Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1Br)[CH3:2].[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[B:17]([OH:20])[OH:18])[CH3:2]
Reactant: CCc1cccc(CC)c1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1B(O)O
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
2,6-Diethyl bromobenzene (38.2 g, 180.2 mmol) is added dropwise through an additional funnel over a 1 hour period to a solution of n-BuLi (2.0 M in cyclohexane, 99.1 mL, 198.2 mmol) in THF (380 mL) at −75° C. After addition, the reaction mixture is stirred at −75° C. for 30 minutes; trimethyl borate (28.1 g, 270.3 mmol) is added slowly over a 40 minute period. The reaction mixture is warmed to room temperature overnight. 2N HCl (250 mL) is added slowly and the resulting mixture is stirred for 1 hour. The organic layer is separated and the aqueous layer is extracted with ether (2×200 mL). The combined organic layers are dried over anhydrous Na2SO4 and the solvents are removed in vacuo. Hexane (400 mL) is added to the residue and a white precipitate is formed. Filtration and drying in vacuo give 2,6-diethylphenyl boronic acid as a white solid. 1H NMR: (CDCl3) 7.22 (t, 1H), 7.04 (s, 2H), 4.65 (s, 2H), 2.64 (q, 4H), 1.22 (t, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH:8]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:9](=[O:12])[CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28]([OH:30])=[O:29].[F-].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:17]([O:16][C:14]([NH:13][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[C:9](=[O:12])[CH2:10][O:30][C:28](=[O:29])[C:27]1[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:26]=1[CH3:25])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OCc1ccccc1)C(=O)CBr
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A heterogeneous solution containing 3-benzyloxycarbonylamino-5-bromo-4-oxo-pentanoic acid tert-butyl ester, 109, (9.89 g, 24.7 mmol), 2,6-dimethyl benzoic acid (4.45 g, 29.6 mmol), and KF (3.58 g, 61.8 mmol) in 250 mL of DMF is stirred at rt for 12 h. The solution is diluted with EtOAc, washed with water, saturated NaHCO3, and brine, dried (MgSO4), and concentrated in vacuo. Purification of the crude material by flash chromatography on silica gel (hexane/EtOAc) yields 11.3 g of the desired product as a white solid.
Reaction SMILES: O.NN.[F:4][C:5]([F:41])([F:40])[C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[C:16]([CH2:19][O:20][N:21]4C(=O)C5=CC=CC=C5C4=O)=[N:17][N:18]=[C:14]3[CH2:13][N:12]=[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[C:10]=2[CH:39]=1>C(O)C>[NH2:21][O:20][CH2:19][C:16]1[N:15]2[C:9]3[CH:8]=[CH:7][C:6]([C:5]([F:41])([F:40])[F:4])=[CH:39][C:10]=3[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])=[N:12][CH2:13][C:14]2=[N:18][N:17]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-trifluoromethyl-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-trifluoromethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([CH:3]1[CH:8]([CH3:9])[CH:7]([CH2:10][O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][C:5](=[O:16])[CH:4]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)[CH3:2]>C1COCC1.[NH4+].[Cl-].C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:8]([CH3:9])[CH:7]([CH2:10][O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)([OH:16])[CH:4]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:21][CH:22]=1)[CH3:2]
Reactant: CCC1C(c2ccc(Oc3ccccc3)cc2)C(=O)CC(CO[Si](C)(C)C)C1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1C(C)C(CO[Si](C)(C)C)CC(O)(c2ccc(OC)cc2)C1c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-ethyl-4-methyl-2-(4-phenoxy-phenyl)-5-trimethylsilanyloxymethyl-cyclohexanone (1.8 g, 3.8 mmol) in THF (10 mL) at −10° C. was added Grinard reagent (1.0 M, 7.5 mL). The reaction mixture was stirred at 25° C. for 1 h and then refluxed for 30 min. The reaction mixture was then cooled and diluted with aqueous saturated NH4Cl (100 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over MgSO4 and purified on SiO2 (100% ethyl acetate) to yield crude product 3-ethyl-1-(4-methoxy-phenyl)-4-methyl-2-(4-phenoxy-phenyl)-5-trimethylsilanyloxymethyl-cyclohexanol. NMR showed S: R product ratio or 2:1. Further purification provide pure 3-ethyl-1-(4-methoxy-phenyl)-4-methyl-2-(4-phenoxy-phenyl)-5-trimethylsilanyloxymethyl-cyclohexanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:21]([O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH2:28])([CH3:24])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[C:21]([O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:31])[CH3:32])[NH:28][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.5 %

