Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C@@H:18]1[CH2:27][C@H:26]([CH3:28])[C:21]2([O:25][CH2:24][CH2:23][O:22]2)[C@H:20]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:19]1)=O)C1C=CC=CC=1.C(ON1C(=O)CCC1=O)(OCC1C=CC=CC=1)=O>CO.C(Cl)Cl.CCOC(C)=O.[Pd]>[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C@H:18]1[CH2:27][C@@H:26]([CH3:28])[C:21]2([O:22][CH2:23][CH2:24][O:25]2)[C@@H:20]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:19]1.[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C@@H:18]1[CH2:27][C@H:26]([CH3:28])[C:21]2([O:22][CH2:23][CH2:24][O:25]2)[C@H:20]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:19]1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OCc2ccccc2)C12OCCO2
Agent: [Pd]
Agent: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H]1C[C@H](c2ccncc2N)C[C@H](NC(=O)OCc2ccccc2)C12OCCO2
Product: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OCc2ccccc2)C12OCCO2
Reaction time: 20 h
Yield: 28 %
Yield: 13 %

Procedure:
(+/−)-Benzyl ((6R,8R,10S)-8-(3-((benzoxycarbonyl)amino)pyridin-4-yl)-10-methyl-1,4-dioxaspiro[4.5]decan-6-yl)carbamate (1.0 equiv.) was dissolved in MeOH (0.10 M) and degassed with Argon to vacuum. Pd/C (0.05 equiv.) was added and the mixture was stirred under a H2 balloon for 20 hrs. The mixture was filtered and concentrated. The crude and CBZ-OSu (0.99 equiv.) were dissolved in DCM (0.20 M). The reaction was stirred at room temperature for 2 hrs. The solution was diluted with EtOAc and washed with water, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by ISCO chromatography. Purification was completed via SFC (40% EtOH, 15 mL/min, OJ column) to yield benzyl (6S,8S,10R)-8-(3-aminopyridin-4-yl)-10-methyl-1,4-dioxaspiro[4.5]decan-6-ylcarbamate (28% yield, 99% ee) and benzyl (6R,8R,10S)-8-(3-aminopyridin-4-yl)-10-methyl-1,4-dioxaspiro[4.5]decan-6-ylcarbamate (13% yield, 99% ee). LC/MS (m/z)=398.2 (MH+), Rt=0.64 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:23])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.O>ClCCl>[F:11][C:12]1[CH:13]=[C:14]([C:15]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)=[O:16])[CH:18]=[C:19]([F:23])[C:20]=1[O:21][CH3:22]
Reactant: COc1c(F)cc(C(=O)Cl)cc1F
Reactant: c1cc2c(cn1)NCCO2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(F)cc(C(=O)N2CCOc3ccncc32)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
In a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (60 mg, 0.44 mmol) and 3,5-difluoro-4-methoxy-benzoyl chloride (120 mg, 0.572 mmol) were dissolved in dichloromethane (1 ml). Triethylamine (0.080 ml, 0.57 mmol) was added thereto and stirred at room temperature for 1 hour. After completion of the reaction by adding water to the reaction mixture, the organic layer was extracted with dichloromethane, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:ethyl acetate:n-hexane=1:2:5. The fractions containing the product were collected and evaporated to obtain the target compound 28 as white solid (102 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:23][C:24]1[CH:25]=[C:26]([C:35](=[O:37])[CH3:36])[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH2:33]Br>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:29]4[CH:28]=[CH:27][C:26]([C:35](=[O:37])[CH3:36])=[CH:25][C:24]=4[Br:23])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1ccc(OCCCBr)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(Br)c1
Yield: 68.6 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.1 g, 9.5 mmol ). K2CO3 (2.0 g)-1-[3-bromo-4-(3-bromopropoxy)phenyl]ethanone (3.1 g, 9.2 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of reaction, the solvent was concentrated and the mixture was extracted into dichloromethane (200 ml). The insolubles were filtered off. The dichloromethane was concentrated again. The crude residue was purified by flash chromatography over a silica gel column. (SiO2, 49 g; eluted with dichloromethane, 500 ml; 1% methanol:dichloromethane, 600 ml; 3% methanol; 97% dichloromethane, 600 ml). The material thus obtained (3.26 g, 72%) was recrystallized from ethanol (40 ml) to give 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol -3- yl)-1-piperidinyl]-propoxy]-3-bromophenyl]ethanone as light yellow crystals (3.0 g), m.p.=126°-128° C. ANALYSIS: Calculated for C23H24BrFN2O3: 58.12%C 5.09%H 5.89%N Found: 57.64%C 5.35%H 5.55%N
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[C:14]([CH2:16][C:17]([NH2:19])=[O:18])#[N:15].[Na].[N-]=[N+]=[N-]>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[C:14]([NH2:15])=[C:16]([C:17]([NH2:19])=[O:18])[N:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCC(N)=O
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(Cn2nnc(C(N)=O)c2N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
A stirred mixture of 4-methylbenzyl bromide (1.3 g, 7.0 mmol) and sodium azide (754 mg, 11.6 mmol) in ethanol (8 ml) was refluxed under a nitrogen atmosphere for 3 hours, cooled to ambient temperature, and filtered. Separately, 2-cyanoacetamide (588 mg, 7.0 mmol) was added to a stirred, refluxing solution of sodium (167 mg, 7.2 mmol) in ethanol (15 ml), followed by dropwise addition of the above azide solution over 20 min. The resulting slurry was PG,15 refluxed 1 hour, cooled to ambient temperature, and refrigerated. The precipitate was collected by filtration, washed with ethanol, and dried under vacuum to provide 1.12 g (69%) of 1-(4-methylbenzyl)-5-amino-1,2,3-triazole-4-carboxamide, m.p. 223°-225° C.
Reaction SMILES: [C:1]([N:5]([CH2:25][C:26]([OH:28])=O)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]([F:19])([F:18])[CH2:15]2)=[C:10]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CO>[C:1]([N:5]([CH2:25][C:26](=[O:28])[NH:32][CH3:31])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]([F:18])([F:19])[CH2:15]2)=[C:10]([O:20][CH2:21][CH:22]2[CH2:23][CH2:24]2)[N:9]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)N(CC(=O)O)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), {tert-butyl-[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-acetic acid (Example 24) was reacted with a 2 M solution of methanamine (CAN 74-89-5) in MeOH in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=411.5 [MH+].
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.[NH2:14][OH:15].Cl.CC([O-])=O.[Na+]>CCO.CCOC(C)=O>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:14][OH:15])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CC1(C)CCC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)CCC(=NO)c2ccccc21
Temperature: 25 °C

