Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]2=[C:11]([NH2:13])[CH:12]=1.[O-:14][C:15]#[N:16].[Na+]>Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:15]([NH2:16])=[O:14])[C:6]2[CH2:7][CH:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1cc(NC(N)=O)c2c(c1)OC(C)C2

Procedure:
2.5 grams of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine are dissolved in 16 cc of 0.1N HCl and upon gradual addition of 1.1 gram of sodium cyanate to the resulting solution a white crystalline solid precipitates. The reaction mixture is then heated in a water-bath and, after 90 minutes, cooled and filtered. By recrystallizing the obtained precipitate from ethyl alcohol 1.9 gram (61 percent of theoretical) of the desired product is obtained. M.p. 204°-06° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[Br:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34](O)=[O:35])[CH:29]=1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:34]([C:30]2[CH:29]=[C:28]([Br:27])[CH:33]=[CH:32][N:31]=2)=[O:35])[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cc(Br)ccn1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cc(Br)ccn2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-bromo-pyridine-2-carboxylic acid.
Reaction SMILES: [CH2:1]([C:4](O)=O)[CH2:2]S.C(S)C(O)=O.[CH2:12]([C:14]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][CH3:16])[OH:13].C(O)C(O)C>>[CH2:12]([C:14]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][CH3:16])[OH:13].[CH2:2]=[CH:1][CH3:4]
Reactant: O=C(O)CCS
Agent: CCC(CO)(CO)CO
Agent: O=C(O)CS
Solvent: CC(O)CO
Product: C=CC

Procedure:
Referential Example 1 was repeated but using 278 g of mercaptopropionic acid, 250 g of thioglycollic acid, 181 g of trimethylolpropane and 133 g of propylene glycol to give trimethylolpropane-propylene glycolmercaptopropionic acid-thioglycollic acid ester as a transparent liquid having 2.5 functional bases on an average. This is designated hereinafter as compound (b-4).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[C:35]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.O1CCOCC1.C(Cl)(Cl)Cl>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[C:35]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-n2ccnc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-n2ccnc2)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-4-(1H-imidazol-1-yl)benzamido)-4-phenylbenzoate (0.12 g) in ethyl acetate (3.6 mL), methanol (1.8 mL), and dioxane (1.8 mL), 10% palladium-carbon (61 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture, 10% palladium-carbon (30 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Chloroform was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: chloroform] to obtain 0.084 g of tert-butyl 2-(2-hydroxy-4-(1H-imidazol-1-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: C([NH:8][CH2:9][CH:10]([OH:23])[CH2:11][O:12][C:13]1[C:21]2[C:17](=[N:18][C:19](=[O:22])[N:20]=2)[CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH2:8][CH2:9][CH:10]([OH:23])[CH2:11][O:12][C:13]1[C:21]2[C:17](=[N:18][C:19](=[O:22])[N:20]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: O=C1N=c2cccc(OCC(O)CNCc3ccccc3)c2=N1
Agent: [Pd]
Solvent: CO
Product: NCC(O)COc1cccc2c1=NC(=O)N=2

Procedure:
1.6 g of palladium-on-charcoal catalyst are added to a solution of 15.5 g of 4-(3-benzylamino-2-hydroxypropoxy)benzimidazol-2-one in 160 ml of methanol, and the mixture is hydrogenated until the calculated amount of hydrogen has been absorbed. The catalyst is filtered off and the solvent distilled off to leave 4-(3-amino-2-hydroxypropoxy)-benzimidazol-2-one, which melts at 188°-190° after recrystallization from ethanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[F:28][C:26]([F:29])([F:27])[CH2:25][N:21]1[C:20]([C:14]2[CH:15]=[C:16]3[N:12]([C:11]4[CH:30]=[C:7]([CH:4]5[CH2:3][CH2:2][N:1]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:6][CH2:5]5)[CH:8]=[CH:9][C:10]=4[O:19][CH2:18][CH2:17]3)[N:13]=2)=[N:24][CH:23]=[N:22]1
Reactant: NC(=O)CBr
Reactant: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(C3CCNCC3)ccc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)CN1CCC(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
A mixture of 9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (180 mg, 0.43 mmol) in DMF (1 mL) was treated with potassium carbonate (89 mg, 0.65 mmol) and bromo acetamide (77 mg, 0.56 mmol) and then stirred at RT for 18 h. The reaction mixture was partitioned between ethyl acetate and water, the aqueous layer extracted with ethyl acetate and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated in diethyl ether to give 143 as a pale yellow solid (115 mg, 54%). 1H NMR (DMSO-d6, 400 MHz): δ 8.21 (s, 1 H); 7.75 (d, J=2.2 Hz, 1 H); 7.28 (dd, J=8.4, 2.2 Hz, 1H); 7.20 (d, J=8.3 Hz, 1 H); 7.15 (s, 2 H); 6.97 (s, 1 H); 5.73 (q, J=8.8 Hz, 2 H); 4.49 (t, J=6.0 Hz, 2 H); 3.20 (t, J=6.0 Hz, 2 H); 2.96-2.85 (m, 4 H); 2.62-2.52 (m, 1 H); 2.24-2.14 (m, 2 H); 1.84-1.66 (m, 4 H). LCMS: RT=6.55 min, M+H+=476
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10](NCCNC(=O)OC(C)(C)C)=[O:11])[CH:3]=1.C(OCC)(=[O:25])C.CCCCCC>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]([OH:11])=[O:25])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: COc1cnc(C(=O)NCCNC(=O)OC(C)(C)C)cc1Cl
Solvent: CCCCCC
Product: COc1cnc(C(=O)O)cc1Cl