Procedure:
Under atmosphere of argon, to a solution of N-benzyloxycarbonylleucine (26.5 g) and leucine t-butyl ester hydrochloride (22.4 g) in methylene chloride (20.0 ml.) were added 1-hydroxybenzotriazole (HOBt) (14.2 g) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) hydrochloride (20.1 g) at 0° C. Thereto was added N-methylmorpholine (11.5 ml) over a period of 5 minutes and the mixture was stirred for 20 hours at room temperature. The reaction solution was concentrated and to the residue were added ice-water and ethyl acetate. In order to dissolve HOBt that appeared, was added sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and combined organic layer was washed with 10% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and was concentrated to give the title compound (43.2 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:24])[CH:5]=1.Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=1>>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:17][CH:18]=3)[N:13]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH3:33])[CH:31]=3)[C:12]=2[CH3:24])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(S(C)(=O)=O)ccc23)c1
Reactant: CCn1cc(Br)cn1
Product: CCn1cc(-n2c(C)c(Sc3cccc(C(=O)OC)c3)c3ccc(S(C)(=O)=O)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-methanesulfonyl-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([F:11])[CH:3]=1.[Li]CCCC.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1
Reactant: COCc1cc(F)cc(F)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,3-difluoro-5-(methoxymethyl)benzene (0.970 g, 6.13 mmol) in THF (24 mL) at −78° C., a solution of n-BuLi in hexanes (1.6 M, 9.58 mL, 15.3 mmol) was slowly added through a dripping funnel. When addition was done, the mixture was kept at −78° C. for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.75 mL, 18.4 mmol) was then added in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was quenched with aq. NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give sub-title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 6.82 (m, 2H), 4.43 (s, 2H), 3.38 (s, 3H), 1.37 (s, 12H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)=[CH:4][C:3]=1Br.[CH3:18][N:19]1CCCC1=O>>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: CN1CCCC1=O
Reactant: Nc1c(Br)cc(-n2cnnc2)cc1C(F)(F)F
Product: N#Cc1cc(-n2cnnc2)cc(C(F)(F)F)c1N

Procedure:
The following compound, m.p. 283°, was similarly prepared to the prevous Preparation using 4-(4-amino-3-bromo-5-trifluoromethylphenyl)-1,2,4-triazole, cuprous cyanide and 1-methyl-2-pyrrolidone as the starting materials: ##STR148##
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH2:17][CH2:18]2)#[N:14].Br[CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1>O1CCCC1>[C:13]([C:15]1([CH2:24][CH:25]2[O:29][CH2:28][CH2:27][O:26]2)[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH2:17][CH2:18]2)#[N:14]
Reactant: N#CC1CC2CCC1CC2
Reactant: BrCC1OCCO1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CC1(CC2OCCO2)CC2CCC1CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
84 ml of diisopropylamine are dissolved in 300 ml of absolute tetrahydrofuran. 39.9 ml of n-butyllithium (1.5 molar in hexane) are added at -20° C. under dry argon. After 30 minutes at room temperature, the mixture is cooled down to -78° C. and 8.1 g of 2-cyanobicyclo[2.2.2]octane in 30 ml of absolute tetrahydrofuran are stirred in, and, after 30 minutes at 0° C., the mixture is again cooled down to -78° C. and 10 g of 2-bromomethyl-1,3-dioxolane in 30 ml of tetrahydrofuran are added dropwise. The mixture is stirred for a further 45 minutes at -78° C., warmed up to room temperature and evaporated, and the residue is taken up in 2N acetic acid and ether, washed three times with water and dried over sodium sulfate and the solvent is removed. The crude product is chromatographed on silica gel with ethyl acetate/cyclohexane (1:6) as the mobile phase. 7.9 g of the title compound are obtained as a colorless oil.
Reaction SMILES: O=C1N(CC(OC(C)(C)C)=O)C2C=CC=CC=2N1.[O:19]=[C:20]1[N:24]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]1[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1>>[O:19]=[C:20]1[N:24]([CH2:25][C:26]([OH:28])=[O:27])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]1[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccncn2)c2ccccc21
Agent: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Product: O=C(O)Cn1c(=O)n(-c2ccncn2)c2ccccc21