Procedure:
4,4-Dimethyl-3,4-dihydro-2H-naphthalen-1-one (2.2 g, 12.6 mmol) was dissolved in EtOH (10 ml) and NH2OH.HCl (1.05 g, 15.2 mmol) and NaOAc (2.0 g, 24 mmol) were added. The mixture was heated to reflux for 2 h upon which a yellow suspension is formed. The suspension is cooled down to RT and diluted with EtOAc, washed with H2O, dried (MgSO4), filtered and concentrated to give 4,4-Dimethyl-3,4-dihydro-2H-naphthalen-1-one oxime.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH:9]([NH2:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:18][CH:9]([C:8]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:19])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:29])=[O:28]
Reactant: CC1CCN(C(=O)C(N)CCc2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(C(=O)C(CCc2ccccc2)NS(=O)(=O)c2ccccc2Cl)CC1
Reaction time: 16 h

Procedure:
A mixture of 29 mg (0.11 mmol) of 1-(4-methylpiperidin-1-yl)-1-oxo-4-phenylbutan-2-amine, 2-chlorobenzenesulfonyl chloride, and 0.19 mL (0.11 mmol) of iPr2NEt in 4 mL of CH2Cl2 is stirred for 16 h, concentrated, and purified by preparative HPLC to provide Example 1
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[CH3:32][C:33]1[NH:34][C:35]([CH2:38][NH2:39])=[N:36][N:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][CH2:38][C:35]1[NH:34][C:33]([CH3:32])=[N:37][N:36]=1)=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cc1nnc(CN)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)[nH]1
Reaction time: 1 h
Yield: 31.4 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol), (5-methyl-4H-1,2,4-triazol-3-yl)methanamine (11.70 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.3 min) to provide 2-hydroxy-N-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12 mg, 0.022 mmol, 31.7% yield) as a single enantiomer. LCMS=526.4 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.51-7.76 (7 H, m), 5.21 (1 H, s), 4.46-4.66 (2 H, m), 2.52 (3 H, s); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [C:1]1([C:7]([CH2:33][CH3:34])=[CH:8][C:9]2[N:10]=[CH:11][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl>CO.[Pd]>[C:1]1([CH:7]([CH2:33][CH3:34])[CH2:8][C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCC(Cc1c[nH]cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 15.2 %

