Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH3:13])[CH:9]=[C:10]([CH3:12])[CH:11]=1)=[C:3]([Cl:5])[Cl:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C1C=CC=CC=1>[CH3:13][C:8]1[CH:9]=[C:10]([CH:11]=[C:6]([C:2]([Cl:1])=[C:3]([Cl:5])[Cl:4])[CH:7]=1)[CH2:12][Br:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(C(Cl)=C(Cl)Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cc1cc(CBr)cc(C(Cl)=C(Cl)Cl)c1
Yield: 60.8 %

Procedure:
To a refluxing solution of 5-(trichloro-vinyl)-m-xylene (32.28 g) and dibenzoyl peroxide (3.43 g) in 1300 ml of benzene, N-bromosuccinimide (30.21 g) was added in portions. The resulting mixture was heated at reflux for 30 minutes at which point no N-bromosuccinimide was evident. The reaction mixture was concentrated under reduced pressure and the residue triturated with 250 ml of hexane. The precipitated succinimide was collected by filtration and thoroughly washed with hexane. The filtrate was concentrated and the residue chromatographed on silica (petroleum ether) to give 26.2 g of the desired benzyl bromide.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH:7]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1>O.O1CCCC1>[CH2:30]([O:29][CH:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:22][CH:23]=2)=[CH:11][CH:10]=1)[C:6]([OH:36])=[O:5])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.6 %

Procedure:
Lithium hydroxide hydrate (0.036 g; 0.85 mmole) dissolved in water (2.6 ml) was slowly added at room temperature to a solution of 2-hexyloxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid methyl ester (described in Example 16) (0.37 g; 0.77 mmole) in tetrahydrofuran (3.5 ml). The reaction mixture was stirred at room temperature for 3.5 hours and then evaporated to remove tetrahydrofuran. The residue was acidified with potassium hydrogen sulfate (1 M) until pH<2 and then extracted with ethyl acetate. The organic phase was washed with brine and dried. Evaporation to remove the solvent gave 0.349 g (97.5%) of 2-hexyloxy-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic acid.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:8]2)[O:4][NH:3]1>Br>[F:26][C:24]([F:25])([F:27])[C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C@H:9]1[CH2:8][C@H:7]([C:5]2[O:4][NH:3][C:2](=[O:1])[CH:6]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(C(F)(F)F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3cccc(C(F)(F)F)c3)C2)o[nH]1
Reaction time: 8 h
Yield: 42.9 %

Procedure:
Hydrogen bromide (33% in acetic acid, 10 mL) was added to a reaction flask containing trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.25 g, 0.65 mmol). The reaction was stirred vigorously overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(3-(trifluoromethyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (91 mg, 43%). 1H NMR (600 MHz, cd3od) δ 1.94-2.05 (m, 1H), 2.11-2.30 (m, 3H), 3.09-3.26 (m, 3H), 3.37-3.47 (m, 2H), 3.58-3.66 (m, 1H), 5.83 (s, 1H), 7.53-7.67 (m, 4H). HRMS Calculated for [C16H17F3N2O2+H]+: 327.1320. Found: 327.1322
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)C.[OH-].[K+].C(O)C>O>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:25])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Yield: 74.5 %

Procedure:
A solution of 2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (17.7 g, 0.051 mole), potassium hydroxide pellets (4.5 g, 0.080 mole), 95% ethanol (150 ml), and water (10 ml) was refluxed for 21/2 hrs. The ethanol was evaporated in vacuo, the residue acidified with glacial acetic acid, and the mixture filtered. The filter cake was suspended in water (300 ml) and filtered. The filter cake was air dried (17 g) and recrystallized from ethanol-water to give 12.21 g (75%) of a white solid, mp 240°-241° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:14]=[CH:15][C:16](/[C:21](/[C:40]2[CH:45]=[CH:44][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:42][CH:41]=2)=[CH:22]/[C@@H:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[C:26](=[O:39])[CH2:25][CH2:24]2)=[N:17][C:18]=1[O:19][CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[Pd].[Br-].[Zn+2].[Br-]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16](/[C:21](/[C:40]2[CH:41]=[CH:42][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:44][CH:45]=2)=[CH:22]/[C@@H:23]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[C:26](=[O:39])[CH2:25][CH2:24]2)=[N:17][C:18]=1[O:19][CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(/C=C/CCO[Si](C)(C)C(C)(C)C)c(OC)n2)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCO[Si](C)(C)C(C)(C)C)c(OC)n2)c(OC)c1
Yield: 61.8 %