Procedure:
Essentially following the procedures described for Intermediate 7, but using tert-butyl (2-oxo-3-pyrimidin-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step B in place of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, the title compound was prepared. MS: m/z=271 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:40])([F:39])[C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:49])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([F:19])([F:20])[F:21])=[O:49])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:39])([F:40])[C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
0.12 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole was dissolved in 10 mL of chloroform, and 44 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.095 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14](=[O:21])[CH2:15][C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17]>ClCCl>[Br:1][CH:15]([C:16]([CH:18]1[CH2:19][CH2:20]1)=[O:17])[C:14]([C:5]1[CH:6]=[CH:7][C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:9][C:4]=1[Cl:3])=[O:21]
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(C(=O)CC(=O)C2CC2)c(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)C(Br)C(=O)C2CC2)c(Cl)c1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Under an inert atmosphere, bromine (0.24 g) is slowly added dropwise to a solution of (1-[2-chloro-4-(methylsulphonyl)phenyl]-3-(cyclopropyl)propan-1,3-dione (0.43 g) in 25 ml of dichloromethane cooled to 5° C., then the mixture is stirred overnight at room temperature.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][N:50]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][N:50]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1ccc(N)nc1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution triphenylphosphine (177 mg, 0.68 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (132 mg, 0.74 mmol) in small portions. The reaction mixture was allowed to warm to 25° C. over 30 min and then was treated with 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (prepared as in Example 3A, 200 mg, 0.68 mmol). The reaction mixture was stirred at 25° C. for 30 min and then treated with 2-amino-5-methylpyridine (154 mg, 1.42 mmol). The resulting reaction mixture was stirred at 25° C. for 1 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford impure 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamide as a red solid. The impure product was further purified by precipitation from 1/1 hexanes/ethyl acetate to afford pure 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamide (80 mg, 31%) as an off-white solid: mp 184-185° C.; EI-HRMS m/e calcd for C21H26N2O3S (M+) 386.1664, found 386.1664.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[F:17].O.[NH2:19][NH2:20]>CS(C)=O>[F:17][C:3]1[C:2](=[N:19][NH2:20])[N:7]=[C:6]([CH3:8])[NH:5][C:4]=1[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Cc1nc(Cl)c(F)c(NCc2ccccn2)n1
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(=NN)c(F)c(NCc2ccccn2)[nH]1
Reaction time: 8 h
Yield: 39 %

Procedure:
6-Chloro-5-fluoro-2-methyl-N-(2-pyridinylmethyl)-4-pyrimidinamine (0.2517 g, 0.999 mmol) was dissolved in 2 mL of DMSO and 1 mL of hydrazine monohydrate. The resulting reaction mixture was stirred overnight. Then the reaction mixture was purified by RP-HPLC to provide 5-fluoro-2-methyl-6-[(2-pyridinylmethyl)amino]-4(1H)-pyrimidinone hydrazone as a beige solid (0.0954 g, 39%). LCMS: (M+H)+=249.3.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:27]([OH:32])(=[O:31])[CH:28]([CH3:30])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:28]([C:27]([OH:32])=[O:31])[CH3:30])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)O)cc1

Procedure:
A flask containing 10.0 g (27.7 m moles) 4-(hexadecylamino)benzoic acid, 3.3 g. (36 m moles) lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].CCC(N)C(O)=O.[CH3:37][O:38][CH2:39][CH2:40][OH:41]>>[CH3:37][O:38][CH2:39][CH2:40][O:41][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]
Reactant: CC1(C)C(NC(=O)c2ccc(Br)c(S(=O)(=O)N3CCOCC3)c2)[C@@]2(C)CC[C@@H]1C2
Reactant: COCCO
Agent: CCC(N)C(=O)O
Product: COCCOc1ccc(C(=O)NC2C(C)(C)[C@@H]3CC[C@@]2(C)C3)cc1S(=O)(=O)N1CCOCC1

Procedure:
Compound 2L was prepared from 4-bromo-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide 2.4.AaBa and 2-methoxyethanol 3.3 following the procedure described in Example 2I.
Reaction SMILES: [CH2:1](P(=O)(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[F:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH:26]=O>CN(C)C=O>[F:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1/[CH:26]=[CH:1]\[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=Cc1ccncc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cnccc1/C=C\c1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 10 %

