Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:43]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCN)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCNC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
A solution of 192.4 mg of crude tert-butyl (3RS,4RS)-4-[4-(2-amino-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 3 ml of methylene chloride was treated at 0° C. with 51.7 ml of triethylamine and 64.9 mg (0.462 mmol, 2.0 eq.) of benzoyl chloride and the mixture was stirred at 0° C. for 0.75 hr and at room temperature for 3 hours. The reaction mixture was poured into an ice/water mixture, made basic with saturated sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The organic phases were washed once with water and once with saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The colourless oil was separated on silica gel using a 95:5 mixture of methylene chloride and acetone as the eluent. There were obtained 44.9 mg (33% of theory) of tert-butyl (3RS,4RS)-4-[4-(2-benzoylamino-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in the form of a light yellow oil; MS: 581 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=3[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@H:23]1[O:25][CH2:24]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:22][C@H:23]4[O:25][CH2:24]4)[C:10]=3[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: CCc1ccc(-c2cc3c(O)cccc3o2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)s1

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(5-ethylthiophen-2-yl)-4-hydroxybenzo(b)furan (750 mg), (S)-glycidyl nosylate (875 mg) and potassium carbonate (1.27 g), a crude product of the title compound was quantitatively obtained as a yellow oil.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH:3]=[CH2:4].[CH:7](=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11]>O1CCCC1>[CH2:4]=[CH:3][CH2:2][CH2:1][CH:7]([OH:12])[CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCC[Mg]Br
Reactant: C=CCCC=O
Solvent: C1CCOC1
Product: C=CCCC(O)CCC=C
Temperature: 25 °C

Procedure:
3-Butenyl-magnesium bromide (125 mL, 0.5 M in tetrahydrofuran, 62.5 mmol) was added drop wise to a stirred and cooled (−78° C.) solution of pent-4-enal (4 g, 48.07 mmol) in dry tetrahydrofuran (160 mL). After the addition, the solution was warmed to room temperature and then quenched with NH4Cl solution. The mixture was partitioned with diethyl ether and the organic phase was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 5-15% diethyl ether in hexanes to give the title compound as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1.[H-].[Na+]>CN(C)C=O>[C:13]([C:8]1[CH:9]=[C:10]([CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:7])[O:12][C:18]1[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH:23]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1[N+](=O)[O-]
Yield: 6.4 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2,6-di-t-butylhydroquinone (4.44 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (8.60 g), sodium hydride (55 wt. %, 2.18 g) and anhydrous N,N-dimethylformamide (50 ml) and the reaction mixture was purified to give the title compound (0.60 g).
Reaction SMILES: ClC1C=CC(C2NC(C3C=CC([O:19]C)=CC=3OCC)=NC2CCC)=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[N:38]([C:39]([N:41]3[CH2:46][CH2:45][N:44](C)[CH2:43][CH2:42]3)=[O:40])[C:37]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=3[O:56][CH2:57][CH3:58])=[N:36][CH:35]2[CH2:59][CH:60]2CCC[CH2:61]2)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[N:38]([C:39]([N:41]3[CH2:46][CH2:45][NH:44][C:43](=[O:19])[CH2:42]3)=[O:40])[C:37]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=3[O:56][CH2:57][CH3:58])=[N:36][CH:35]2[CH2:59][CH2:60][CH3:61])=[CH:30][CH:29]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Reactant: CCCC1N=C(c2ccc(OC)cc2OCC)NC1c1ccc(Cl)cc1
Product: CCCC1N=C(c2ccc(OC)cc2OCC)N(C(=O)N2CCNC(=O)C2)C1c1ccc(Cl)cc1

Procedure:
4-[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-propyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-propyl-4,5-dihydro-1H-imidazole (Example 18) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 499.2113, calculated for C26H32N4O4Cl [(M+H)+]499.2107.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Mg].[C:16](OC(=O)C)(=[O:18])[CH3:17].[Cl-].[NH4+]>CCOCC>[C:9]1([CH2:8][CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][C:16](=[O:18])[CH3:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: BrCCCCOCCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)CCCCOCCc1ccccc1
Temperature: 25 °C
Yield: 88 %

