Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:30][C:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[S:33][C:32]=1[C:46](=O)[CH3:47]>C1(C)C=CC=CC=1.C1COCC1>[CH3:2][O:3][CH:4]=[C:46]([C:32]1[S:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)=[CH:35][C:31]=1[CH3:30])[CH3:47]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC=C(C)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Reaction time: 0.5 h

Procedure:
To a solution of (methoxymethyl)triphenyl phosphonium chloride (3.96 g, 10.76 mmole) in toluene/THF (2:1, 60 mL), is added potassium t-butoxide (1.21 g, 10.76 mmole) in one portion and stirred for 30 minutes. To the resulting ylide, is injected into a solution of 1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanone (1.53 g, 5.38 mmole). The reaction is stirred for 2 hours, and then concentrated on rota vapor. The residue is purified on a silica gel column, eluting with 0-10% ethyl acetate in hexane and concentrated to provide 2-(2-Methoxy-1-methyl-vinyl)-3-methyl-5-(4-trifluoromethyl-phenyl)-thiophene as brown oil. The generated vinyl ether is treated with concentrated HCl(aq) (2 mL) in THF(60 mL) at 60° C. for 2 hours. The solvents are removed on rota vapor, and the residue is purified on a silica gel column, eluting with 0-20% ethyl acetate in hexane and concentrated to provide the titled compound as colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH3:8])=[N:5][CH:4]=1)[CH3:2].C([Li])CCC.[C:14](OCC)(=[O:16])[CH3:15]>C1COCC1>[CH2:1]([C:3]1[S:7][C:6]([CH2:8][C:14]([CH3:15])=[O:16])=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(C)s1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cnc(CC(C)=O)s1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
600 mg (4.72 mmol) of 5-ethyl-2-methyl-1,3-thiazole [M. Poite et al., Bull. Chem. Soc. Fr., 2078-2085 (1962)] are dissolved in 20 ml of abs. THF and, at −78° C., 2.08 ml (5.18 mmol) of n-butyllithium (2.5 M solution in hexane) are added dropwise. After stirring at −78° C. for two hours, 706 mg (8.02 mmol) of ethyl acetate are added as a solution in 10 ml of abs. THF. The mixture is stirred at −78° C. for 1 h and then warmed to room temperature. It is then hydrolyzed with sodium bicarbonate solution, and the mixture is extracted three times with diethyl ether. The combined organic phases are dried with magnesium sulfate, and the solvent is removed in a rotary evaporator. The crude product is purified by MPLC (Biotage 40M cartridge, eluent: isohexane/ethyl acetate 80:20). 50 mg (6% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:11])=[C:5]([NH:9]N)[CH:6]=[CH:7][CH:8]=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1.C(O)(=O)C>C(OCC)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:9][C:5]3[C:6]([CH:22]=2)=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=3[F:11])=[CH:17][CH:16]=1
Reactant: NNc1cccc(Cl)c1F
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2cc3ccc(Cl)c(F)c3[nH]2)cc1
Temperature: 105 °C

