Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][C:14]2[N:23]3[N:24]=[C:25]([NH2:27])[N:26]=[C:22]3[C:21]3[CH:20]=[CH:19][C:18]([NH:28][CH2:29][CH2:30][OH:31])=[CH:17][C:16]=3[N:15]=2)=[CH:11][C:10]=1[O:34][CH3:35])C1C=CC=CC=1.C(OC1C=CC(CC2N3N=C(N)N=C3C3C=CC(F)=CC=3N=2)=CC=1OC)C1C=CC=CC=1>>[NH2:27][C:25]1[N:26]=[C:22]2[N:23]([C:14]([CH2:13][C:12]3[CH:32]=[CH:33][C:9]([OH:8])=[C:10]([O:34][CH3:35])[CH:11]=3)=[N:15][C:16]3[CH:17]=[C:18]([NH:28][CH2:29][CH2:30][OH:31])[CH:19]=[CH:20][C:21]=32)[N:24]=1
Reactant: COc1cc(Cc2nc3cc(NCCO)ccc3c3nc(N)nn23)ccc1OCc1ccccc1
Agent: COc1cc(Cc2nc3cc(F)ccc3c3nc(N)nn23)ccc1OCc1ccccc1
Product: COc1cc(Cc2nc3cc(NCCO)ccc3c3nc(N)nn23)ccc1O
Yield: 86 %

Procedure:
Operating as in Example 83, but employing 5-(4-benzyloxy-3-methoxy-benzyl)-8-(2-hydroxy-ethylamino)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, prepared as described in Example 67, instead of 5-(4-benzyloxy-3-methoxy-benzyl)-8-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, the title compound was obtained in 86% yield.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:21](Cl)([Cl:23])=[O:22]>C1(C)C=CC=CC=1>[CH2:1]([N:6]([C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:19])([CH3:20])[C:9]=2[CH:8]=1)[C:21]([Cl:23])=[O:22])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (51) (200 mg, 0.73 mmole) in 2 mL toluene was treated with 0.4 mL of a 20% phosgene solution in toluene, stirred at room temperature for 12 hours and concentrated in vacuo to provide 0.24 g of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride (53) as a pale yellow solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[O:17])[CH:13]=[CH:12][C:11]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)C)(C)(C)C.C(OC(=O)NCC1C=C(Br)C=CC=1OC1C=CC(Cl)=C(Cl)C=1)(C)(C)C.C1CCN2C(=NCCC2)CC1.C(N1CCNCC1)(C)C.F[B-](F)(F)F>C1COCC1>[Cl:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[Cl:34])[O:27][C:11]1[CH:12]=[CH:13][C:14]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH:24]([CH3:25])[CH3:26])[CH2:22][CH2:23]2)=[O:17])=[CH:15][C:10]=1[CH2:9][NH:7][CH3:6]
Reactant: CC(C)N1CCN(C(=O)c2ccc(Oc3ccc(Cl)c(Cl)c3)c(CN(C)C(=O)OC(C)(C)C)c2)CC1
Agent: CC(C)(C)OC(=O)NCc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)N1CCNCC1
Agent: F[B-](F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CNCc1cc(C(=O)N2CCN(C(C)C)CC2)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 56 %