Procedure:
[2-(4-Bromobutoxy)ethyl]benzene (10.0 g) in dry ether (80 ml) was added dropwise to magnesium turnings (0.946 g) under nitrogen with stirring to give a gentle reflux. The reaction mixture was refluxed for 1 h, allowed to cool to room temperature and added dropwise to acetic anhydride (8.07 g) in dry ether (55 ml) at -70° under nitrogen with stirring over 1.5 h. The reaction mixture was stirred at -70° for 2 h, allowed to warm to -10° , then treated with saturated ammonium chloride (100 ml). The organic layer was separated and the aqueous layer re-extracted with ER (150 ml). The combined organic extracts were washed with 2N aqueous sodium hydroxide (150 ml), brine (150 ml), dried and evaporated to give an oil (7.54 g) which was purified by FCC eluting with ER-CX (1:3) to give the title compound as a colourless oil (4.34 g). T.l.c. (ER-CX 1:3) Rf 0.25.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[OH:27].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:26][C:22]1[C:21]([OH:27])=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(F)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(F)c1O
Yield: 50.2 %

Procedure:
The product is prepared according to the procedure described in Example 2, stage 2, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (Example 1, stage 2), 357 mg of 2-amino-6-fluorophenol and 600 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 4 ml of pyridine and 4 ml of dimethylformamide. 335 mg of N-(3-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: CO.[N+:3]([C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[NH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])([O-])=O>[Pt]=O.O1CCCC1>[NH2:3][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[NH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21]
Reactant: N#Cc1cccc(Nc2ccc3c(c2[N+](=O)[O-])CCCC3)c1
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cccc(Nc2ccc3c(c2N)CCCC3)c1
Reaction time: 29 h
Yield: 55 %

Procedure:
To a methanol (10 mL) and anhydrous tetrahydrofuran (30 mL) solution of 3-(1-nitro-5,6,7,8-tetrahydronaphthalen-2-ylamino)benzonitrile (1.52 g, 5.17 mmol was added platinum oxide (50 mg), and the mixture was hydrogenated for 29 hours at room temperature under atmospheric pressure. After removal of the catalyst by filtration, the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give the titled compound as yellow powder (747 mg, yield 55%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[CH2:18]2)[CH2:13][CH2:14][NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:31](OCC(F)(F)F)=[O:32]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[CH2:18]2)[CH2:13][CH2:14][N:15]([CH:31]=[O:32])[OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: O=COCC(F)(F)F
Reactant: CCOc1cc(C(CCNO)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CCN(O)C=O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC

Procedure:
(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide was prepared by the procedure of Example 7 from N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (0.7 g, 1.7 mmol) and 2,2,2-trifluoroethyl formate (2.2 g, 17 mmol) in THF (10 mL) to give a white solid (480 mg, 64% yield): mp: 79-81° C. 1H NMR (DMSO-d6) δ 1.31 (t, J=7 Hz, 3H, CH3), 1.99 (s, 3H, CH3), 2.32-2.42 (m, 2H, CH2), 3.40-3.52 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.98-4.02 (m, 2H, CH2), 4.14 (d, J=17 Hz, 1H, NCHH), 4.54 (d, J=17 Hz, 1H, NCHH), 5.23-5.28 (m, 1H, NCH), 6.92-6.96 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H, CH), 8.24-8.27 (m, 1.5H, Ar, CH), 9.64 (s, 0.5H, OH), 10.07 (s, 0.5H, OH), 10.30 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.70, 24.50, 28.34, 28.52, 43.39, 45.81, 46.19, 46.74, 51.14, 51.92, 55.45, 63.81, 111.97, 112.39, 116.63, 117.39, 119.66, 131.60, 132.70, 137.02, 142.21, 142.30, 147.96, 148.54, 157.35, 168.21, 168.38, 168.51; Anal Calcd for C23H27N3O6+0.4H2O: C, 61.57; H, 6.25; N, 9.36; H20, 1.61. Found: C, 61.77; H. 6.18; N, 8.97; H2O, 0.55.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][NH:5][N:4]=1)=[O:2].[CH2:8]=[O:9].C(N(CC)CC)C>CC(C)=O>[OH:9][CH2:8][N:5]1[CH:6]=[CH:7][C:3]([CH:1]=[O:2])=[N:4]1
Reactant: O=Cc1cc[nH]n1
Reactant: C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccn(CO)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
The mixture of 0.96 g of 3-formyl-1H-pyrazole, 0.60 g of paraformaldehyde and 0.3 ml of triethylamine was stirred at 100° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure to obtain 1.21 g of 1-(hydroxymethyl)-3-formyl-1H-pyrazole. The crude product was used for next process without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C@:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)([CH3:18])[N:15]([CH2:27][C:28]([OH:30])=[O:29])[C:14](=[O:31])[C:9]21[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O[C:37]1[C:42]([F:43])=[C:41]([F:44])[C:40]([F:45])=[C:39]([F:46])[C:38]=1[F:47])=O>CN(C=O)C>[F:25][C:23]1[CH:24]=[C:19]([C@@:16]2([CH3:18])[N:15]([CH2:27][C:28](=[O:30])[O:29][C:37]3[C:38]([F:47])=[C:39]([F:46])[C:40]([F:45])=[C:41]([F:44])[C:42]=3[F:43])[C:14](=[O:31])[C:9]3([CH2:10][CH2:11][CH2:12][CH2:13]3)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:17]2)[CH:20]=[C:21]([F:26])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12CCCC2
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)C(=O)C12CCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of [(8R)-6-(tert-butoxycarbonyl)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetic acid (254 mg, 0.579 mmol, described in Intermediate 21) in DMF (2 mL) was added pentafluorophenyl trifluoroacetate (0.7 mL, 4.07 mmol). The reaction mixture was stirred for 4 h at ambient temperature, then partitioned between saturated aqueous NaHCO3 (30 mL) and EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified on silica gel, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:27]([O-:29])=[O:28])[C:5]([O:9][CH2:10][N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)N1COc1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)N1COc1c(F)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-fluoro-5-(phthalimido)methoxybenzene (5.0 g, 16.4 mmol) was slowly added to a stirred mixture of con. sulfuric acid-con. nitric acid (10:1, 20 ml) at −20° C. Solution was then warmed to ambient temperature and allowed to stir for 1 hr. Addition to ice-water resulted in a light yellow precipitate which was separated by filtration. Column chromatography on silica gel in hexane-methylene chloride (3:7) furnished the title compound (3.2 g); 1H NMR (CDCl3, 300 MHz) 4.06 (3H, s), 7.54 (1H, d, J=8.5 Hz), 7.84 (2H, m), 7.97 (2H, m) ppm.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[O:62][CH3:63])[C:50]1=[O:64]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:48][C@H:49]1[CH2:55][CH2:54][CH2:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[O:62][CH3:63])[C:50]1=[O:64])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccccc1N1CCCC[C@H](N)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccccc4OC)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (23 mg, 0.040 mmol) and Intermediate 62 (14 mg, 0.040 mmol) to give a white solid (10 mg, 31% yield). Anal. Calcd. for C44H54N4O7S m/z 782.4. found: 783.3 (M+H)+; 1H NMR (400 MHz, chloroform-d) δ ppm 7.08-7.33 (10H, m), 6.98-7.08 (2H, m), 6.91-6.98 (2H, m), 5.31 (1H, t, J=4.67 Hz), 5.08-5.18 (1H, m), 4.91-5.02 (1H, m), 4.76 (1H, dd, J=10.17, 6.32 Hz), 4.03-4.35 (4H, m), 3.84-3.96 (1H, m), 3.80 (3H, s), 3.68 (3H, s), 3.29-3.46 (1H, m), 3.04-3.23 (2H, m), 2.65-2.91 (5H, m), 2.30-2.49 (3H, m), 1.90-2.05 (3H, m), 1.57-1.90 (8H, m), 1.41-1.56 (3H, m).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=1>>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH:3]2[CH2:4][N:1]([C:17]3[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=3)[CH2:2]2)=[N:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(OC2CNC2)nc1
Reactant: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(C(F)(F)F)cn3)C2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Example 8.8 is prepared analogously to 8.1. 2-(Azetidin-3-yloxy)-5-trifluoromethyl-pyridine and (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1) are used as starting materials. Reaction conditions are stirring for 12 h at 50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C(#N)C.[CH2:13]([NH2:16])[CH2:14][CH3:15].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:16][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCCNCc1ccc(Cl)cc1
Reaction time: 0.75 h