Procedure:
To a stirred solution of 4-(2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (260 mg) at r.t. in methanol (5 ml) and dichloromethane (2 ml) under an argon atmosphere was added 10% Pd/C (26 mg). The mixture was then stirred at r.t. under a hydrogen atmosphere for 17 hours. The catalyst was filtered off and washed with methanol. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1 to give 4-(2-phenyl-butyl)-1H-imidazole (18 mg) as colorless gum. MS (ISP): 201.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.C(=O)([O-])[O-].[Na+].[Na+].Br[CH:19]1[CH2:24][CH2:23][O:22][C:20]1=[O:21].Cl>O.C(OC(=O)C)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[C:19]3([CH2:24][CH2:23][O:22][C:20]3=[O:21])[S:11][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1S
Reactant: O=C1OCCC1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1OCCC12Sc1cc(Cl)ccc1C2=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 8.3 %

Procedure:
In 200 ml of water were dissolved 14.2 g of 4-chlorothiosalicylic acid and 20 g of sodium carbonate, and 19.1 g of α-bromo-γ-butyrolactone was added dropwise to the solution under ice-cooling. After stirring the solution at room temperature for 6 hours, 35 ml of concentrated hydrochloric acid was added to the reaction solution at room temperature to acidify. After stirring at room temperature for 3 hours, the precipitate was collected, washed with water and dried, resulting in crude α-[(2-carboxy-5-chlorophenyl)thio]-γ-butyrolactone. The crude product was dissolved in 150 ml of acetic anhydride and 30 ml of triethylamine, and heated under a stream of nitrogen at 130° C. for 10 minutes. The reaction solution was evaporated to dryness under reduced pressure, and the resulting residue was chromatographed on a column of activated carbon and silica gel. Recrystallization from ethanol of the resultant crude crystals yielded 1.60 g of 6-chloro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione as colorless needles. Melting point: 157°-158° C.
Reaction SMILES: Br.N1CCC[C@H]1C([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=O.[N+](C1C=CC([O:26][C:27](=[O:44])[C@H:28]([C@H:40]([CH2:42][CH3:43])[CH3:41])[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=CC=1)([O-])=O.ON1C2C=CC=CC=2N=N1.CN(CCCN)C>CN(C)C=O.C(N(CC)CC)C>[CH2:33]([O:32][C:30]([NH:29][C@H:28]([C:27]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:44])[C@H:40]([CH2:42][CH3:43])[CH3:41])=[O:31])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1.[NH:29]1[CH2:43][CH2:42][CH2:40][C@H:28]1[C:27]([OH:26])=[O:44]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Br
Agent: CN(C)CCCN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Product: O=C(O)[C@@H]1CCCN1
Reaction time: 16 h
Yield: 240.9 %

Procedure:
Prolyl-proline hydrobromide (4.24 g) is dissolved in a mixture of dimethylformamide (40 ml) and triethylamine (2.8 ml). Benzyloxycarbonyl-isoleucine p-nitrophenyl ester (9.27 g) and 1-hydroxybenzotriazole (3 g) are added and the mixture is stored at room temperature for 16 hours. Dimethylaminopropylamine (1 ml) is added and after 2 hours the solvent is removed in vacuo. The residue is dissolved in ethyl acetate (200 ml) and washed sequentially with 0.1 N hydrochloric acid, and water. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to yield 13.8 g solid. This material is applied to a silica gel column (300 g) in ethyl acetate and eluted with the same solvent. The fractions containing the desired above-titled tripeptide are pooled and concentrated to dryness.
Reaction SMILES: [OH:1][C:2]1[C:19]2[C@@H:18]3[C@@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1.[H-].[Na+].[CH2:24]([N:26]([CH2:31][CH3:32])[S:27](Cl)(=[O:29])=[O:28])[CH3:25]>CS(C)=O>[CH2:24]([N:26]([CH2:31][CH3:32])[S:27]([O:1][C:2]1[C:19]2[C@@H:18]3[C@@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:21][S:27]([N:26]([CH2:31][CH3:32])[CH2:24][CH3:25])(=[O:29])=[O:28])[CH:3]=1)(=[O:29])=[O:28])[CH3:25]
Reactant: CCN(CC)S(=O)(=O)Cl
Reactant: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1CCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN(CC)S(=O)(=O)Oc1cc2c(c(OS(=O)(=O)N(CC)CC)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@H]1CC2
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A solution of 250 mg. of 1,3-dihydroxy-8α-estra-1,3,5(10)-trien-17-one in 6.5 ml. of dimethyl sulfoxide is mixed under cooling and nitrogen with 250 mg. of NaH (50% suspension in oil), and agitated for 30 minutes at room temperature. A solution of 1.05 g. of diethylaminosulfonyl chloride in 2 ml. of dimethyl sulfoxide is then added to the mixture, and the latter is agitated for 25 hours at room temperature. The mixture is introduced into acetic ice water (NaCl), the organic substances are extracted with ether, and the extracts are washed, dried, and evaporated. After purificationby chromatography, 150 mg. of 1,3-bis(diethylaminosulfonyloxy)-8α-estra-1,3,5(10)-trien-17-one is produced.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](O)(=[O:39])[CH2:36][CH2:37][CH3:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 82.2 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by butyric acid (27 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction, was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-(cis-4-Butyrylamino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (89 mg) as a white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.[CH2:6]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N=C=NC(C)C)(C)C>>[CH2:6]([CH:13]1[CH2:18][CH2:17][N:16]([C:3](=[O:5])[CH2:2][Br:1])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)CBr
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CC(C)N=C=NC(C)C
Product: O=C(CBr)N1CCC(Cc2ccccc2)CC1

