Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=O.C(OP([CH2:35][C:36]#[N:37])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[CH:35][C:36]#[N:37]
Reactant: COc1cc(C(=O)c2ccc(OC)c(OC)c2OC)cc(OC)c1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(=CC#N)c2ccc(OC)c(OC)c2OC)cc(OC)c1OC
Yield: 76 %

Procedure:
(2,3,4-trimethoxyphenyl)-(3,4,5-trimethoxyphenyl)methanone (2.87 g, 7.92 mmol), cyanomethylphosphonic acid diethyl ester (2.50 ml, 15.84 mmol) in anhydrous THF (15 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 15.84 ml, 15.84 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (20% EtOAc in hexane) to give 3-(2,3,4-trimethoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile as an off-white solid (2.32 g, 76%); mp, 125-127° C.: 1HNMR (DMSO-d6) δ 7.01-6.85 (m, 2H, Ar), 6.63-6.61 (m, 2H, Ar), 5.95 (s, 1H, double bond proton), 3.87-3.32 (multiple singlets, 18H, 6OCH3); 3C NMR (CDCl3) δ 160.6, 160.2, 155.5, 153.3, 153.1, 152.4, 151.8, 142.6, 139.5, 134.7, 133.8, 126.2, 125.8, 125.4, 118.4, 118.0, 107.2, 107.1, 106.4, 106.1, 104.8, 95.9, 61.2, 61.1, 61.0, 61.0, 56.4, 56.4, 56.2; Anal. Calcd. For C21H23NO6 (+0.05 H2O): C, 65.29; H, 6.03; N, 3.63. Found: C, 64.90; H, 5.94; N, 3.55.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH2:13]([C:15]1[C:16]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=1)[CH3:14]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[C:15]([CH2:13][CH3:14])=[CH:20][C:19]([CH3:21])=[CH:18][N:17]=3)[CH2:23][CH2:24]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CCc1cc(C)cnc1N1CCNCC1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Product: CCc1cc(C)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Yield: 65.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 4-bromo-2-fluorobenzoyl chloride (1.1 g) and 1-(3-ethyl-5-methylpyridin-2-yl)piperazine hydrochloride (1 g) described in Preparation Example 54, the title compound (1.1 g) was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>C1COCC1.ClCCl>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)N1CCC(O)CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
11 g (109 mmol) of 4-hydroxy-piperidine and 14.5 ml of triethylamine were dissolved in a mixture of 30 ml of THF and 80 ml of dichloromethane and cooled to 0° C. 10 ml (104 mmol) of methacryloyl chloride were added dropwise within 15 minutes. The solution was stirred at 10° C. for 5 hours. Subsequently, the reaction mixture was filtered over silica gel. After distillation of the solvent the crude product was purified by column chromatography on silica gel with ethyl acetate as the eluent. Therefrom there resulted 14.5 g of 1-(4-hydroxy-piperidin-1-yl)-2-methyl-prop-2-en-1-one in the form of white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9][C:8]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:34])[CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:22][CH:21]=3)=[O:18])=[CH:7][C:6]=2[CH:35]=1.B([O-])([O-])O[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH3:50])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH3:50])=[CH:40][CH:39]=3)=[CH:35][C:6]=2[CH:7]=[C:8]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:34])[CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][CH:25]=2)=[O:18])[CH2:9][CH2:10]1)[CH2:13][CH:14]([CH3:15])[CH3:16]
Reactant: CC(C)CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
In toluene/ethanol/water (=10/1/1, 31.5 ml) was dissolved 7-bromo-1-isopentyl-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.66 g). To the solution were added 4-(2-propoxyethoxy)phenyl borate (0.33 g) and potassium carbonate (0.37 g), and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinepalladium (56 mg), and the mixture was heated to reflux for 16 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1). The purified residue was dissolved in ethyl acetate and filtered to give a solution. The solvent was removed under reduced pressure, followed by recrystallization from isopropyl ether/ethyl acetate to give 1-isopentyl-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 86) (80 mg).
Reaction SMILES: OC(=CC([O-])=O)C.CS(Cl)(=O)=O.[CH2:13]([C:20]1[S:26][CH:25]2[CH:22]([C:23](=[O:48])[N:24]2[C:27](=[C:41](OS(C)(=O)=O)[CH3:42])[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>O1CCCC1.C(N(CC)CC)C>[CH2:13]([C:20]1[S:26][CH:25]2[CH:22]([C:23](=[O:48])[N:24]2[C:27](=[C:41]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[CH3:42])[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reactant: C1COCCN1
Agent: CC(O)=CC(=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Reaction time: 0.42 h