Procedure:
10% palladium-activated carbon (50 mg) and zinc(II) bromide (25 mg) were added to a solution of (5R)-5-[(E)-2-{5-[(1E)-4-{[tert-butyl(dimethyl)silyl]oxy}but-1-en-1-yl]-6-methoxypyridin-2-yl}-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (226 mg) in methanol (5 mL), and the mixture was stirred at room temperature for five hours in a hydrogen atmosphere. The reaction solution was diluted with ethyl acetate and filtered through celite. The filtrate was sequentially washed with water and brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:9) to give (5R)-5-[(E)-2-[5-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-6-methoxypyridin-2-yl]-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (140 mg, 62%).
Reaction SMILES: [C:1]([N:10]1[CH2:27][CH2:26][C@@:17]23[C:18]4[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=4[CH2:24][C@@H:11]1[C@@H:12]2[CH2:13][CH2:14][O:15][CH2:16]3)([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:2].[CH2:28](I)[CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([N:10]1[CH2:27][CH2:26][C@@:17]23[C:18]4[CH:19]=[C:20]([O:25][CH2:28][CH3:29])[CH:21]=[CH:22][C:23]=4[CH2:24][C@@H:11]1[C@@H:12]2[CH2:13][CH2:14][O:15][CH2:16]3)([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: CCI
Reactant: O=C(Oc1ccccc1)N1CC[C@]23COCC[C@H]2[C@H]1Cc1ccc(O)cc13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc2c(c1)[C@]13CCN(C(=O)Oc4ccccc4)[C@H](C2)[C@@H]1CCOC3

Procedure:
A mixture of XXVIII (0.005 m) from Step (c) above, ethyl iodide (0.01 m) and potassium carbonate (2 g) in 20 ml acetonitrile is heated at reflux for 18 hours. The mixture is filtered and the filtrate concentrated. The residue is treated with water and extracted with methylene chloride. The extracts are dried (MgSO4), filtered and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].O>N1C=CC=CC=1>[C:26]([N:6]([CH2:5][C:4]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CNc2ccccc2Oc2ccccc2)c(OC)c1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(CN(C(C)=O)c2ccccc2Oc2ccccc2)c(OC)c1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a solution of 1.00 g of N-(2,4-dimethoxy benzyl)-2-phenoxyaniline in 1.18 g of pyridine was added 0.76 g of acetic anhydride, followed by stirring at room temperature for a day. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:3) to give 1.09 g of N-acetyl-N-(2,4-dimethoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:28])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:26]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(C[PH](=O)OCCc1ccc(N)cc1)C(=O)OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)CC(C[PH](=O)OCCc1ccc(NC(=O)c2ccccc2)cc1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
2-[(4-Aminobenzyl)methoxyphosphinoylmethyl]4-methylpentanoic acid benzyl ester (230 mg, 0.57 mmole), benzoyl chloride (96 mg, 0.68 mmole), and triethylamine (69 mg, 0.68 mmole) were combined in cold (ice bath) chloroform (10 ml). After stirring for 1 hour at ice bath temperature the reaction mixture was diluted with chloroform (150 ml) and washed with water (20 ml), 1N hydrochloric acid (2×20 ml) and saturated sodium bicarbonate solution (2×20 ml) and dried with magnesium sulfate. After filtration and concentration the yellow residue was chromatographed (ethyl acetate) to give 190 mg (66%) of 2-[(4-Benzoylaminobenzyl)methoxy phosphinoylmethyl]4-methylpentanoic acid benzyl ester as a light yellow oil.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13]([Cl:38])=[CH:14][C:15]2[N:21]3[CH2:22][CH2:23][CH2:24][C@@H:25]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C@H:20]3[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=3[O:17][C:16]=2[CH:37]=1>C(Cl)Cl.C(N(CC)CC)C>[Cl:38][C:13]1[C:12]([N:11]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:37][C:16]2[O:17][C:18]3[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=3[C@@H:20]3[C@H:25]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23][CH2:22][N:21]3[C:15]=2[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc2c(cc1Cl)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)c(N(S(=O)(=O)c4ccccc4)S(=O)(=O)c4ccccc4)cc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 40 °C
Reaction time: 4 h
Yield: 105.5 %