Procedure:
[2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-piperazine-1-carbonyl)-benzyl]-methyl-carbamic acid tert-butyl ester. To a solution of [5-bromo-2-(3,4-dichloro-phenoxy)-benzyl]-carbamic acid tert-butyl ester (327.0 mg, 0.71 mmol) in THF (2 mL) were added DBU (0.30 mL, 2.0 mmol), 1-isopropyl piperazine (0.30 mL, 2.5 mmol), Hermann's catalyst (31.9 mg, 0.034 mmol), tri-t-butylphosphium tetrafluoroborate (26.4 mg, 0.091 mmol), and Mo(CO)6 (211.0 mg, 0.80 mmol). After 6 min in a microwave reactor at 125° C., the mixture was cooled to rt and concentrated. Purification by FCC gave the desired product (212.5 mg, 56%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:15]([O:19][C:20]([C:22]1[CH:32]=[C:31]([OH:33])[C:25]2[CH2:26][CH:27]([CH2:29][OH:30])[O:28][C:24]=2[CH:23]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([C:22]1[CH:32]=[C:31]([O:33][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:25]2[CH2:26][CH:27]([CH2:29][OH:30])[O:28][C:24]=2[CH:23]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(CO)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(CO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
Benzyl bromide (1.8 mL, 15.2 mmol) and Cs2CO3 (4.89 g, 15.0 mmol) were added to a solution of 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (4.0 g, 15.0 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with H2O (60 mL) and extracted EtOAc (2×60 mL). The organic layers were washed with H2O (2×100 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 30-40% EtOAc in hexanes to give a pale yellow oil (4.43 g, 83% yield). 1H NMR (400 MHz, CDCl3) δ 7.34-7.45 (m, 5 H) 7.19 (s, 1 H) 7.09 (s, 1 H) 5.13 (s, 2 H) 4.96-5.03 (m, 1 H) 3.85 (ddd, J=12.00, 6.95, 3.28 Hz, 1 H) 3.74 (dt, J=12.13, 6.06 Hz, 1 H) 3.27 (dd, J=16.42, 9.60 Hz, 1 H) 3.01 (dd, J=16.42, 7.07 Hz, 1 H) 1.58 (s, 9 H); LCMS for C21H24O5 m/z 357.00 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26]1[NH:30][C:29]2[C:31]3[CH2:32][C:33]([CH3:43])([CH3:42])[O:34][C:35]=3[C:36]([C:38](OC)=O)=[CH:37][C:28]=2[N:27]=1>C1COCC1>[Cl:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[C:19]=1[NH:25][C:26]1[NH:30][C:29]2[C:31]3[CH2:32][C:33]([CH3:43])([CH3:42])[O:34][C:35]=3[C:36]([C:38]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=4)[N:14]=3)=[CH:37][C:28]=2[N:27]=1
Reactant: COc1cc(OC)cc(C(N)=NO)c1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2noc(-c3cc4nc(Nc5c(Cl)cccc5Cl)[nH]c4c4c3OC(C)(C)C4)n2)c1
Yield: 20.6 %

Procedure:
The title compound was prepared by following the procedure as described for Example-156 using N′-hydroxy-3,5-dimethoxybenzimidamide (Intermediate-54, 0.075 g, 0.30 mmol), sodium hydride (0.021 g, 0.51 mmol), methyl 2-((2-chloro-6-chlorophenyl)amino)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Step-1 of Intermediate-6, 0.100 g, 0.255 mmol) and THF to afford 0.029 g of the desired product. 1HNMR (DMSO-d6): δ 1.29 (d, J=7.8 Hz, 6H), 3.09 (s, 2H), 3.85 (s, 6H), 6.58 (s, 1H), 7.30 (m, 3H), 7.44 (d, 1H), 7.78 (s, 1H). MS [M+H]+: 552.09.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[N:6]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(C2CC2)nn1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-cyclopropyl-1H-pyrazole-5-amine (250 mg, 2.0 mmol), 4-(2-chloroethyl)morpholine HCl salt (372 mg, 2.0 mmol) and potassium carbonate (829 mg, 6.0 mmol) in dry DMF (10 mL) was stirred at room temperature overnight. After being diluted with ethyl acetate (50 mL), the reaction mixture was filtered through a pad of Celite and rinsed with ethyl acetate (2×15 mL). The combined filtrates were concentrated in vacuo and purified by ISCO (CH2Cl2-MeOH—NH4OH: 100:0:0 to 90:10:1) on silica gel to afford the desired amino-pyrazole.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:26][N:27]2[CH2:30][CH:29]([C:31]([O:33]C)=[O:32])[CH2:28]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2].[OH-].[Na+]>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:26][N:27]2[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[O:10][N:9]=1)[CH3:2]
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)cc2)n1
Yield: 83.3 %