Procedure:
One suspends p-nitrobenzyl α-[3-benzyl-7-oxoethylidene)-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylideneacetate (2.265 g) in anhydrous tetrahydrofuran (30 ml), adds dropwise a solution of triethylamine (1.11 g) and methanesulfonyl chloride (630 mg) in tetrahydrofuran (2 ml) at 1 to 2° C, and stirs for 25 minutes. To the produced solution of p-nitrobenzyl α-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, one adds a solution of morpholine (480 mg) in tetrahydrofuran (2 ml), and stirs for 15 minutes to give a solution of p-nitrobenzyl α-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -20° C, adds pyridine (396 mg) and a solution of bromine in carbon tetrachloride (1 mole/liter: 5 ml), pours into diluted hydrochloric acid after 15 minutes, and extracts with ethyl acetate. The extract solution is washed with water, dried over magnesium sulfate, and evaporated. Purification of the obtained residue by chromatography over silica gel (50 g), from the fraction eluted with a mixture of benzene containing 10% ethyl acetate gives p-nitrobenzyl α-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-bromo-1-morpholinoethylidene)acetate (2.36 g). Yield: 78%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19]([CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:18](=[O:40])[N:17](COC(=O)C(C)(C)C)[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>O1CCCC1.CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19]([CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:18](=[O:40])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c21
Temperature: 25 °C
Reaction time: 0.28 h
Yield: 87.4 %

Procedure:
4-[1,3-Bis(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-7-(2-vinylphenyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (704 mg) was dissolved in tetrahydrofuran (7 ml) and methanol (14 ml), sodium hydride (51 mg) was added to the solution, and the mixture was stirred at room temperature for 17 minutes. The reaction mixture was diluted with chloroform and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 510 mg of the title compound from the elution fraction of hexane-ethyl acetate (2:3).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:8]2C=[CH:12][C:11](C(O)=O)=[CH:10][CH:9]=2)C=[CH:6][CH:7]=1.[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.O>C1C=CC=CC=1>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:24][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1cccc(-c2ccc(C(=O)O)cc2)c1
Reactant: O=C(O)c1ccc(Br)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCOC(=O)c1ccc(Br)cc1

Procedure:
Preparation of 3′-methyl-4-biphenylcarboxylic acid with OXO-C10 alcohols (NGP-87): Decyl 4-bromobenzoate was Prepared from the Condensation of 4-bromobenzoic acid and OXO-C10 alcohols by Refluxing in Benzene with Water Removal via a Dean-Stark Trap
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[N:11]=1>O>[ClH:9].[ClH:9].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: FC(F)(F)c1ccc(Nc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Solvent: O
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(C(F)(F)F)cc3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
684 mg of trans-1,4-diaminocyclohexane is taken to approximately 150° C. then 229 mg of the product obtained in Stage 1 above is added, the reaction medium is maintained under agitation at 140° C. for 5 hours then left to return to ambient temperature. Then 15 ml of water is added, followed by extracting with dichloromethane, drying and evaporating the solvent. The residue is chromatographed on silica (eluent: MeOH/NH4OH 98/2), taken up in 10 ml of ethanol, 6 ml of an ethanolic solution of hydrochloric acid is added, followed by separating, washing with ether, drying under reduced pressure at 60° C. and 159 mg of expected product is recovered.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.C(O)(=O)C>[Zn].O>[ClH:1].[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
385.0 mg (1.05 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzothio-phene-2-carboxamide hydrochloride are suspended in 10 ml of a 1:1 mixture of acetic acid and water. 300.0 mg (4.59 mmol) of zinc are added, and the mixture is then stirred at RT for 1 h. The reaction mixture is filtered through kieselguhr, and the filter cake is washed with methanol. The filtrate is concentrated under reduced pressure and the residue is purified by preparative HPLC. The product fraction is dissolved in 4M HCl in dioxane, concentrated under reduced pressure and recrystallized from acetonitrile. 233 mg (59.5% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([O:33][C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([O:33][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:35][CH:36]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(OC2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(OC4CCCCC4)cc3)c2CC1)C(F)(F)F
Yield: 37.7 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 0.43 mmol) with 4-cyclohexyloxy-benzylamine (58 mg, 0.285 mol) in anhydrous toluene (1 mL). Purify the crude mixture by chromatography on silica gel eluting with cyclohexane/EtOAc (9:1) to give 7-chloro-6-(4-cyclohexyloxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (78 mg, 69%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1C(OC)=C(C(CSC2C=CC([F:44])=CC=2)=CC=1)C(OC)=O>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:44])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC
Reactant: COC(=O)c1c(CSc2ccc(F)cc2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 68, starting from methyl 3-bromo-6-(4-fluorophenylthiomethyl)-2-methoxybenzoate (Intermediate 75) and used without further characterisation.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:18]=[C:19](C)[CH:20]=1)[O:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:8].[N+:22]([C:25]1[CH:26]=[C:27]([S:31]([CH2:34][CH2:35]O)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[C:27]([S:31]([CH2:34][CH2:35][O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:3]=[CH:2][CH:20]=[CH:19][CH:18]=2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]
Reactant: Cc1cc(C)cc(OCC(=O)NCCCCCC(=O)O)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(COc1ccccc1)NCCCCCC(=O)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 89 %