Procedure:
In analogous manner, from 3.3 g of 4-chloro-5-methoxy-2-pyridinecarboxylic acid there was obtained t-butyl [2-(4-chloro-5-methoxypyridine-2-carboxamido)ethyl]carbamate as pale yellow crystals (ethyl acetate/n-hexane), m.p. 132°-133°, which, in turn, was converted into N-(2-aminoethyl)-4-chloro-5-methoxypyridine-2-carboxamide hydrochloride, white crystals (methanol/ether), m.p. 256°-257°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C1([C@H](N)C)C=CC=CC=1>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)c1ccc(F)cc1
Agent: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: O=C(O)[C@H](O)c1ccc(F)cc1
Temperature: 60 °C
Yield: 48.8 %

Procedure:
The reaction was performed in a 1 L reactor under an atmosphere of nitrogen with 200 rpm stirring. 2-(4-Fluorophenyl)-2-hydroxyacetic acid (139 g, 816.98 mmol) was charged into the reactor. Ethanol (800 mL) was added which resulted in a turbid mixture. The mixture was heated to reflux with a ramp of 1° C./min. (R)-(+)-1-phenylethylamine (68.5 mL, 531.04 mmol) was then added within 5 minutes. The clear homogenous solution was then allowed to slowly cool to 60° C. with a ramp of 1° C./min. When that temperature was reached, seeds of 95:5 diastereomeric purity was added (˜100 mg). Crystallisation now slowly initiated. The temperature was ramped down to 20° C. with 0.5° C./min. When that temperature was reached the mixture was allowed to stir for another 2 hours. The mixture was then filtrated. This furnished crystals of the ammonium salt (95 g). This salt was then re-crystallised from ETOH (99.5%, 800 mL) using the following procedure: In a 1 L reactor and under an atmosphere of nitrogen, the salt obtained above was charged into the reactor. EtOH (800 mL) was added (a suspension was obtained) and the temperature was then increased to reflux with a ramp of 1° C./min. When all salt was dissolved, the temperature was ramped down with 1° C./min-->65° C. When that temperature was reached (clear homogenous solution), seeding crystals were added (approximately 0.5 g was added). Crystallization initiated immediately but very slowly. The temperature was then ramped down to 20° C. with 0.5° C./min. The mixture was then stirred (200 rpm) over night. After filtration and drying in vacuo, 67.9 g of the salt was obtained. Chiral HPLC analysis of the free acid of the salt showed an enantiomeric excess of 95.2% (97.6:2.4 er). The salt was recrystallized one more time from ETOH (99.5%, 500 mL) using the same procedure as described above but the mixture was only allowed to stir for 2 hours at room temperature instead of stirring over night. After filtration and drying, 56.3 g of crystals of the ammonium salt were obtained. Chiral HPLC analysis of the free acid showed an enantiomeric excess of 99.1%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH3:33])[C:30]([NH2:32])=[O:31])=[CH:25][CH:24]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:33][N:29]([C:26]1[CH:27]=[CH:28][C:23]([NH:11][C:7]2[N:8]=[CH:9][C:10]3=[C:2]([CH3:1])[N:3]=[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=4)[N:5]3[N:6]=2)=[CH:24][CH:25]=1)[C:30]([NH2:32])=[O:31]
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Reactant: CN(C(N)=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(Nc3ccc(N(C)C(N)=O)cc3)ncc12
Yield: 40.3 %