Procedure:
Prepared as stated above for compound (22) from bromo acetic acid (935mg, 6.78 mmol) and 4-benzyl piperdine (1.02 g, 5.82 mmol) and diisopropylcarbodiimide (856 mg, 6.78 mmol) to afford compound 23, 1.53 g, (89%), (MH+) m/z 297.88.
Reaction SMILES: [C:1]1([C:7](F)(F)F)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-:12].[Cl-:13].[Cl-].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([Cl:13])[Cl:12])=[CH:18][CH:17]=1
Reactant: [Cl-]
Reactant: Fc1ccccc1
Reactant: FC(F)(F)c1ccccc1
Agent: [Al+3]
Product: Fc1ccc(C(Cl)(Cl)c2ccccc2)cc1

Procedure:
From benzotrifluoride (146 mg, 1 mmol), AlCl3 (400 mg, 3 mmol) and fluorobenzene (96 mg, 1 mmol), light yellow oil (335 mg, 131% crude).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=[O:24])C>>[CH:1]1([C:4](=[O:24])[C:5](=[CH:12][O:13][CH2:14][CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(=O)CC1CC1
Reactant: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C1CC1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
Ethyl β-cyclopropyl-α-ketopropionate (247.0 g, 1.58 mole) [prepared according to the procedure described in J. Am. Chem. Soc., 70 , 497 (1948)], triethyl orthoformate (468.3 g, 3.16 mole) and acetic anhydride (484.0 g, 4.74 mole) were combined and the solution was stirred at reflux for 4 h and at ambient temperature for 17 h. The excess reagents were distilled at water aspirator pressure (maximum head temperature permitted was 72° C.) and the oily pot residue was stirred at 10° C. with a mixture of ether and water. The ether layer was separated, washed once with cold water and dried over Na2SO4. Removal of the solvent gave 321.5 g (96%) of an orange-red liquid that was used directly in the next step.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4].Cl.[NH:22]1[CH2:37][CH2:36][CH2:35][C@H:23]1[C:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])=[O:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([N:22]1[CH2:37][CH2:36][CH2:35][C@H:23]1[C:24]([O:26][C:27]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:28])=[O:25])=[O:13])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4]
Reactant: O=C(OC(=O)[C@@H]1CCCN1)c1ccccc1
Reactant: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
Boc-Gly-Nleu-OH (12.5 g, 0.043 mol.), HCl.Pro-OBz (11 g, 0.046 mol.) and HOBt (6.0 g, 0.045 mol.) were dissolved in 300 ml DMF and the solution was chilled to 0° C. Triethylamine (12 ml) was added slowly while stirring the solution. After 5 minutes, EDC (8.5 g, 0.043 mol.) was added to the solution and the stirring was continued at room temperature overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 350 ml ethyl acetate. The ethyl acetate solution was washed by H2O, saturated NaHCO3, brine, saturated NaHSO4 and brine again until the pH of the brine layer was about 7. The organic layer was dried by Na2SO4 and the ethyl acetate was removed under reduced pressure to get the crude product. Column chromatography (elution solvents: E/H, 3:1) was carried out to obtain the pure product (17.5 g, 85%). TLC Rf=0.45 (developing solvents: E/H, 3:1).