Procedure:
The title compound (0.15 g) was synthesized in a yield of 86% as a white crystalline solid using by conducting the similar reaction to that mentioned in Example 3 (3e) using methyl 1-({4-ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylate (0.180 g, 0.39 mmol) that was obtained in Example 13 (13b) and a 1N aqueous solution of sodium hydroxide (1.2 ml, 1.2 mmol).
Reaction SMILES: S([O-])([O-])(=O)=O.[Bi+3:6].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Bi+3].[N+:18]([O-:21])([OH:20])=[O:19].[Bi]=O>>[N+:18]([O-:21])([O-:20])=[O:19].[Bi+3:6].[N+:18]([O-:21])([O-:20])=[O:19].[N+:18]([O-:21])([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: O=[Bi]
Agent: [Bi+3]
Product: O=[N+]([O-])[O-]

Procedure:
There are three forms of bismuth nitrate, two of which are insoluble in water. One way to obtain soluble bismuth nitrate is to roast the bismuth sulfate first at a low temperature (200° C.) to convert it to the oxide, and then subject the oxide to concentrated nitric acid. The molar ratio of acid to bismuth oxide should be greater than or equal to 4:1 in order to avoid producing insoluble bismuth nitrate. Using this method, the bismuth was completely dissolved. Fine crystals of soluble bismuth nitrate were then formed through evaporation of a majority of the liquor, followed by filtration.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[O:24]2)[CH2:20][CH2:19]1)=[O:17].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:40][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[O:24]2)[CH2:20][CH2:19]1)=[O:17])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)OC(=O)c3ccccc34)cnc12
Reactant: NCc1ccccc1
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)OC(=O)c3ccccc34)cnc12
Yield: 76.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(3-oxo-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.160 g, 0.352 mmol) obtained in step 2 and benzylamine (0.100 mL, 0.881 mmol), the title compound (0.142 g, 76%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:14][O+:15](C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:14][OH:15])[CH:3]=1
Reactant: C[O+](C)C
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: OCc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.8 %

Procedure:
4-chloropyridine-N-oxide (4.4 g) was dissolved in methylene chloride (68 ml), trimethyloxonium tetrafluoroborate (5.0 g) was added to the mixture, and the mixture was stirred for 90 minutes at room temperature. The solvent was removed under reduced pressure, the obtained residue was dissolved in methanol, and an aqueous solution (6.8 ml) of ammonium peroxodisulfate (1.54 g) was added thereto under heat reflux. An aqueous solution (3.4 ml) of ammonium peroxodisulfate (0.77 g) was further added to the mixture after 30 minutes, the mixture was stirred for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give (4-chloro-2-pyridinyl)methanol (3.0 g).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>[OH-].[Na+].O>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([N:2]2[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cnc(CC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 4-imidazole acetic acid hydrochloride (1 g, 6.15 mmol) in 6.2 mL of 1 N NaOH and 18 mL of water was added 4-toluenesulfonyl chloride (1.29 g, 6.77 mmol) and the mixture was stirred at ambient temperature. The pH of the mixture was maintained at 8.5 by addition of 1 N NaOH. After 3 hours, a total volume of 12 mL of 1 N NaOH was added and a clear solution was obtained. This solution was extracted with ether and the aqueous solution was acidified to pH 1 with 3 N HCl. The mixture was cooled in an ice bath and N-(4-Toluenesulfonyl)imidazole-4-yl-acetic acid was isolated by filtration (white crystals, 1.10 g, 63% yield). m.p. 105-106° C. (decomp); 1H NMR (CDCl3) δ 10.0 (br, 1H), 8.04 (s, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.28 (s, 1H), 3.65 (s, 2H), 2.45 (s, 3H). 13C NMR (CD3OD) δ 173.6, 148.1, 138.9, 138.0, 136.1, 131.6, 128.7, 117.0, 34.0, 21.6.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CCCCC)=C=[O:17]>>[CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:2]([C:1]([NH2:8])=[O:17])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCN=C=O
Agent: O=C1CN(Cc2ccccc2)C(=O)N1
Product: CCCCCC(N)=O

