Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][S:5][C:6]1[N:11]=[C:10]([C:12](Cl)=[O:13])[CH:9]=[CH:8][N:7]=1>C(Cl)Cl>[CH3:1][N:2]([C:12]([C:10]1[CH:9]=[CH:8][N:7]=[C:6]([S:5][CH3:4])[N:11]=1)=[O:13])[NH2:3]
Reactant: CSc1nccc(C(=O)Cl)n1
Reactant: CNN
Solvent: ClCCl
Product: CSc1nccc(C(=O)N(C)N)n1
Temperature: -78 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
To a −78° C. stirred solution of methyl hydrazine (17 mL, 318 mmol) in CH2Cl2 (500 mL) is added dropwise a solution of 2-methylsulfanyl-pyrimidine-4-carbonyl chloride (20 g, 106 mmol) in CH2Cl2 (500 mL). The reaction mixture is stirred for 2 hours at −78° C. and then slowly warmed to room temperature. The reaction mixture is concentrated under reduced pressure to give a purple oil. Purification over silica (EtOAc/hexanes 1:1) affords 6.98 g (33% yield) of the desired compound. 1H NMR (300 MHz, CDCl3) δ 8.69-8.64 (m, 1H), 7.35-7.08 (m, 1H), 3.40 (s, 3H), 3.36 (s, 2H), 2.59 (s, 3H); ESI/MS: 199.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.CCN(CC)CC.[F:23][C:24]([F:32])([F:31])[C:25]1[CH:29]=[C:28]([NH2:30])[NH:27][N:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[F:23][C:24]([F:32])([F:31])[C:25]1[CH:29]=[C:28]([NH:30][C:13]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([Br:12])[N:4]=2)=[O:15])[NH:27][N:26]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2) (100 mg, 0.350 mmol) in dry NMP (2 ml) was added NEt3 (0.097 ml, 0.699 mmol) followed by 3-(trifluoromethyl)-1H-pyrazol-5-amine (48.0 mg, 0.318 mmol). The mixture was stirred at RT for 5 minutes, before treating with HATU (133 mg, 0.350 mmol). The resulting orange solution was stirred at RT for 10 minutes and then partitioned between EtOAc (50 ml) and 1M NaOH (30 ml). The organic portion was separated and washed with 1M NaOH (20 ml), water (20 ml), dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by chromatography on silica eluting with iso-hexane/EtOAc (gradient of 0 to 50% EtOAc) afforded the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH3:15])[C:9]([CH:16]([CH3:18])[CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>C(#N)C>[CH2:27]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH3:15])[C:9]([CH:16]([CH3:18])[CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH:26]=[CH2:25]
Reactant: COCOc1cc(O)c(C(=O)OC)cc1C(C)C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(OCOC)c(C(C)C)cc1C(=O)OC
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A mixture of methyl 2-hydroxy-5-isopropyl-4-(methoxymethyloxy)benzoate (995 mg, 3.92 mmol) and anhydrous potassium carbonate (650 mg, 4.71 mmol) in acetonitrile (25 ml) was treated with allyl bromide (0.356 ml, 4.11 mmol) and the mixture was stirred and held at reflux for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo, water (30 ml) was added and the organic material was extracted with dichloromethane (2×30 ml). The combined organic extracts were evaporated to dryness in vacuo to afford methyl 2-allyloxy-5-isopropyl-4-(methoxymethyloxy)benzoate (1125 mg, 97%) as pale yellow oil. 1H NMR (DMSO-d6) 7.58 (1H, s), 6.78 (1H, s), 6.03 (1H, m), 5.52 (1H, dm), 5.33 (2H, s), 5.28 (1H, dm), 4.61 (2H, m), 3.78 (3H, s), 3.42 (3H, s), 3.19 (1H, m), 1.18 (6H, d). MS: [M+Na]+ 317.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30](I)[CH3:31].O>CN(C=O)C.C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH:15]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)[CH2:30][CH3:31])=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCOC(=O)c1ccc(NCc2nccnc2OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(NC(CC)c2nccnc2OCc2ccccc2)cc1
Reaction time: 36 h