Procedure:
(3-Chloro-2-fluoro-phenyl)-hydrazine hydrochloride (Apollo Scientific, Ltd., 221 mg, 1.12 mmol) and 4-acetyl-benzoic acid methyl ester (200 mg, 1.12 mmol) are treated with anhydrous ZnCl2 (382 mg, 2.81 mmol) and acetic acid (10 mL). The reaction is heated to 105° C. for 48 hours. After cooling to room temperature, the reaction is diluted with ethyl acetate and sequentially washed with H2O (5×) followed by saturated aqueous NaCl. The organics are then dried over Na2SO4 and filtered. After concentration, the crude product is purified by preparative RP LC-MS to give 4-(6-chloro-7-fluoro-1H-indol-2-yl)-benzoic acid methyl ester as an off-white solid: ESMS m/z 304.0 (M+H+).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[CH2:12][CH2:13][CH:14]=1.Cl>C1COCC1>[CH3:25][O:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[CH2:15][N:11]1[CH2:12][CH2:13][CH:14]=[C:9]([CH2:8][CH2:7][C:6]([OH:27])=[O:5])[C:10]1=[O:26]
Reactant: COC(=O)CCC1=CCCN(Cc2ccc(OC)cc2OC)C1=O
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CCC=C(CCC(=O)O)C2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
11 mg of LiOH.H2O solution (0.262 mM) was added to 0.75 ml of THF solution containing 58 mg of 3-[1-(2,4-dimethoxy benzyl)-2-oxo-1,2,5,6-tetrahydro pyridine-3-yl]-propionic acid methyl ester (d) (0.174 mM) in a dropwise manner at 0° C. After the reaction mixture was stirred for 2 hrs at 0° C. and for 1 hr at room temperature, 5% HCl was added to the mixture to pH 2. Then the mixture was extracted three times with 10 ml of ethyl acetate, the organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with methanol/chloroform (1:10) solvent mixture as an eluant to give 44 mg of the title compound (f1) (yield: 80%).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:21][CH2:20]1)=[O:18])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.[OH-].[Li+]>O1CCCC1.CO>[O:35]=[C:26]1[N:25]([CH:22]2[CH2:21][CH2:20][N:19]([C:17]([NH:16][C@H:4]([CH2:5][C:6]3[CH:7]=[C:8]4[C:12](=[C:13]([CH3:15])[CH:14]=3)[NH:11][N:10]=[CH:9]4)[C:3]([OH:36])=[O:2])=[O:18])[CH2:24][CH2:23]2)[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A stirred solution of (R)-methyl-2-(4-(2-oxo-1,2-dihydroquinazolin-3 (4H)-yl)piperidine-1-carboxamido)-3 (7-methyl-1H-indazol-5-yl)propanoate (2.24 g, 4.57 mmol) in 1:1 tetrahydrofuran/methanol (25 mL) was cooled to 0° C. To this mixture was added 2N lithium hydroxide (11.4 mL, 22.8 mmol) in several portions. The reaction mixture was stirred at room temperature for 4.5 h, and then more lithium hydroxide solution (2 mL) was added. Stirring was continued for a further 3 h, and then the mixture was stored at 0° C. overnight. The mixture was concentrated in vacuo and the resulting residue was dissolved in water, cooled to 0° C., and treated with cold 6N hydrochloric acid at 0° C. until pH 2 was attained. The resulting precipitate was collected by filtration, washed with cold water and ether, and then dried under high vacuum overnight to give 1.53 g (80%) as a white solid. Mass spec.: 477.31 (MH)+. HPLC tR=1.87.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:23](=O)[CH3:24]>C(Cl)Cl.CO>[CH2:23]([N:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[CH:14]=2)[CH2:19]1)[CH3:24]
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CCNC2
Reactant: CC=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCN1CCc2cc(OCCCN3CCCCC3)ccc2C1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a 25 mL round-bottom flask is placed 6-(3-Piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (700 mg, 2.01 mol), MP-CNBH3 (2.5 g, 6.05 mmol, 2.42 mmol/g) and DCM/MeOH (9 mL/1 mL). Then, acetaldehyde is added (0.7 mL, 12 mmol) and the reaction is allowed to stir overnight. The reaction is then filtered, washed with DCM/MeOH and concentrated. Column chromatography in 9:1 DCM:MeOH affords 2-ethyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline (493 mg, 71%) of a viscous oil. Mass spec hit M+1, 303; LCMS>95% @ 230 nm and ELSD. Array synthesis followed this general procedure in 4 mL vials to make the following compounds:
Reaction SMILES: [NH:1]([CH2:3][C@@H:4]([OH:7])[CH2:5][CH3:6])[NH2:2].[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][C:18](=[N:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:23]=2[F:30])SC)=O)[CH:12]=[C:11]([Cl:31])[N:10]=1>CC(O)(C)C>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]2[N:1]([CH2:3][C@@H:4]([OH:7])[CH2:5][CH3:6])[N:2]=[C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[C:23]=3[F:30])[N:17]=2)[CH:12]=[C:11]([Cl:31])[N:10]=1
Reactant: CC[C@H](O)CNN
Reactant: CSC(=Nc1ccc(F)c(F)c1F)NC(=O)c1cc(Cl)nc(Cl)c1
Solvent: CC(C)(C)O
Product: CC[C@H](O)Cn1nc(Nc2ccc(F)c(F)c2F)nc1-c1cc(Cl)nc(Cl)c1
Reaction time: 8 h

