Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[O:29][C:30]3[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-]#N.[Na+].[CH3:41][OH:42]>C(Cl)Cl.CCOC(C)=O.O=[Mn]=O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:24]([C:25]([F:27])([F:26])[F:28])=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[O:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:42][CH3:41])=[O:35])=[CH:36][CH:37]=3)=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=Cc1ccc(Oc2c(-c3ccc(OCc4ccccc4)cc3)c(C(F)(F)F)cc3ccccc23)cc1
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2c(-c3ccc(OCc4ccccc4)cc3)c(C(F)(F)F)cc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 4-{[2-{4-[(phenylmethyl)oxy]phenyl}-3-(trifluoromethyl)-1-naphthalenyl]oxy}benzaldehyde (187) (0.23 g, 0.45 mmol) in MeOH (4 mL) and CH2Cl2 (2 mL) was added NaCN (0.12 g, 2.26 mmol) followed by MnO2 (0.56 g, 5.42 mmol). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc (50 mL) and filtered through a pad of celite on top of a layer of silica gel. The filtrate was washed with water, brine, dried over Na2SO4, filtered, and concentrated to give the crude product as a light yellow solid, which upon trituration with 1% MeOH in hexanes, gave 0.21 g (86%) of the title compound (188) as a white solid. mp 131-132° C. 1H NMR (400 MHz, CDCl3): δ 3.85 (s, 3H), 5.01 (s, 2H), 6.58 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.6 Hz, 2H), 7.30-7.44 (m, 5H), 7.55-7.66 (m, 2H), 7.79 (d, J=8.8 Hz, 2H), 7.89 (d, J=8.2 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 8.24 (s, 1H). LCMS (ESI): m/z 551 (M+Na)+.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.[Si:10]([O:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C@H:20]([CH:36]=[O:37])[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C@H:20]([CH:36]([OH:37])[C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Ic1ncn2ccsc12
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C(O)c2ncn3ccsc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 69.5 %

Procedure:
7-[[(2S,4R)-4-t-Butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]hydroxymethyl]-imidazo[5,1-b]thiazole (4.18 g) was prepared in the same manner as in step a) of Synthesis Example 1, except that 3.39 g of 7-iodoimidazo[5,1-b]thiazole and 4.61 g of (2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine-2-aldehyde were used as the starting compounds.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:33]([N:36]([CH3:54])[C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[C@H:39]([CH2:44][S:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)(=[O:47])=[O:46])[CH2:38]1)([CH3:35])[CH3:34].[OH-].[Na+]>C1COCC1>[CH:33]([N:36]([CH3:54])[C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:5](=[O:7])[CH2:4][CH2:3][C:2](=[O:1])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@H:39]([CH2:44][S:45]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)(=[O:46])=[O:47])[CH2:38]1)([CH3:35])[CH3:34]
Reactant: O=C(O)CCC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CCC(=O)c2cccc(C(F)(F)F)c2)[C@H](CS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Commercially available 4-oxo-4-(3-trifluoromethylphenyl)butyric acid (45.5 mg, 0.185 mmol) was dissolved in dry THF (3 mL). To the above solution was added triethyl amine (18.7 mg, 0.185 mmol) and isobutyl chloroformate (25.3 mg, 0.185 mmol) at 0° C. The mixture was stirred at 0° C. for 5 min. before the solution of (1R,3R,4S)—N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)cyclohexane-1,4-diamine (see 30b) (50 mg, 0.154 mmol) in dry THF (3 mL) was added. The resulting mixture was warmed up to room temperature. The reaction was completed by 0.5 h. The mixture was treated with 1 N NaOH (5 mL) and extracted with CH2Cl2 (10 mL×2) The organic extracts were washed with water, brine and evaporated. The residue was chromatographed on silica gel (4% NH4OH/MeOH/CH2Cl2) to give the product (53 mg). MS found:(M+1)+: 553.32
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([NH2:12])[C@H:9]([OH:13])[C@H:8]([OH:14])[CH:7]=1)=[O:5])[CH3:2].CS(O)(=O)=O>CCC(=O)CC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([NH2:12])[C@@H:9]2[O:13][C:6]([CH2:11][CH3:10])([CH2:7][CH3:8])[O:14][C@@H:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](O)[C@@H](O)[C@H](N)C1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CCC(=O)CC
Product: CCOC(=O)C1=C[C@H]2OC(CC)(CC)O[C@H]2[C@H](N)C1
Temperature: 25 °C
Yield: 174.4 %