Procedure:
1-Benzylimidazolidine-2,4-dione (100 mg, 0.526 mmol) and 1-isocyanatopentane (71.4 mg, 0.63 mmol) were reacted in analogy to example 1. Yield: 15 mg (9%), M+H+: 304.18.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[C:12]2=[N:11][C:10]=1[C:23]([OH:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:23]([C:10]2[N:11]=[C:12]3[N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:25])=[CH:29][CH:28]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCCCN1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CCCCN1CCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Yield: 89 %

Procedure:
Coupling of 6-(benzyloxy)-1-butyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.87 mmol) and 4-fluorobenzylamine (0.120 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.349 g (88% yield) of the title amide as white crystals; mp 107-109° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.96 (3H, t, J=7.3 Hz, CH3), 1.33-1.43 (2H, m, CH2), 1.56-1.63 (2H, m, CH2), 3.41 (2H, t, J=7.4 Hz, CH2), 3.70 (2H, t, J=8.9 Hz, CH2), 4.13 (2H, t, J=8.9 Hz, CH2), 4.50 (2H, d, J=5.8 Hz, NCH2), 5.10 (2H, s, OCH2), 7.0 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.33-7.37 (3H, m, aromatics), 7.46-7.48 (2H, m, aromatics), 7.68 (1H, broad t, NH). MS (ESI+) m/e 451 [M+H+].
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].C([Si](C)(C)[O:27][C@@H:28]1[CH2:33][C:32](=[CH:34]/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][C:40]([CH3:59])([CH3:58])[CH2:41]/[CH:42]=[CH:43]/[C:44]([C:54]([F:57])([F:56])[F:55])([O:49][Si](C)(C)C)[C:45]([F:48])([F:47])[F:46])[CH2:31][C@@H:30]([O:60][Si](C(C)(C)C)(C)C)[CH2:29]1)(C)(C)C>O1CCCC1>[F:46][C:45]([F:47])([F:48])[C:44]([C:54]([F:55])([F:56])[F:57])([OH:49])/[CH:43]=[CH:42]/[CH2:41][C:40]([CH3:59])([CH3:58])[CH2:39][CH2:38][CH2:37]/[CH:36]=[CH:35]/[CH:34]=[C:32]1[CH2:33][C@@H:28]([OH:27])[CH2:29][C@H:30]([OH:60])[CH2:31]1
Reactant: CC(C)(C/C=C/C(O[Si](C)(C)C)(C(F)(F)F)C(F)(F)F)CCC/C=C/C=C1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C/C=C/C(O)(C(F)(F)F)C(F)(F)F)CCC/C=C/C=C1C[C@@H](O)C[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
1.40 g of tetrabutylammoniumfluoride trihydrate (4.45 mmol) in 6 ml of tetrahydrofuran was carefully dried by stirring during 2 h at room temperature over 1.78 g of 3 Å molecular sieve. This solution was then added to the above prepared 270 mg of (1R,3R)-1,3-bis-(tert-butyl-dimethyl-silanyloxy)-5-((2E,9E)-12,12,12-trifluoro-7,7-dimethyl-11-trifluoromethyl-11-trimethylsilanyloxy-dodeca-2,9-dienylidene)-cyclohexane (0.371 mmol) and kept for 1.5 h at 40°. The reaction mixture was then poured onto crushed ice/NH4Cl, extracted twice with ether, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/ethylacetate=25/75) yielded 165 mg of the title compound as colourless oil. Typically, this product is contaminated with small amounts of 2Z-isomer which can be removed by HPLC.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12]Br)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].C1COCC1.[OH-].[NH4+:20]>O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:12][NH:20][C:5]2=[O:6]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc(Br)c1CBr
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NCc2c(Br)cccc21
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of methyl 3-bromo-2-(bromomethyl)benzoate (27 mmol) in THF (100 mmol) was added ammonium hydroxide (9 mL) dropwise at rt. The reaction mixture was allowed to stir overnight and then diluted with 30 mL of water. The solution was extracted with DCM, dried over Na2SO4, filtered and concentrated to give 4-bromoisoindolin-1-one (5.20 g, 91%).
Reaction SMILES: [C:1]1([CH:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Mg]Br>O1CCCC1>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH:12]([C:13]#[N:14])[C:15]#[N:16]
Reactant: N#CC(C#N)=Cc1cccc2ccccc12
Reactant: COc1ccccc1[Mg]Br
Solvent: C1CCOC1
Product: COc1ccccc1C(c1cccc2ccccc12)C(C#N)C#N
Reaction time: 1.5 h