Procedure:
A mixture of 6-(2-phenoxyacetylamino)-n-hexanoic acid (made in analogy to Intermediate 15, 3.15 g, 11.9 mmol, 1.1 eq), 2-(m-nitrobenzenesulfonyl)ethanol (2.5 g, 10.8 mmol), and p-toluenesulfonic acid hydrate (0.5 g) in 100 mL of benzene was refluxed overnight with Dean-Stark trap. Thereafter water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 solution, dried over MgSO4, and concentrated under reduced pressure. The residual oil was purified by column chromatography (1% MeOH in CH2Cl2) to give 4.6 g (89%) of 6-(2-phenoxy-acetylamino)-n-hexanoic acid 2-(3-nitrobenzenesulfonyl)ethyl ester.
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][S:8][CH2:7]1)(=O)=O.[C:11]([O-:14])(=[S:13])[CH3:12].[K+]>CC(C)=O>[CH3:12][C:11]([S:13][CH:6]1[CH2:10][CH2:9][S:8][CH2:7]1)=[O:14]
Reactant: CS(=O)(=O)OC1CCSC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SC1CCSC1
Yield: 52 %

Procedure:
A mixture of 1.6 g. (8.8 mmole) of crude 3-methylsulfonyloxy-thiolane and 1.5 g. (8.8 mmole) potassium thioacetate in 40 ml. acetone was refluxed under nitrogen for 20 hr. The mixture was then concentrated in vacuo and the residue was partitioned between 40 ml. ethyl acetate and 40 ml. water. The ethyl acetate layer was separated and washed with 30 ml. water and 30 ml. saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromographed on silica gel eluting with methylene chloride to yield 740 mg. (52%) of the title compound.
Reaction SMILES: C(N1[CH2:13][C@@H:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][C@H](C(OC)=O)[C@H]1C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:33]C(=C)C.C(N1C[C@@H](O)C[C@H](C(OC)=O)[C@H]1C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.S(=O)(=O)(O)O>>[C:15]([O:14][C:12]([CH3:11])([CH3:13])[CH3:33])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C(C)C
Reactant: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: COC(=O)[C@H]1C[C@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Product: CC(C)(C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Part 1. 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-tert-butoxypiperidine-2,3-dicarboxylate: Isobutylene (2.96 mL, 0.0313 mol) was collected at −78 Celsius. To the cold isobutylene was added 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (0.60 g, 0.0016 mol) tetrahydrofuran (3.00 mL, 0.0370 mol), sulfuric acid (0.021 mL, 0.00039 mol). The reaction was sealed and allowed to warm up to rt and stirred at rt overnight. The mixture was cooled to −78 Celsius again. The seal was replaced with a septa connecting with a balloon. The reaction was then allowed to warm up to rt gradually to allow the evaporating of excess isobutylene. The residue was diluted with EtOAc, neutralized with aq. sodium hydroxide. The organic layers were washed with brine, dried. The residue was purified on silica gel, eluting with 0 to 30% EtOAc in hexane, to afford the tert-butyl ether (0.35 g, 51%). MS (ESI): (M+H)+=440.25.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:22]3[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]3)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
A 100 mL round-bottom flask was charged with 4-(morpholin-4-yl)-2(trifluoromethyl)benzaldehyde (1.00 g, 3.86 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.720 g, 3.86 mmol, 1.00 equiv), 1,2-dichloroethane (15 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 1.60 g (97% yield) of tert-butyl 4-[[4-(morpholin-4-yl)-2(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 430 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.N[C@H](C([NH:19][C@H:20]([C:28]([O:30][CH3:31])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)CC1C=CC=CC=1.Cl.[N:33]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([OH:37])=[O:36]>O1CCCC1>[C:44]([O:43][C:41]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([OH:37])=[O:36])=[O:42])([CH3:47])([CH3:45])[CH3:46].[NH2:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:31][O:30][C:28](=[O:29])[C@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:19]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](N)Cc1ccccc1
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
687 mg of triethylamine are added to a mixture of 944 mg of Phe-Phe-OMe.HCl D 10 and 1,293 mg of Boc-Pro≈SO2 in 20 ml of absolute tetrahydrofuran, whereupon the mixture develops a deep red coloration. It is stirred for 1 hour at 20° C. The pale yellow mixture is then worked up as described in Example D 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][C:12]([CH3:20])([CH3:19])[C:11]=2[CH:10]=[C:9]([Se:21][C:22]#[C:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[CH:8]=1.O.[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][C:7]1[C:16]2[C:15]([CH3:17])([CH3:18])[CH2:14][CH2:13][C:12]([CH3:19])([CH3:20])[C:11]=2[CH:10]=[C:9]([Se:21][C:22]#[C:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)[CH:8]=1
Reactant: COC(=O)c1ccc(C#C[Se]c2cc(OCc3cccc(F)c3)c3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2c(OCc3cccc(F)c3)cc([Se]C#Cc3ccc(C(=O)O)cc3)cc21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
650 mg (1.2 mmol) of methyl 4-[4-(3-fluorobenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl]benzoate are dissolved in 20 mL of THF. 10 mL of water are added, followed by addition of 240 mg (6 mmol) of sodium hydroxide. The medium is stirred for 4 hours at 80° C. and then acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The residue obtained is purified by chromatography (eluent: 1/1 heptane/ethyl acetate) and then recrystallized in a heptane/ethyl acetate mixture. A pure yellow crystalline solid is obtained (m=577 mg; yield=90%; m.p.=206° C.