([CH2:12][C:13]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][O:22][Si:49]([C:46]([CH3:48])([CH3:47])[CH3:45])([CH3:51])[CH3:50])[N:18]=3)=[C:6]2[C:4]([OH:5])=[O:3])[CH2:10]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CCOC(=O)C1=C(c2nc(CCCO)co2)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO[Si](C)(C)C(C)(C)C)co3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
To a sol. of compound C4 (7.68 g, 14.7 mmol) in EtOH (80 mL) was added aq. 1M NaOH (80 mL). The reaction mixture was heated to 80° C. overnight. The mixture was partially concentrated under reduced pressure. The residue was acidified with aq. 3M HCl, and this aq. phase was extracted with EtOAc (5 mL). The organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. To a sol. of this crude product (6.5 g) in dry DMF (60 mL) was added imidazole (4.01 g, 58.9 mmol), and the mixture was cooled to 0° C. TBDMS-Cl (5.55 g, 36.8 mmol) was added, and the reaction mixture was stirred at rt for 2 h. Imidazole (1.5 g, 22.1 mmol) and TBDMS-Cl (2.23 g, 14.8 mmol) were added, and the mixture was stirred for 3 h. The reaction mixture was cooled to 0° C. (ice-water bath), and aq. sat. NH4Cl was slowly added. The resulting mixture was extracted with heptane/Et2O and the combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in a mixture of THF (60 mL), MeOH (20 mL) and water (20 mL). To this sol. was added K2CO3 (1.017 g). The mixture was stirred for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in TBME, and was washed with aq. sat. NH4Cl. The aq. layer was extracted with TBME. The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. Drying the residue under high vacuum yielded the title compound (10 g, quantitative) that was used without purification. LC-MS: tR=1.12 and 1.16 min; ES+: 608.32.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1.[I-].[K+].[CH3:30][CH:31]=[CH:32][CH2:33][NH2:34]>O1CCCC1>[F:26][C:2]([F:27])([F:1])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][NH:34][CH2:33][CH2:32][CH:31]=[CH2:30])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1
Reactant: CC=CCN
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 39, 8-(trifluoromethyl)-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and methylallylamine in tetrahydrofuran are reacted to give 8-(trifluoromethyl)-1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 44 8-Chloro-1-[(allylpropylamino)methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][NH2:10])=[O:8].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][NH:10][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([C:12]([F:11])([F:22])[F:23])=[CH:14][CH:15]=1)=[O:8]
Reactant: NNC(=O)c1sccc1Cl
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: O=C(NNC(=O)c1sccc1Cl)c1ccc(C(F)(F)F)cc1

Procedure:
Compounds of this invention with Formula VI may be prepared as illustrated by the exemplary reaction in Scheme 6. Reaction of 3-chloro-thiophene-2-carboxylic acid hydrazide with 4-trifluoromethylbenzoyl chloride produces N-(3-chloro-thiophene-2-carbonyl)-N′-(4-trifluoromethylbenzoyl)-hydrazine, followed by treating with thionyl chloride produces 5-(3-chloro-2-thienyl)-3-(4-trifluoromethylbenzoyl)-[1,3,4]-oxadiazole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.C(OCC)(=O)C>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1NC1CCNCC1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a solution of 4-(2-methoxyphenylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.7 g, 8.8 mmol) in methanol (30 mL) was added 4N hydrochloric acid in ethyl acetate (20 mL) at room temperature. After stirring for 1 h, the resulting suspension was concentrated in vacuo. The residue was partitioned between chloroform and 1N sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 10-20% methanol in chloroform to furnish 4-(2-methoxyphenylamino)-piperidine (1.8 g, 8.7 mmol, 99%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](OCC)=[O:11])=[CH:7][C:6]=2[CH:15]=1.[NH3:16]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH2:16])=[O:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: CCOC(=O)c1cc2cc(C)ccc2o1
Reactant: N
Solvent: CO
Product: Cc1ccc2oc(C(N)=O)cc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Ethyl 5-methylbenzofuran-2-carboxylate, (1.19 g, 5.83 mmol) was suspended in 20 ml of 7M NH3 in MeOH. The mixture was stirred at 50° C. in a sealed tube overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure to give pure 5-methylbenzofuran-2-carboxamide, as a white solid (1.02 g). LCMS retention time=1.00 minutes (LC method 3); MS (m+1)=175.8. 1H NMR (400 MHz, DMSO-d6) δ 2.40 (s, 3H), 7.45 (d, J=0.9 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.53 (t, J=0.7 Hz, 1H), 7.63 (br. s., 1H), 8.05 (br. s., 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].C[C@@H]1CCCN[C@@H]1CN1C(=O)C2C(=CC=CC=2)C1=O.[Br:44]C1C=CC(C)=CC=1C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[Br:44])=[O:11]
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Product: Cc1ccc(Br)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, starting with 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-bromo-5-methylbenzoic acid. ESI-MS (m/z): 325, 327 [M]+, [M+2]+.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[BrH:10].BrBr>>[Br:10][C:3]1[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[S:1][CH:2]=1
Reactant: c1cc2sccc2cn1
Reactant: Br
Agent: BrBr
Product: Brc1csc2ccncc12
Temperature: 105 °C
Reaction time: 8 h