Procedure:
In a similar manner as described for Example 41, 5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 45) (0.025 g, 0.09 mmol), N-(4-bromophenyl)-N-methylurea (0.02 g, 0.09 mmol), Pd2(dba)3 (0.008 g, 0.01 mmol), 2-(Di-t-butylphosphino)biphenyl (0.008 g, 0.03 mmol), and NaOtBu (0.011 g, 0.11 mmol) in 1,4-dioxane (1 mL) gave N-methyl-N-[4-({5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-yl}amino)phenyl]urea (0.016 g) as a yellow solid. 1H NMR (Acetone-d6): δ9.11 (s, 1H), 8.99-8.95 (m, 1H), 8.82-8.76 (m, 1H), 8.69-8.66 (m, 1H), 7.95-7.91 (m, 1H), 7.80-7.76 (m, 2H), 7.74-7.69 (m, 3H), 7.57-7.52 (m, 2H), 6.30 (bs, 1H), 5.61 (bs, 1H), 2.76 (d, J=4.8 Hz, 3H), 2.57 (s, 3H). MS m/z 442 (M+1).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[C:20]2[S:16][C:17](=[O:22])[NH:18][C:19]2=[O:21])=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)OCCOc1ccc(C=O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)OCCOc1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 87.5 %

Procedure:
4-(2-isopropoxyethoxy)benzaldehyde obtained in step (0.98 g, 4.71 mmol) and 2,4-thiazolidinedione (0.55 g, 4.71 mmol) were dissolved in 20 ml of toluene, piperidine (0.23 ml, 2.36 mmol) and acetic acid (0.13 ml, 2.36 mmol) were subsequently added thereto, and the resulting solution was heated overnight under reflux in a Dean-Stark water trap. Then, the mixture thus obtained was cooled and filtered. The precipitate was washed with ether or hexane and dried to afford Derivative 1 having the above formula, (5-(4-(2-isopropoxyethoxy)benzylidene)thiazolidine-2,4-dione) (1.26 g, yield: 87.5%) as yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:18][CH3:19])=[C:6]([C:10]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[O:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5]([O:18][CH3:19])=[C:6]([C:10]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[O:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1c(-c2coc(C(=O)O)c2)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(N)cccc1-c1coc(C(=O)O)c1
Yield: 73.3 %

Procedure:
4-(3-nitro-2-methoxy-phenyl)-furan-2-carboxylic acid 28c (500 mg, 1.9 mmol) was dissolved in 15 mL of ethyl acetate followed by addition of 100 mg of palladium on carbon and ammonium formate (429 mg, 7.6 mmol). The reaction mixture was heated to reflux for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered to remove palladium on carbon and concentrated under reduced pressure to obtain the title compound 4-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid 28d (325 mg, yield 73.4%) as a yellow oil.
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH:5][C@@H:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1Cl>[CH3:13][C@H:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:4][NH:5]1
Reactant: C[C@H](NCCBr)c1ccccc1
Agent: Br
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1Cl
Product: C[C@@H]1NCCc2ccccc21
Temperature: 145 °C
Reaction time: 0.67 h
Yield: 70 %

Procedure:
10.0 g(30.1 mmole) of (S)-(-)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 12(1) above was suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145° C. 13.47 g(96.54 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at constant temperature, cooled to room temperature and poured onto 250 g of ice-water with stirring. 30 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide, and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.10 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH:10]([CH3:18])[C:11]([O:16][CH3:17])=[CH:12][C:13](Cl)=[O:14])=[CH:7][CH:6]=1.[CH3:29][NH2:30]>C1COCC1>[CH3:29][NH:30][C:13](=[O:14])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]([O:9][C:8]1[CH:19]=[CH:20][C:5]([O:4][C:3]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:24][C:2]=2[Cl:1])=[CH:6][CH:7]=1)[CH3:18]
Reactant: COC(=CC(=O)Cl)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reaction time: 1 h

Procedure:
A mixture of 4-[4-(2-chloro-4-trifluoromethylphenoxy) phenoxy]-3-methoxy-2-pentenoyl chloride (15 mm) and THF (15 ml.), at 0°, is prepared and then slight excess of methylamine introduced. The reaction mixture is allowed to stand under nitrogen for about one hour. Then the reaction is allowed to rise to RT and solvent removed. The residue is taken up in methylene dichloride, washed, dried and solvent removed under vacuum to yield N-methyl 4-[4-(2-chloro-4-trifluoromethylphenoxy) phenoxy]-3-methoxy-2-pentenamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:51][CH:52]([NH:61][C:62]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[O:63])[CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=O)=O)=CC=1>>[CH2:65]([O:64][C:62]([NH:61][CH:52]([CH2:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[CH2:51][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1)=[O:63])[C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Reactant: Cc1ccc(S(=O)(=O)OCC(CCc2ccccc2)NC(=O)OCc2ccccc2)cc1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCC(CCc4ccccc4)NC(=O)OCc4ccccc4)cc3)cc21