Procedure:
A flask was charged with (1-naphthalenylmethylene)-propanedinitrile (408 mg, 2 mmol) and 10 mL anhydrous tetrahydrofuran. To this stirred solution was added, at room temperature, 2-methoxy phenyl magnesium bromide (2.4 mL, 2.4 mmol, 1 M in tetrahydrofuran). The reaction was stirred 1.5 hours, after which it was quenched with 1 N hydrochloric acid and taken up in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated to dryness. Following purification on silica (20% ethyl acetate/hexanes) 551 mg product was isolated as an off white foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:17][C:11]1[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(COc2cccnc2N)c1F
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c1F

Procedure:
A mixture of 2-amino-3-(2-fluoro-3-methylbenzyloxy)pyridine (2.00 g, 0.0086 mol), 4chlorophenyl isothiocyanate (1.75 g, 0.0103 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 3.21g (93%), m.p. 184°-187 ° C.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]([O:18][CH3:19])=[CH:4][CH:3]=1.[F-].[Cs+].[C:22]([C:26]1[CH:31]=[CH:30][C:29](/[C:32](/[Sn](CCCC)(CCCC)CCCC)=[CH:33]\[C@@H:34]2[N:38]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[O:48][CH3:49])[C:37](=[O:50])[CH2:36][CH2:35]2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].O>CN(C)C=O.[Cu](I)I.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(OCC)(=O)C>[C:22]([C:26]1[CH:31]=[CH:30][C:29](/[C:32](/[C:2]2[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[N:7]=2)=[CH:33]\[C@@H:34]2[N:38]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[O:48][CH3:49])[C:37](=[O:50])[CH2:36][CH2:35]2)=[CH:28][CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC)c1ccc(C(C)(C)C)cc1
Reactant: COc1ccc(COc2nc(I)ccc2OC)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2nc(/C(=C/[C@H]3CCC(=O)N3Cc3ccc(OC)cc3OC)c3ccc(C(C)(C)C)cc3)ccc2OC)cc1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
6-Iodo-3-methoxy-2-[(4-methoxybenzyl)oxy]pyridine obtained in Reference Example 4-33 (657 mg), cesium fluoride (269 mg), copper iodide (185 mg) and tetrakis(triphenylphosphine)palladium(0) (102 mg) were added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(tributylstannyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-26 (604 mg) in N,N-dimethylformamide (6 mL), and the mixture was stirred at 65° C. for 1.5 hours. Water and ethyl acetate were added to the reaction solution. After filtration through celite, the organic layer was washed with brine. The organic layer dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-methoxy-6-[(4-methoxybenzyl)oxy]-pyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a yellow oil (449 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[CH2:21]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[C:33]([F:40])[C:32]=1[F:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:21]([C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[N:4][C:5]([C:8]3[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=3)=[N:6][CH:7]=2)=[C:33]([F:40])[C:32]=1[F:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
Reactant: CCCCCCCCCCc1ccc(B(O)O)c(F)c1F
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCc1ccc(-c2cnc(-c3ccc(OCCCCCC)nc3)nc2)c(F)c1F
Yield: 39.2 %

Procedure:
The reaction of 2 mmol of 5-bromo-2-(6-hexyloxypyridin-3-yl)pyrimidine, 2 mmol of 4-decyl-2,3-difluorophenylboronic acid, 4 mmol of sodium carbonate and 0.02 mmol of tetrakis(triphenylphosphine)palladium(0) in 8 ml of toluene, 3 ml of ethanol and 3 ml of water is carried out analogously to the procedure indicated for Example 1a). The crude product is separated off by column chromatography on silica gel 60 using ethyl acetate as eluent and is recrystallized from acetonitrile, giving 0.4 g (39%) of colorless crystals, X 96 SA 127 I.