Procedure:
Intermediate D3 (0.143 g, 0.00137 mol) was added to a solution of intermediate D10 (0.3 g, 0.000457 mol) in t-BuOH (40 ml). The reaction mixture was stirred overnight at reflux. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography over silica gel (eluent: EtOAc/heptane gradient from 20/80 to 50/50). The desired fractions were collected and the solvent was evaporated. Yield: 0.160 g of intermediate D11 (81%; S-enantiomer).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](F)=[O:6].[NH3:12]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH2:12])=[O:6]
Reactant: O=C(F)c1ccc(F)c(Br)c1
Reactant: N
Solvent: O
Product: NC(=O)c1ccc(F)c(Br)c1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
800 g (3.6 moles) of 3-bromo-4-fluoro-benzoyl fluoride were metered into 760 g of 25% strength aqueous ammonia solution (11 moles of NH3), which had been diluted with a further 760 ml of water, at a rate such that an internal temperature of 40° to 50° C. was maintained by the weakly exothermic reaction. After stirring for a further 30 minutes, the crystalline product was isolated by filtration, washed with water and dried. 765 g (97% of theory) of 3-bromo-4-fluoro-benzoic acid amide with a melting point of 131°-133° C. were obtained.
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[NH:14][C:13]1=[O:20])=O)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C@H:12]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[NH:14][C:13]1=[O:20]
Reactant: [H][H]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1N

Procedure:
(3S,4S)-3-benzyloxycarbonylamino-4-acetoxy-azetidin-2-one (912 mg, 3.28 mmol) is hydrogenated with 1 g of 10% palladium on activated carbon in 35 ml of ethyl acetate at 50 psi hydrogen pressure at room temperature for 1.5 hours. After removal of catalyst by filtration, desubstitution (3S,4S)-3-amino-4-acetoxy-azetidin-2-one in ethyl acetate is obtained.
Reaction SMILES: [OH:1][CH:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[C:5]([CH3:12])=[CH:4][CH:3]1[O:13][CH3:14].[N+:15]([C:18]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21])([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:19]=1[C:20]([O:1][CH:2]1[C:8]([CH3:9])([CH3:10])[CH2:7][C:6](=[O:11])[C:5]([CH3:12])=[CH:4][CH:3]1[O:13][CH3:14])=[O:21])([O-:17])=[O:16]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC1C=C(C)C(=O)CC(C)(C)C1O
Product: COC1C=C(C)C(=O)CC(C)(C)C1OC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 61.5 %

Procedure:
5-Hydroxy-4-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU154) obtained in Example 4 (5.95 g, 30 mM) was treated with 2,4-dinitrobenzoic acid according to the procedures described in Example 20. The mixture was re-crystallized twice from a mixed solution of ethyl acetate and hexane to obtain 7.24 g (61.5%) of 5-(2,4-dinitrobenzoyloxy)-4-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU407) as reddish needles. Melting point: 147.5° to 149° C.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CS(O[CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1)(=O)=O>CS(C)=O.[Cl-].[Na+].O>[C:1](=[S:3])([O:4][CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1)[CH3:2]
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reactant: CC([O-])=S
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=S)OC1CCC2(CC1)OCCO2
Temperature: 40 °C
Yield: 64.8 %