Procedure:
A solution of 48.3 g 4-chlorobenzyl chloride in 40 ml. acetonitrile was added to a mixture of 18 g. propylamine, 12.6 g. sodium hydroxide, 50 ml. acetonitrile and 30 ml. water. The mixture was shaken intermittently for 45 minutes. An exothermic reaction occurred and a white solid separated in the lower phase. After a period of four days the reaction mixture was poured into a liter of water and the organic phase isolated with ether. Distillation of the ethereal extract gave an oily product N-4-chlorobenzyl-N-propylamine, m.p. 101°-106° C./1.7-2.5 mm. Hg.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCCCCC>[Cl:19][C:18]([Cl:21])([Cl:20])[CH2:17][O:16][C:14]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC(Cl)(Cl)Cl

Procedure:
L-phenylalanine was reacted with 2,2,2-trichloroethyl chloroformate in a 2N sodium bicarbonate solution, and after the usual working-up there was obtained the desired acid as crystals, melting point 126° (from methylene chloride/hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([CH:19]=[CH:20][C:21]#[N:22])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>O1CCCC1.CO.[Pd]>[C:21]([CH2:20][CH2:19][C:11]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:9][CH:10]=1)#[N:22]
Reactant: N#CC=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: N#CCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
2.94 g (10.16 mmol) of 3-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrol-4-yl]acrylonitrile [prepared as described in step (iv) above] were dissolved in a mixture of 20 ml of tetrahydrofuran and 20 ml of methanol, after which 2.94 g of 10% palladium on carbon were added to the solution. The mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was washed with a mixture of 30 ml of diethyl ether and 30 ml of ethanol to give 1.80 g (yield 61%) of the title compound as a pale orange powder.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:37])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:36])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:35])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:34])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:33])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:3][C:4]([OH:6])=[O:5].[Na].O.Cl>CCCCCO>[CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:37])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:36])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:35])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:34])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:33])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Agent: Cl
Agent: [Na]
Solvent: CCCCCO
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC(=O)O

Procedure:
82 g of 3,7,11,15,19,23,27-heptamethyl-2,6,10,14,18,22,26-octacosaheptaenoic acid was dissolved in 1 l of n-amyl alcohol and 74 g of metallic sodium was added portionwise while the solution was vigorously stirred. After metallic sodium was completely dissolved, the reaction solution was poured into iced water and was made acidic by adding 300 ml of 6 N hydrochloric acid. It was then extracted with 1 l of n-hexane, washed with water, dried and concentrated. 78 g of colorless, oily 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenoic acid was obtained as the crude product. The product was then added dropwise to 500 ml of an ethereal suspension of 10 g of lithium aluminum hydride while being cooled by ice and stirred. After stirring was continued for 30 minutes, 10 ml of water with 10 ml of a 15% caustic soda solution, and 30 ml of water were sequentially added. The precipitated crystal was filtered and washed twice with 200 ml of ether. The filtrate was concentrated and the concentrate was defined by silica gel column chromatography, providing the captioned 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenol as a colorless oily matter.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([CH3:28])[CH:20]=4)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:29]C(N(C)C)=O.N1CCCC1>CN(C=O)C>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:20]=[C:21]5[C:22](=[CH:23][CH:24]=4)[NH:25][CH:29]=[CH:28]5)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)ccc1[N+](=O)[O-]
Reactant: CC(=O)N(C)C
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc3[nH]ccc3c2)C1
Temperature: 130 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a stirred solution of 1-cyclobutyl-4-{[3-(3-methyl-4-nitrophenoxy)azetidin-1-yl]carbonyl}-1,4-diazepane (40 mg, 0.16 mmol) in DMF (2 ml) was added DMF.DMA (100 μl, 0.75 mmol) and pyrrolidine (100 μl, 0.75 mmol) at 130° C. in one portion. The suspension was stirred for 2 h at 130° C. then cooled to room temperature and concentrated at reduced pressure. The residue was dissolved in 1:1 THF/MeOH (4 ml) and Raney Nickel (0.7 ml, 50% w/v in H2O) and hydrazine (0.7 ml, 1M solution in THF) were added. The reaction was stirred at room temperature for 3 hours then filtered over celite and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 95:5:1) to give the title compound (43 mg, 37%) as light brown oil.