Procedure:
In a 25 ml two necked round bottom flask equipped with a dean stark separator, a reflux condenser, a thermometer, a magnetic stirrer and an inert gas supply, 0.90 g (4.47 mmol) (3R,4S,5R)-5-amino-3,4-dihydroxy-cyclohex-1-enecarboxylic acid ethyl ester was suspended in 9.0 ml 3-pentanon, 0.32 ml (4.92 mmol) methanesulfonic acid was added, the mixture was heated to reflux, with a dean stark separator for 2 hours. The reaction mixture was cooled to r.t., diluted with 9.0 ml ethyl acetate and the mixture was extracted with 9.0 ml 1M aqueous sodium hydrogen carbonate solution. The organic layer was dried over about 1 g sodium sulfate and filtered. The filter cake was washed with about 9 ml of ethyl acetate and the combined filtrates were evaporated in a rotary evaporator at 40° C./10 mbar to yield as the crude intermediate 1.05 g (3aR,7R,7aS)-7-amino-2,2-diethyl-3a,6,7,7a-tetrahydro-benzo[1,3]dioxole-5-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][CH:7]=[CH:6]1)(=O)[CH3:2].[CH2:10](O)[CH2:11]CC.CC(C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:5]1([O:4][CH2:1][CH2:2][CH2:10][CH3:11])[CH2:9][CH2:8][CH:7]=[CH:6]1
Reactant: CCCCO
Reactant: CC(=O)OC1C=CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: CC(C)=O
Solvent: O
Product: CCCCOC1C=CCC1

Procedure:
2-Cyclopentenyl acetate (0.30 g) and n-butanol (0.40 g) were mixed and stirred vigorously at 40° C. for 4 hours with a solution of 0.020 g of tetrabutylammonium hydrogen sulfate in 0.25 g of water. At the end of the reaction period acetone was added to give a single phase, and the solution was analyzed by gas chromatography using an Apiezon column programmed at 60-220° C. Peaks for the cyclic compounds had the following relative areas.
Reaction SMILES: C(O)(=O)C(O)=[O:3].C([O:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:30][C@H:31]([NH:33][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH2:44][C:45]([F:48])([F:47])[F:46])[CH3:32])=[CH:25][C:26]=2[C:28]#[N:29])[CH2:21][CH2:20]1)(=O)C1C=CC=CC=1.[OH-].[K+:50].O>CO>[OH-:3].[K+:50].[OH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:30][C@H:31]([NH:33][CH2:34][CH2:35][O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH2:44][C:45]([F:48])([F:46])[F:47])[CH3:32])=[CH:25][C:26]=2[C:28]#[N:29])[CH2:21][CH2:20]1
Reactant: C[C@H](Cc1cc(C#N)c2c(c1)CCN2CCCOC(=O)c1ccccc1)NCCOc1ccccc1OCC(F)(F)F
Reactant: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](Cc1cc(C#N)c2c(c1)CCN2CCCO)NCCOc1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.6 %

Procedure:
3-{7-Cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}-propyl benzoate monooxalate(10.0 g) was dissolved. in methanol (40 mL), then an aqueous potassium hydroxide solution, which was prepared from potassium hydroxide (2.93 g) and water (10 mL) was added little by little, and the mixture was stirred at room temperature for overnight. To the reaction mixture, water (150 mL) was added and extracted with ethyl acetate (150 mL and 50 mL) successively. The combined ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (7.86 g).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:24]=[CH:25][CH:26]=1)=[CH2:20])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:22]=2)[CH3:20])[C:9]=1[OH:8])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C(c1cccc(-c2ccccn2)c1)c1cccc(C(C)(C)C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(c1cccc(-c2ccccn2)c1)c1cccc(C(C)(C)C)c1O
Yield: 84.7 %