Procedure:
To a solution of 5.4 g of thieno[3,2-c]pyridine and 120 ml of 48% (w/w) hydrobromic acid was added a solution of 4.4 ml of bromine in 60 ml of 48% (w/w) hydrobromic acid. A solid precipitated out of solution and the resultant mixture was maintained at 105° C. for 6 hours in a sealed vessel after which it was allowed to cool to room temperature overnight. The mixture was then poured over ice layered with methylene chloride and the mixture was made basic (pH9) with ammonium hydroxide. The layers were separated and the aqueous layer was extracted two times with methylene chloride. The combined extracts were refrigerated overnight and then dried over magnesium sulfate to render a tan solid, a portion of which was taken up in 300 ml of diethyl ether. An insoluble material formed and was removed by filtration. The diethyl ether was concentrated to about 50 ml from which crystals of the desired subtitle intermediate formed and were collected.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][OH:36])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:21][C:22]4[CH:23]=[C:24]([N:28]5[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][OH:36])[CH2:32][CH2:33]5)[CH:25]=[CH:26][CH:27]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: Nc1cccc(N2CCN(CCO)CC2)c1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(N5CCN(CCO)CC5)c4)nc23)cc1

Procedure:
2-(4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanol was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (75.0 mg, 0.244 mmol) and 2-[4-(3-amino-phenyl)-piperazin-1-yl]-ethanol (60.0 mg, 0.271 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (33.0 mg, 0.0604 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.052 g, 43%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.5 Hz, 1H), 8.26 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.5 Hz, 1H), 7.45 (s, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.02 (t, J=7.1 Hz, 1H), 6.96-6.92 (m, 1H), 6.87 (s, 1H), 6.62-6.58 (m, 1H), 3.70 (t, J=5.3 Hz, 2H), 3.30-3.26 (m, 4H), 3.11 (s, 3H), 3.74-2.70 (m, 4H), 2.64 (t, J=5.3 Hz, 2H). MS=493 (MH)+.
Reaction SMILES: FC1C=C(O)C=CC=1F.BrCCCCCCCCCO.[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[F:39])[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35].FC1C=C(C=CC=1F)OCCCCCCCCC(O)=O.Cl.Cl.[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH2:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>>[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH:77][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:36]=[CH:37][C:38]([F:39])=[C:22]([F:21])[CH:23]=1)[CH2:73][N:74]([CH3:75])[CH3:76])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCCOc1ccc(F)c(F)c1
Agent: Cl
Agent: O=C(O)CCCCCCCCOc1ccc(F)c(F)c1
Agent: OCCCCCCCCCBr
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCOc1ccc(F)c(F)c1

Procedure:
The title compound, m/e=413.6 ([M−H]−), was produced in analogy with example 18, steps 1 to 4. Thus, 3,4-difluorophenol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-(3,4-difluoro-phenoxy)-nonan-1-ol, which was oxidized in step 2 to 9-(3,4-difluoro-phenoxy)-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-(3,4-difluoro-phenoxy)-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1.[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:30](O)=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:30]([O:14][C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9]1)=[O:31]
Reactant: O[C@@H]1CCCN(Cc2ccccn2)C1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CCCN(Cc2ccccn2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1
Yield: 54.7 %

Procedure:
(3R)-1-(2-Pyridinylmethyl)-3-piperidinol (117 mg) [see Preparation 35] was added to a stirred solution of (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid (150 mg) [see Preparation 3], triphenylphosphine (192 mg) and diethyl azodicarboxylate (0.115 ml) in dry tetrahydrofuran (6 ml). The reaction mixture was stirred at reflux for 16 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 0.5M aqueous hydrochloric acid. The aqueous layer was then basified with 15% sodium hydroxide and the product extracted with ethyl acetate. The organic layer was then separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 98:2, by volume, ethyl acetate:methanol to afford (3S)-1-(2-pyridinylmethyl)-3-piperidinyl (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (140 mg) as a yellow oil. The hydrochloride salt was prepared by dissolving the title compound in ethyl acetate and bubbling hydrogen chloride gas through the solution, to afford the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH2:5][C:6]1[C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:4]1[C:3](=[O:2])[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[CH:11][C:6]=2[CH2:5]1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccccc1OC
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccccc1C1Cc2cnc(Nc3ccccc3)nc2N(c2ccccc2)C1=O
Temperature: 110 °C

Procedure:
To a solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(2-dimethoxy-phenyl propionic acid methyl ester (181.8 mg, 0.40 mmol) (from Example 7b supra) was added 5% concentrated sulfuric acid in glacial acetic acid (3 mL) in one portion. The reaction mixture was heated at 110° C. for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate (100 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was crystallized from ethyl acetate-hexanes to give 6-(2-methoxy-phenyl)-8-phenyl-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid. (Yield 119.4 mg, 67.2%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][CH:13]=[C:12](B(O)O)[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:20]=2)[CH:7]=1
Reactant: Cc1ccc(Cl)cc1Br
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)cc1-c1cccc(-c2ccccc2)c1
Yield: 73.5 %

Procedure:
To a 2 L round bottle flask equipped with reflux condenser, stir bar, nitrogen feed, and oil bath were added 2-bromo-4-chlorotoluene (20.67 g, 98.59 mmol), 3-biphenylboronic acid (20.50 g 103.52 mmol), sodium carbonate (158 mL, 315 mmol), Aliquat 336 (4.00 g) and toluene (600 mL). Solution was purged with nitrogen for 20 minutes before adding tetrakis(triphenylphospine)palladium(0) (1.14 g, 0.98 mmol) and purged for another 10 minute. The reaction was then heated under nitrogen for 18 hour. After cooing to ambient temperature, the organic phase was separated, washed with 10% HCl (200 mL), water (200 mL) and saturated brine (200 mL). This solution was dried with magnesium sulfate (50 g) for 3 hour and the solvent was removed by rotary evaporation. The crude product was filtered, washing with hexane. Product containing fractions were identified by UPLC and collected. Low boiling point is impurities and solvents were removed by Kruger-Rohr distillation to give the product as colorless oil (20.2 g, 77%).