Procedure:
Potassium thioacetate (21.39 g, 187 mmol) was added to a stirred mixture of 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (29.5 g, 125 mmol) in DMSO (31.2 ml) and the mixture was heated at 40° C. for 24 h. The mixture was cooled, brine was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried, and evaporated. The residue was purified by column chromatography on silica gel using a Biotage 65i cartridge, eluting with EtOAc/isohexane to give 1,4-dioxaspiro[4.5]dec-8-yl ethanethioate (17.5 g, 81 mmol, 64.8% yield) as a red oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=2)[NH2:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[C:5]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([N:17]=[C:1]=[O:2])[CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc(CCCc2ccccc2)c1
Solvent: Cc1ccccc1
Product: O=C=Nc1cccc(CCCc2ccccc2)c1
Reaction time: 6 h
Yield: 95.8 %

Procedure:
170 g of phosgene are dissolved in 200 ml of toluene at -10° C. At the same temperature, 145 g of 3-(3-phenylpropyl)-aniline in 300 ml of toluene are then slowly added dropwise. The mixture is warmed slowly, the introduction of phosgene is started when 60° C. is reached, and the mixture is brought to the boil. After 6 hours, excess phosgene is flushed out with nitrogen and the mixture is distilled. 156 g of 3-(3-phenylpropyl)-phenyl isocyanate, of boiling point 107°-110° C./0.1 mbar, are obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[Br-:12].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:12][C:9]1[C:2]([F:1])=[C:3]([CH:6]=[C:7]([F:11])[C:8]=1[OH:10])[CH:4]=[O:5]
Reactant: O=Cc1cc(F)c(O)cc1F
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(F)c(O)c(Br)c1F
Temperature: 40 °C
Reaction time: 7 h
Yield: 86169.1 %

Procedure:
To a solution of 2,5-difluoro-4-hydroxybenzaldehyde (37.5 g, 0.237 mmol) in dichloromethane (1.5 L) was added pyridinium tribromide (75.9 g, 0.237 mmol). The reaction mixture was stirred at 40° C. for 7 hrs then at room temperature overnight. The reaction was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to give 48.4 g of crude 3-bromo-2,5-difluoro-4-hydroxybenzaldehyde use as this in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Temperature: 130 °C
Reaction time: 72 h
Yield: 37.4 %

Procedure:
5-Bromo-2-fluoropyridine (3.0 g) was dissolved in DMF (18 ml), and K2CO3 (1.31 g) and tert-butyl piperazine-1-carboxylate (1.76 g) were added thereto, followed by stirring at 130° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (1.21 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[CH3:40][N:41](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:40]([C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:22])([F:21])[F:23])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:31][CH2:32][CH3:33])[O:34][CH2:35][CH3:36])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12])#[N:41]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
A mixture of diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (20.0 mg, 0.0318 mmol), zinc cyanide (3.74 mg, 0.0318 mmol), Pd(PPh3)4 (5.52 mg, 0.00477 mmol) in DMF (0.5 mL) was evacuated and purged with N2 three times. The mixture was irradiated in a microwave reactor at 150° C. for 5 minutes. The crude mixture was passed though a Thiol-SPE cartridge to remove Pd and subsequently purified by MDP. The title compound was obtained as white solid (13.5 mg, 74% yield). 1H NMR (400 MHz, CDCl3) δ=1.29 (t, J=7.1 Hz, 6 H), 3.20 (d, J=21.5 Hz, 2 H), 3.24 (s, 3 H), 4.09 (quin, J=7.3 Hz, 4 H), 4.54 (s, 2 H), 7.31-7.39 (m, 2 H), 7.49 (d, J=8.1 Hz, 2 H), 7.56 (br. s., 1 H), 7.70 (d, J=8.8 Hz, 1 H), 8.44 (s, 1 H), 8.70 (d, J=8.3 Hz, 1 H), 10.85 (s, 1 H). MS (ES+): m/z 575.21 (100) [MH+]; HPLC: tR=1.08 min (UPLC, purity).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1.O>O1CCCC1>[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:9]=1[C:10]([N:12]([CH2:35][C:34]1[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)[CH2:13][C:14]12[CH2:23][CH:18]3[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]3)[CH2:21]1)[CH2:15]2)=[O:11]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(I)ccc1Cl
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(CC23CC4CC(CC(C4)C2)C3)C(=O)c2cc(I)ccc2Cl)cc1
Temperature: 25 °C