Procedure:
Ethyl 4-(2-benzyloxypyrazin-3-ylmethylamino)benzoate (455 mg) was dissolved in dry DMF (4 mL) and added to a suspension of sodium hydride (51 mg of a 60% dispersion in mineral oil) in DMF (4 mL) precooled to 0° C. under argon dropwise over fifteen minutes. After stirring for thirty minutes at 0° C. ethyl iodide (0.12 mL) was added and the mixture stirred for 36 hours. The solution was poured into water (50 mL) and the mixture made acidic with glacial acetic acid. The organic phase was then extracted with ethyl acetate (3×50 mL), washed with water (50 mL) and brine (50 mL) and dried (MgSO4). After removal of the solvent, the residue was purified by MPLC (eluting 20% ethyl acetate in hexane, silica) to give ethyl 4-(1-(2-benzyloxypyrazin-3-yl)prop-1-ylamino)benzoate as an oil which was used in the next step without further purification, (260 mg).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:20]([C@H:28]3CCN3C)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:35]1([C:40]([O-:42])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:20]([CH:28]3[O:41][C:40](=[O:42])[N:35]4[CH2:39][CH2:38][CH2:37][CH:36]34)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:34])([F:33])[F:1])[CH:8]=1
Reactant: O=C([O-])N1CCCC1
Reactant: C[C@@H](O[C@H]1OCC[C@@H]([C@H]2CCN2C)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: C[C@@H](O[C@H]1OCC[C@@H](C2OC(=O)N3CCCC23)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (2R or S)-2-[(R or S)-((2R,3R,4R)-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-yl)hydroxymethyl]-1-pyrrolidinecarboxylate (Example 41, Isomer B) according to the method of Example 42.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O-:16])=[O:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])Cc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2ccccc2)cc1
Yield: 462.5 %

Procedure:
A suspension of (4′-biphenyl)acetate acid (6.4 g) in 60 ml of ethanol is added with 1.1 g of para-toluensulfonic acid, then the reaction mixture is refluxed for 4 hours 30 minutes. The solvent is evaporated off, the residue is dissolved in diethyl ether and the resulting organic phase is washed three times with a saturated aqueous solution of sodium hydrogencarbonate and once with brine. The organic phase is then dried over sodium sulfate and the solvent is evaporated off to give 7.1 g of the product as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[C:18]([CH2:31][CH3:32])([CH2:29][CH3:30])[NH:17][CH:16]2[C:33](O)=[O:34])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:41][C@@H:40]([CH2:42][CH2:43][NH2:44])[CH2:39][O:38]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:41][C@H:40]([CH2:39][OH:38])[CH2:42][CH2:43][NH:44][C:33]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[C:18]([CH2:31][CH3:32])([CH2:29][CH3:30])[NH:17]1)=[O:34]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CCC1(CC)NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC1(CC)NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 48c (0.33 g, 0.62 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.15 g, 1 mmol), HATU (0.34 g, 0.89 mmol) and iPr2NEt (1 g, 7.8 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (0.4 g, 95%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:30](OCC)=[O:31])[N:18]([CH2:28][CH3:29])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:11][CH:10]=1>>[CH:1]1([NH:7][C:30]([C:17]2[N:18]([CH2:28][CH3:29])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=3)[N:16]=2)=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1CC
Product: CCn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl

Procedure:
Using essentially the same procedure as Example 42, Step C, but using neat cyclohexylamine (2 mL), ethyl 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-ethylimidazole-2-carboxylate (30 mg, 0.073 mmol) from Example 42, Step B was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes). HPLC/MS: 476 (M+1), 478 (M+3); Rt=5.04 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11](O)[C:10]1=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+]>CO.[Cl-].[Na+].[Cl-].[Cl-].[Cl-].[Ti+3]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[NH:11][C:10]1=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CO
Product: C[C@@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C

Procedure:
A solution of 4.98 of (3S-trans)-3-t-butoxycarbonylamino-1-hydroxy-4-methylazetidinone in 200 ml of methanol is treated with 132 ml of 4.5 M ammonium acetate and then 66 ml of 1.5 M titanium trichloride and stirred for 4.5 hours. The aqueous solution is diluted with an equal volume of 8% sodium chloride and extracted with ethyl acetate to give 3.48 g of crude product. Recrystallization from ether-hexane yields 3.3 g of the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH3:18])[C:3]([N:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:28])[NH:1][CH:2]([CH3:18])[C:3]([N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(N)C(=O)N(c1ccccc1)c1ccccc1
Product: Cc1cccc(NC(=O)NC(C)C(=O)N(c2ccccc2)c2ccccc2)c1
Yield: 43.2 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with (RS)-2-amino-N,N-diphenylpropionamide (1.2 g) and 3-methylphenyl isocyanate (0.66 g), and after recrystallization in methanol, (RS)-2-[3-(3-methylphenyl)ureido]-N,N-diphenylpropionamide (0.8 g), m.p. 197° C., is obtained.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:12]=[O:13])=[CH:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: OCc1ccc(OC2C=CCCC2)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(OC2C=CCCC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77 %