Procedure:
A solution of 5 (1.12 g, 2.67 mmol) in methanol (40 mL) and ethyl acetate (80 mL) was treated with 20% palladium on activated carbon (0.2 g, 0% wet) and hydrogenated in a Parr shaker at 10 psi for 3.5 hr. The catalyst was filtered off and washed with ethyl acetate. The solvent was removed on a rotary evaporator and the crude product was purified by chromatography on silica (80 g) with 2% ethyl acetate in hexane (1 L), then 4% (2 L) to yield pure A2 (0.75 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=2)[CH2:30][CH2:29]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCCc1cc(CCC=O)n(-c2cccc(Cl)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2cccc(Cl)c2)n1

Procedure:
312 mg (84.2%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(3-chlorophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (236.75 mg, 0.814 mmol), 1-(2-fluorophenyl)piperazine (192.9 mL, 1.221 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: CO[C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C@@H:19]3[CH2:22][CH2:21][N:20]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:16]=2)[O:8][N:7]=1.[CH3:31][NH2:32].O>O1CCOCC1>[CH3:31][NH:32][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C@@H:19]3[CH2:22][CH2:21][N:20]3[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH:16]=2)[O:8][N:7]=1
Reactant: COC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)on1
Reactant: CN
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)on1
Temperature: 120 °C
Yield: 66 %

Procedure:
To a solution of 3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-isoxazolyl]propionic acid methyl ester (330 mg, 0.79 mmol) in 1,4-dioxane (4 mL) was added 40 wt % solution of methylamine in H2O (2.7 mL, 31.6 mmol). The mixture was heated at 120° C. for 12 h, cooled, and concentrated. The residue was dissolved in water and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by CC on SiO2 with EtOAc/hexane 2:1 to give N-methyl-3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-isoxazolyl]propionamide (217 mg, 66%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:5][N:4]=1.[CH3:23][S-:24].[Na+]>CO>[CH3:15][C:14]([C:12]1[CH:13]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:24][CH3:23])[N:7]=2)[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(-c2nc(CCl)no2)cc(C(C)(C)C)c1O
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCc1noc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Temperature: 75 °C

Procedure:
A mixture of 2.3 g (0.007 mole) of 4-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol and 0.7 g (0.009 mole) of sodium thiomethoxide in methanol (90 ml) is heated at 75° C. for 1.5 hours. The solution is concentrated to one-third the volume (~30 ml) and diluted with water (50 ml), acidified (pH 4) with 1N hydrochloric acid and extracted with ethyl acetate (2×50 ml). The organic phase is washed with saturated sodium chloride (2×40 ml), dried (anhydrous magnesium sulfate) and evaporated to give a solid. Recrystallization from ethyl acetate and hexane affords 1.3 g (55%) of analytically pure (2,6-bis(1,1-dimethylethyl)-4-[3-[(methylthio)methyl]-1,2,4-oxadiazol-5-yl]phenol, mp 97°-98° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])[CH3:2].ClC(Cl)(Cl)C(O)=O.[N-:20]=[N+]=[N-].[Na+]>>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][NH:20][C:7]2=[O:12])[CH3:2]
Reactant: CCc1cccc2c1CCC2=O
Reactant: [N-]=[N+]=[N-]
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [Na+]
Product: CCc1cccc2c1CCNC2=O
Temperature: 0 °C
Yield: 21.3 %