Procedure:
Analogously to Method I, 0.250 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 259b) and 0.281 g of 2-benzyloxycarbonylamino-4-phenylbutyl toluene-4-sulphonate are reacted. The title compound is obtained as a colourless oil. Rf=0.27 (2:1 EtOAc-heptane); Rt=6.01.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCO.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.O>[F:11][C:5]1[C:4]([CH3:12])=[CH:3][C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1cc(Br)cc(C(=O)O)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: [K+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cccc(F)c2)cc(C(=O)O)c1F
Temperature: 85 °C
Yield: 75.2 %

Procedure:
To a solution of 5-bromo-2-fluoro-3-methyl-benzoic acid (697 mg, 2.99 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (502 mg, 3.59 mmol, 1.2 eq) in a mixture of EtOH (10 mL), dioxane (20 mL) and H2O (10 mL) were added K2CO3 (142 mg, 1.03 mmol, 2.5 eq) and Pd(PPh3)4 (345 mg, 0.30 mmol, 0.1 eq). The mixture was heated at 85° C. overnight. The reaction was quenched by addition of 1M HCl and the aqueous phase extracted with EtOAc. The organic extract was dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by chromatography to give the title compound as a solid (558 mg, 73%).
Reaction SMILES: [C-]#[N:2].[Na+].S(=O)(=O)(O)O.[C-]#N.[CH2:11]([C:13]([CH2:24][CH3:25])(O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:12].[OH-].[Na+]>C(O)(=O)C>[CH2:11]([C:13]([NH2:2])([CH2:24][CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:12]
Reactant: [C-]#N
Reactant: CCC(O)(CC)Cc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCC(N)(CC)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Powdered sodium cyanide (1.18 g, 24 mmol) was placed in a flask and covered with 5.5 mL of acetic acid. A mixture of sulfuric acid (3 mL) and acetic acid (2.75 mL) was cooled to 0° C. and then added to the cyanide suspension over a period of 3 minutes. The mixture was stirred for 30 minutes at room temperature, followed by the addition of 1,1-diethyl-2-(4-methoxyphenyl)ethanol (4.6 g, 22 mmol). The mixture was stirred overnight then poured into ice and sodium hydroxide. The product was extracted with ether, and the ether layer dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in 20% sodium hydroxide and refluxed overnight under nitrogen. The reaction was cooled, diluted with water, and extracted with ether. The ether layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase HPLC (C-18 using 0.1% HCl/acetonitrile as the elutant) to give 1.91 g of 1,1-diethyl-2-(4-methoxy-phenyl)ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:9])=[O:8].C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:8]
Reactant: O=C(O)c1[nH]ccc1Cl
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)c1[nH]ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 3-chloro-1H-pyrrole-2-carboxylic acid (15 g, 0.1 mol) in N,N-dimethylformamide (300 mL) and triethylamine (72 mL, 0.52 mmol) under argon atmosphere was added benzyl bromide (61 mL, 0.52 mmol) at 0-5° C. and the reaction was stirred mechanically overnight at room temperature. Next day, the reaction mixture was concentrated in vacuum and the residue was suspended in 4% aqueous solution of sodium bicarbonate (300 mL) and extracted with ethyl acetate (2×250 mL). The organic layers were mixed and washed with more 4% aqueous solution of sodium bicarbonate, water and brine, and were dried (magnesium sulphate, MgSO4) and concentrated under reduced pressure to give 21.4 g of a residue corresponding to the title compound (88% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[N:11]12[CH2:18][CH2:17][C:14]([C:19]([O:21]CC)=O)([CH2:15][CH2:16]1)[CH2:13][CH2:12]2>C1COCC1>[N:11]12[CH2:12][CH2:13][C:14]([C:19]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[OH:21])([CH2:15][CH2:16]1)[CH2:17][CH2:18]2
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2ccc(OC)cc2)C23CCN(CC2)CC3)cc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A solution of 4-(methyloxy)phenylmagnesiumbromide (0.5 M in THF, 6.5 mL, 3.25 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1587 g, 0.866 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.273 g, 89.0%). EI-MS m/z 354(M+H+) Rt (1.74 min).