Procedure:
The alcohol prepared above (4.24 g, 20.7 mmol) was dissolved in 250 mL methylene chloride under an atmosphere of dry nitrogen. Pyridinium chlorochormate (5.62 g, 26.1 mmol) was added over 5 minutes. After stirring at ambient temperature for 72 hours, the mixture was filtered through Celite and concentrated in vacuo. Flash silica gel chromatography eluting with 10% ethyl acetate in hexane afforded 3.25 g (77%) of the title compound.
Reaction SMILES: [C:1]1([N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[S:9][CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:18]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1csc(N(c2ccccc2)c2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(N(c2ccccc2)c2ccccc2)n1

Procedure:
The reaction described in Preparation 15 was repeated, but using 27 g of ethyl 2-diphenylaminothiazole-4-carboxylate, 4.7 g of lithium aluminum hydride and 400 ml of tetrahydrofuran, giving the title compound as pale yellow prisms.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.Br[CH2:37][CH:38]1[CH2:40][CH2:39]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:38]1([CH2:37][CH2:19][C:18]2[O:17][N:16]=[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]=2[C:11]2[O:10][C:9]([C:8]3[CH:7]=[CH:6][C:5]([NH2:26])=[CH:4][C:3]=3[O:2][CH3:1])=[N:13][N:12]=2)[CH2:40][CH2:39]1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: BrCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2CCC2CC2)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 12.2 %