Procedure:
Potassium t-butoxide (18.8 g) was added to a stirred solution of 2-chloro-5-iodo-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)benzamide (prepared as described in WO 99/29661) (60.0 g) in anhydrous tetrahydrofuran (600 mL) at 20° C. under nitrogen. After the addition was complete, 4-methoxybenzyl chloride (20.8 mL) was added. The mixture was heated to reflux for 12 hours and then cooled to room temperature. Water (600 mL) was added and the mixture extracted with dichloromethane (1.2 L then 400 mL). Organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH2:2][CH:3]=[CH2:4].[K+].[CH:8](Br)=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[C:10]1([CH:9]=[CH:8][CH:4]=[CH:3][CH2:2][C:1]([OH:6])=[O:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCC(=O)[O-]
Reactant: BrC=Cc1ccccc1
Agent: [K+]
Solvent: CCO
Product: O=C(O)CC=CC=Cc1ccccc1
Temperature: 105 °C

Procedure:
Proceeding as in Example 1, into a 100 cc flask were placed to react: 4.1 g of potassium 3-butenoate (3.3 10-2 mols), 6 g of styryl bromide, a cis-trans mixture, (3.3 10-2 mols), 2.9 g of Ni(PPh3)3 (3.3 10-2 mols) and 40 cc of ethyl alcohol. The mass was heated up to 105° C. under nitrogen atmosphere, for about 2 hours. Operating as in Example 1, there were obtained 2.2 g of 6-phenyl-3,5-hexadienoic acid, a mixture of isomers containing double cis and trans bonds.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[O:17][CH3:18].Br[C:20]1[N:24]2[N:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:23]2=[N:22][CH:21]=1.C([O-])(O)=O.[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[N:24]3[N:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[N:28][C:23]3=[N:22][CH:21]=2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1F
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F
Temperature: 95 °C
Reaction time: 17 h
Yield: 47 %

Procedure:
A mixture of 2-(4-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.637 g, 2.528 mmol), 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.5 g, 1.873 mmol) and saturated aqueous NaHCO3 (10 ml) in 1,2-dimethoxyethane (25 ml) was degassed by evacuation and refilling with nitrogen three times. Tetrakis(triphenylphosphine)palladium(0) (0.169 g, 0.078 mmol) was added and the mixture was stirred under nitrogen at 95° C. for 17 h. After allowing to cool to ambient temperature, the mixture was diluted with ethyl acetate then filtered through glass fibre paper. The combined filtrates were partitioned between water (100 ml) and ethyl acetate (100 ml). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 25% EtOAc/isohexane), to give 275 mg (47%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 4.00 (3H, s), 7.26 (1H, dd, J 10.9, 8.4 Hz), 7.61-7.64 (1H, m), 7.76 (1H, dd, J 2.1, 8.1 Hz), 8.58 (1H, s), 8.81 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:25]([O:22][CH2:21][C:20]([CH3:24])([CH3:23])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)OCc1ccccc1)C(C)(C)CO
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
To a solution of (S)-benzyl 2-(tert-butoxycarbonylamino)-4-hydroxy-3,3-dimethylbutanoate (0.3 g) in DCM (3 mL) was added DMAP (0.109 g, 0.889 mmol) and acetic anhydride (0.084 mL, 0.889 mmol). The reaction mixture was stirred at rt for 16 hrs, then diluted with EtOAc, washed with sat. NaHCO3, water, sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield an oil. The crude product was purified by silica gel chromatography (0-100% EtOAc in hexane) to yield (S)-benzyl 4-acetoxy-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoate (0.31 g). LC/MS (Cond. N-1): [M+Na]+ 402.22, RT=3.821 min.