Procedure:
Diethyl benzylphosphonate (2.8 ml, 13.4 mmol) was added to a solution of sodium methoxide (0.75 g, 13.6 mmol) in anhydrous dimethylformamide (15 ml) and the resultant mixture stirred at room temperature, under nitrogen, for ten minutes. A solution of 3-fluoropyridine-4-carboxaldehyde [prepared by the method of F. Marsais and G. Queguiner, Tetrahedron, 1983, 39, 2009] (1.55 g, 12.4 mmol) in anhydrous dimethylformamide (10 ml) was added and the reaction mixture stirred at room temperature under nitrogen for 21 hours. The reaction mixture was poured into ice-water (125 ml), the precipitated solid collected under suction and washed with water. The aqueous filtrate was extracted with ethyl acetate (100 ml), the extract dried (MgSO4) and concentrated in vacuo to an off. This off and the solid product were combined and purified by flash chromatography, eluting with 1:2 then 1:1 ethyl acetate/petrol (60°-80° C.), to afford (Z)-3-fluoro-4-(2-phenylethenyl)pyridine (0.25 g, 10%) as a colourless off; δH (CDCl3) 6.55 (1H, d, J 12.3Hz, CH=CHPh), 6.92 (1H, d, J 12.3Hz, CH=CHPh), 7.10 (1H, t, J 5.6Hz, ArH), 7.18-7.27 (5H, m, ArH), 8.18 (1H, d, J 4.9Hz, 6-H) and 8.43 (1H, s, 2-H); and (E)-3-fluoro-4-(2-phenylethenyl)pyridine (0.69 g, 28%) as a white solid; δH (CDCl3) 7.20 (1H, d, J 16.5Hz, CH=CHPh), 7.33-7.43 (4H, m, CH=CHPh and ArH), 7.51 (1H, m, ArH), 7.57 (2H, m, ArH), 8.37 (1H, d, J 5.1Hz, 6-H) and 8.47 (1H, d, J 2.2Hz, 2-H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:13]2[CH:18]=[C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][C:14]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])[CH2:12][CH2:11][CH2:10][CH:9]=1.[CH3:35][N:36]1[CH:40]=[CH:39][N:38]=[C:37]1[CH:41]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:13]2[CH:18]=[C:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:41][C:37]4[N:36]([CH3:35])[CH:40]=[CH:39][N:38]=4)[CH2:21][CH2:20]3)[CH:16]=[CH:15][C:14]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])[CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: Cn1ccnc1C=O
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCC2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccnc1CN1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCC3)c2)CC1

Procedure:
This compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 18) and 1-methyl-1H-imidazole-2-carbaldehyde according to the procedure in Example 21. 1H-NMR (400 MHz, CD3OD): δ 8.03 (m, 2H), 7.50 (d, 1H), 7.42 (s, 1H), 7.20 (m, 2H), 6.02 (m, 1H), 4.22 (s, 2H), 3.96 (s, 3H), 3.30 (m, 2H), 2.82-2.40 (m, 7H), 2.13-1.84 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H29N7O, 456.2 (M+H), found 456.2.
Reaction SMILES: [NH2:1][C@@H:2]([CH:15]([CH3:17])[CH3:16])[C:3]([NH:5][C@@H:6]([CH3:14])[C:7]([O:9]C(C)(C)C)=[O:8])=[O:4].[I:18][CH2:19][C:20](N)=[O:21].NC1C=CC=CC=1C1C[C@@H]2N(C=1)C(=O)C1C=C(OC)C(OCCCOC3C(OC)=CC4C(=O)N5C=C(C6C=CC(OC)=CC=6)C[C@H]5C(=O)N(COCC[Si](C)(C)C)C=4C=3)=CC=1N(COCC[Si](C)(C)C)C2=O>ClCCl>[I:18][CH2:19][C:20]([NH:1][C@@H:2]([CH:15]([CH3:16])[CH3:17])[C:3]([NH:5][C@@H:6]([CH3:14])[C:7]([OH:9])=[O:8])=[O:4])=[O:21]
Reactant: NC(=O)CI
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Agent: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccccc7N)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)CI)C(=O)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of the 97 (100 mg, 0.41 mmol) in dichloromethane was added iodoacetamide-NHS ester (103) (115 mg, 0.41 mmol) and the mixture was stirred at an ambient temperature. After 30 min, the mixture was aspirated onto a 1 mm chromototron plate and eluted with ethyl acetate in hexanes (1:1). A single band was collected and the structure was confirmed: 1H-NMR (400 MHz, CDCl3) δ 6.70 (d, J=7.8 Hz, 1H), 6.27 (d, J=7.0 Hz, 1H), 4.45 (m, 1H), 4.26 (dd, J=8.6, 6.3 Hz, 1H), 3.72 (quart, J=11.3 Hz, 2H), 2.13 (sept, J=6.5 Hz, 1H), 1.47 (s, 9H), 1.38 (d, J=7.1 Hz, 3H), 0.99 (m, 6H); MS (ES+) m/z 412.87 [M+H]+.