Procedure:
To a suspension of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF were added N,N-diisopropyl ethyl amine (128 μL, 0.75 mmol) and bromomethyl-cyclopropane (61 μL, 0.63 mmol) and the reaction mixture was stirred for 24 h at ambient temperature. After addition of potassium bis(trimethylsilyl)amide (0.91 M in THF, 0.82 mL, 0.75 mmol) was added stirring was continued for 15 min and further bromomethyl-cyclopropane (78 μL, 0.80 mmol) was added. After stirring for 18 h at ambient temperature further bromomethyl-cyclopropane (0.12 mL, 1.2 mmol) was added and stirring continued for 24 h at this temperature. The reaction mixture was extracted with aqueous sodium carbonate (saturated, 20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers dried over sodium sulfate. Concentration and then purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=40:40:20 to 0:80:20) afforded the title compound (28 mg, 12%) as a light brown solid. MS: m/e=403.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-])=[CH:4][CH:3]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:11]=[C:12]([C:24]#[N:25])[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccccc1C=Cc1ccc(F)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: N#Cc1cccc(C=Cc2ccc(F)cc2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(4-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a yellow crystalline material. MS: m/e=224 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11](Br)[C:10]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.Cl[C:34]([O:36][CH3:37])=[O:35].O>C1COCC1.CCCCCC.CCOC(C)=O>[CH2:21]([O:20][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:11]=1[C:34]([O:36][CH3:37])=[O:35])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)Cl
Reactant: FC(F)(F)c1cc(Br)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(F)(F)F)cc(OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2-bis-benzyloxy-3-bromo-5-trifluoromethyl-benzene (750 mg, 1.76 mmol) in 10 mL dry THF cooled to −90° C., BuLi (3.3 mL of a 1.6 m solution in hexane, 5.28 mmol, 3 eq.) was slowly added via a syringe and the yellow solution was stirred at low temperature for 15 min. Methyl chloroformate (1.66 g, 17.6 mmol, 10 eq.) was then added to the solution and the reaction mixture was allowed to warm to r.t. where the stirring was continued for 1 h. The mixture was then poured into a separatory funnel containing H2O and EtOAc and the phases were separated. The organic phase was washed with brine, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 10:1) to yield the desired compound as a colorless solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:40])[CH2:18][CH:19]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[N:37][O:38][CH3:39])[CH2:32][CH2:31]3)[C:20](=O)[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CS(O)(=O)=O>[CH3:39][O:38][N:37]=[C:33]1[C:34]2[C:30](=[CH:29][C:28]([C:19]3[CH:18]=[C:17]([CH:14]4[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]4)[O:40][C:20]=3[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:36][CH:35]=2)[CH2:31][CH2:32]1
Reactant: CON=C1CCc2cc(C(CC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)C(=O)c3ccncc3)ccc21
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CON=C1CCc2cc(-c3cc(C4CCNCC4)oc3-c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
The product of Step 3 (3.0 g, 5.5 mmol) was added to a stirred suspension of phosphorus pentoxide (8 g) in dry methane sulphonic acid (50 ml). After stirring at room temperature for 4 hours the reaction mixture was cautiously poured into a stirred solution of ice cold 50% aqueous sodium hydroxide (final pH 10). The mixture was extracted with chloroform, washed with water and brine, dried and concentrated in vacuo and the residue purified by silica gel chromatography to give the title compound (0.66 g, 32%); MS(ES+) m/e 388 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:16]([CH3:32])[CH2:17]/[CH:18]=[CH:19]/[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[F:31])[CH:14]=[CH2:15].[CH3:33][C:34]([CH3:38])=[CH:35][CH:36]=[O:37].C(=O)(O)[O-].[Na+]>C1COCC1.CCCCCC.CCOCC.C(Cl)Cl.C(O)(=O)C>[CH2:13]([N:16]([CH3:32])[CH2:17]/[CH:18]=[CH:19]/[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH2:29][CH:36]([OH:37])[CH:35]=[C:34]([CH3:38])[CH3:33])=[CH:24][C:23]=1[F:31])[CH:14]=[CH2:15]
Reactant: C=CCN(C)C/C=C/COc1ccc(C(C)=O)cc1F
Reactant: CC(C)=CC=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: C=CCN(C)C/C=C/COc1ccc(C(=O)CC(O)C=C(C)C)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 0.86 ml of diisopropylamine in 5 ml of THF is treated dropwise at 0° C. with 3.5 ml of 1.6M butyllithium in hexane. After 15 min. the mixture is cooled to -78° C. and 1.1 g of (E)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-ethanone (Ex. Fa) in 3.9 ml of THF is added dropwise. After 1 hr. at -78° C. 0.7 ml of 3-methyl-2-butenal in 0.8 ml of THF is added dropwise. After 20 min. at -78° C. 0.86 ml of acetic acid in 4.6 ml of ether is added dropwise and the mixture is poured into saturated sodium bicarbonate solution/methylene chloride. The organic phase is dried and evaporated. After silica gel chromatography with (97.5%) methylene chloride/methanol the residue is dissolved in ethanol with 0.24 g of fumaric acid, evaporated and precipitated from methylene chloride with ethyl acetate/ether. There is obtained 0.64 g of (E)-(RS)-1-[4-[4-(allyl-methyl-amino)-but-2-enyloxy]-3-fluoro-phenyl]-3-hydroxy-5-methyl-hex-4-en-1-one.fumarate (1:1), MS: m/e 362 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:40])[NH:10][CH2:11][CH2:12][O:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:27]=3)[O:23][N:22]=2)=[CH:16][C:15]=1[CH2:38][CH3:39])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CC(=O)OCC>[NH2:7][CH2:8][C:9]([NH:10][CH2:11][CH2:12][O:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:27]=3)[O:23][N:22]=2)=[CH:16][C:15]=1[CH2:38][CH3:39])=[O:40]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCNC(=O)CNC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCNC(=O)CN
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a solution of [(2-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (65 mg, 0.115 mmol) in DCM (30 mL), trifluoroacetic acid (262 mg, 2.29 mmol) is added. The mixture is stirred at rt for 16 h before it is diluted with EA and washed with sat. aq. NaHCO3-solution and brine. The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of 7 N NH3 in methanol to give the title compound (32 mg) as a yellow resin; LC-MS: tR=0.70 min; [M+1]+=467.19; 1H NMR (CDCl3): δ 1.24 (t, J=7.0 Hz, 6H), 1.32 (t, J=7.5 Hz, 3H), 2.01 (s br, 2H), 2.39 (s, 3H), 2.49 (s, 3H), 2.76 (q, J=7.5 Hz, 2H), 3.45 (s, 2H), 3.62 (q, J=7.0 Hz, 4H), 3.73-3.80 (m, 2H), 3.95 (t, J=5.0 Hz, 2H), 7.00 (s, 1H), 7.10 (s, 1H), 7.87 (s, 1H), 7.88 (s, 1H), 7.90 (s br, 1H).
Reaction SMILES: [C:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:14](=O)([O-])O.[Na+].O.C(OCC)(=O)C>CN(C)C(=O)C>[CH3:14][O:2][C:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cccc2c1OCCO2
Reaction time: 24 h

Procedure:
3.46 g (19.2 mmol) of the acid obtained in Step A are added to a mixture of 9.62 g (114.6 mmol) of sodium hydrogen carbonate and 3.57 ml (57.6 mmol) of iodomethanie in 40 ml of N,N-dimethylacetamide. After 24 hours' stirling under argon and protected from light, the solvent is removed by evaporation in vacuo. The residue obtained is then taken up in a 1/1 water/ethyl acetate mixture and the aqueous phase is subsequently extracted with ethyl acetate. After drying over magnesium sulphate and filtration, the solvent is removed by evaporation under reduced pressure. The title ester is obtained pure in the form of a white solid after chromatography over silica gel (eluant:AcOEt/PE:25/75).