Procedure:
A mixture of 0.9 g (5.63 mmol) of 2,3-dihydro-4-ethyl-1H-inden-1-one and 20 g of trichloroacetic acid was heated at 60°-65° for 30 minutes. To this was added 2.5 g (38.3 mmol) of sodium azide and the mixture was heated at 60°-65°, under nitrogen, for 18 hours. It was poured into 200 ml of ice water and extracted with methylene chloride. The organic layer was washed with saturated sodium hydrogen carbonate, saturated sodium chloride, dried (MgSO4), and concentrated. The residue was chromatographed (SiO2) using a gradient from pure methylene chloride to 19:1 methylene chloride-methanol to give a solid which was rechromatographed using 98:1 methylene chloride-methanol. Recrystallization from toluene/hexane gave 0.21 g (21%) of product; mp 123°-126°.
Reaction SMILES: Br[CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].[Mg].[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)=[O:9].[NH4+].[Cl-]>CCOCC.C1COCC1>[CH2:3]([CH:2]([CH2:5][CH3:6])[CH:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=1)[OH:9])[CH3:4]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CCC(Br)CC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of 3-bromopentane (0.331 mol) in (C2H5)2O (200 ml) was added dropwise to a solution of magnesium turnings (0.331 mol) in (C2H5)2O, the mixture was stirred at RT for 2 hours and then cooled to 0° C. A solution of N-(4-formylphenyl)acetamide (0.11 mol) in THF (400 ml) was added dropwise and the mixture was stirred for 10 minutes. The mixture was poured into aqueous NH4Cl and extracted with EtOAc. The organic layer was dried, filtered off and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1). The pure fractions were collected and evaporated, yielding 13.5 g (52%) of (±)-N-[4-(2-ethyl-1-hydroxybutyl)phenyl]acetamide (interm. 13).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=1.C(N(CC)CC)C.[F:22][S:23]([F:37])([F:36])([F:35])([F:34])[C:24]1[CH:33]=[CH:32][C:27]([CH2:28][N:29]=[C:30]=[S:31])=[CH:26][CH:25]=1>CN(C)C=O>[F:22][S:23]([F:34])([F:35])([F:36])([F:37])[C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:30](=[S:31])[NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=2)=[CH:32][CH:33]=1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: FS(F)(F)(F)(F)c1ccc(CN=C=S)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(CNC(=S)NCc2ccc(S(F)(F)(F)(F)F)cc2)cc1F
Temperature: 25 °C

Procedure:
N-(4-aminomethyl-2-fluoro-phenyl)-methane sulphonamide (237 mg, 1.09 mmol) was dissolved in dimethylformamide (1 ml) and to this was added triethylamine (132 mg, 1.30 mmol) and 4-(pentafluorosulphanyl)benzylisothiocyanate (300 mg, 1.09 mmol) dissolved in dimethylformamide (1 ml). The reaction mixture was stirred over night at room temperature, the solvent removed under vacuum and the residue dissolved in a little methanol. Following column chromatographic cleaning (silica gel, hexane/ethyl acetate 1:5), the product was obtained as a solid (305 mg, 57% of the theoretical amount).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([NH2:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[N+:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:17][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: CCCCCCN
Product: CCCCCCNc1cccc([N+](=O)[O-])c1
Yield: 78.3 %

Procedure:
Using the general procedure, 3-bromonitrobenzene (202 mg, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (6:1) as eluent afforded the desired product as a light yellow solid (174 mg, 78% yield). Rf=0.5 (hexane/ethyl acetate=5:1).
Reaction SMILES: [CH2:1]([NH:13][CH:14]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P(Cl)(Cl)(Cl)(Cl)Cl.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].[OH-].[Na+]>C1C=CC=CC=1.O>[CH:22]([N:25]([CH:26]([CH3:28])[CH3:27])[CH:14]=[N:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH3:24])[CH3:23]
Reactant: CC(C)NC(C)C
Reactant: CCCCCCCCCCCCNC=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCN=CN(C(C)C)C(C)C
Reaction time: 12 h

Procedure:
A solution of 213 g of dodecylformamide (1.0 mole) in 500 ml of anhydrous benzene is added dropwise at 20°-30° to a suspension of 208 g of phosphorus pentachloride (1.0 mole) in 750 ml of anhydrous benezne. After a further 12 hours of stirring at 30°, the reaction mixture is concentrated in vacuo to dryness. The residue is then dissolved in 100 ml of anhydrous benzene, and 202 g of di-isopropylamine (2.0 moles) added dropwise at 40°-50°. The whole is heated for 2 hours at 50°; water and ice are added, and the mixture rendered alkaline with aqueous sodium hydroxide solution. The organic layer is then separated and concentrated by evaporation. The N1,N 1 -diisopropyl-N2 -dodecyl-formamidine obtained as residue boils at 125°-128°C and 0.03 Torr.
Reaction SMILES: O=C1NC2C=CC=CC=2S[C@H](C2C=CC=CC=2)[C@@H]1NC(=O)[C@H](C)NC(=O)CC1C=CC=CC=1.Br.[NH2:35][C@H:36]1[C:42](=[O:43])[NH:41][C:40]2[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=2[S:38][C@H:37]1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[F:54][C:55]1[CH:56]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:77](O)=[O:78])[CH2:67][C:68]2[NH:69][C:70]3[C:75]([CH:76]=2)=[CH:74][CH:73]=[CH:72][CH:71]=3)=[O:64])[CH:58]=[C:59]([F:61])[CH:60]=1>>[F:61][C:59]1[CH:58]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:77]([NH:35][C@@H:36]2[C:42](=[O:43])[NH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[S:38][C@@H:37]2[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:78])[CH2:67][C:68]2[NH:69][C:70]3[C:75]([CH:76]=2)=[CH:74][CH:73]=[CH:72][CH:71]=3)=[O:64])[CH:56]=[C:55]([F:54])[CH:60]=1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@@H](Cc1cc2ccccc2[nH]1)C(=O)O
Reactant: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Agent: Br
Agent: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1
Product: O=C(Cc1cc(F)cc(F)c1)N[C@@H](Cc1cc2ccccc2[nH]1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (97) was used except that (2,3-cisS)-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide (9d) (105 mg) was used as the amine component and N-[(3,5-difluorophenyl)acetyl]-3-(1H-indol-2-yl)-L-alanine (110b) (119 mg) was used as the acid component to afford the title compound as a 1:1 mixture with the 2S,3S diastereomer (173 mg), white solid, m.p. 85-90° C. 1H NMR (300 MHz, d6-DMSO) δ 2.40 (m, 2H), 3.03 (m, 4H), 4.26 (m, 1H), 4.72 (m, 1H), 5.17 (d, 1H, J=7 Hz), 5.82 (d, 1H, J=6 Hz), 6.89-7.79 (m, 12H), 8.21 (m, 1H), 10.53 (m, 1H). MS APCI, m/z=611(M+1). LC/MS: 2.66 min.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:28]([O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOC(=O)C=Cc1ccc(O)cc1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
4-Hydroxy cinnamic acid (10 g, 61 mmol) was combined with 1-hexadecanol (14.0 g, 58 mmol), p-toluenesulfonic acid (1.2 g, 6.3 mmol) and 100 ml toluene and heated to 140° C. for 24 h with continual removal of water using a Dean-Stark distillation apparatus. The mixture was cooled to room temperature and 50 ml ethyl acetate added. The solution was washed with water, 5% sodium hydrogen carbonate, brine and then dried over magnesium sulfate. The product was recrystallized from ethyl acetate to give 4.8 g 3-(4-hydroxy-phenyl)-acrylic acid hexadecyl ester.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:24]([N:26]3[CH2:30][C@H:29]([S:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])(=[O:33])=[O:32])[CH2:28][C@H:27]3[C:41](O)=[O:42])=[O:25])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:24]([N:26]3[CH2:30][C@H:29]([S:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])(=[O:32])=[O:33])[CH2:28][C@H:27]3[C:41]([NH:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[C:3](=[O:10])[C:4]([NH:6][CH:7]3[CH2:8][CH2:9]3)=[O:5])=[O:42])=[O:25])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide and (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxylic acid in step 1. MS (m/e)=634.15 [M+H+].