Procedure:
N-acylation of an amine of Structure 25 to an amide of Structure 26 Benzenesulfonyl chloride (5 μL, 0.04 mmol) was added under N2 to trans-N-(8-amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2,-trifluoroacetamide (5.0 mg, 0.01 mmol) in a mixture of 1 mL of CH2Cl2 and 25 μL of triethylamine. The resulting mixture was stirred at 40° C. for 4 h. After cooling the mixture was evaporated and the crude compound was purified by chromatography on silica. Elution with toluene/ethyl acetate 1:0→0:1 (gradient) gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-8-[bis(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (7.3 mg, 83%). Data: (m/z)=692 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][C:12]2[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:13]=2[N:14]=1.[OH-].[Na+]>O.O1CCOCC1>[F:21][C:15]1[C:13]2[N:14]=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:22])=[O:2])[S:11][C:12]=2[C:18]([F:19])=[CH:17][C:16]=1[F:20]
Reactant: COC(=O)CCCCCCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCCCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.6 %

Procedure:
To a solution of 7-(4,5,7-trifluorobenzothiazol-2-yl)heptanoic acid methyl ester (407 mg, 1.2 mmol) in a mixture of water (7 ml) and dioxane (7 ml) was added dropwise aqueous 2N sodium hydroxide (4 ml) at room temperature and the mixture was stirred for 5 hours at room temperature. To the mixture further aqueous 2N sodium hydroxide (2 ml) was added dropwise and the resulting mixture was stirred for 1 hour, then diluted with water and extracted with ethyl acetate. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and then evaporated to yield a residue, which was crystallized from isopropyl ether to give 7-(4,5,7-trifluorobenzothiazol-2-yl)heptanoic acid (189 mg, 50%) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH:34][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])/[CH:15]=[CH:14]/[CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylic acid (2 g) and β-alanine ethyl ester hydrochloride (0.84 g) and 1-hydroxybenzotriazole (0.74 g) in dimethylformamide (20 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 ml) at 0° C. The reaction mixture was stirred overnight at room temperature, and then poured into water. The whole was extracted with ethyl acetate, washed with aqueous saturated NaHCO3, water, and brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with CHCl3-MeOH (99:1) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-β-alanine ethyl ester as a colorless oil (2.54 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH3:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CN
Product: CNc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.3 g 1,4-difluoro-2-nitrobenzene are slowly added to a 30 ml 40% aqueous methylamine solution while cooling with ice and the reaction mixture is stirred for 1 hour at ambient temperature. The precipitated product is suction filtered and recrystallised aus water and ethanol umkristallisiert. 6.3 g product are obtained in the form of a solid. M.p.=74-76° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8]Br)[CH2:4][CH2:3]1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.CC(C)([O-])C.[K+]>C(O)CCC>[CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH2:4][CH2:3]1
Reactant: CC1CCC(CBr)CC1
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC1CCC(Cn2ccnc2)CC1
Reaction time: 8 h
Yield: 9.7 %

Procedure:
4-Methylcyclohexylmethyl bromide (3.1 g; 0.0164 M) was added dropwise to a refluxing solution of imidazole (1.12 g; 0.0165 M) in a solution of potassium tertiary butoxide (1.85 g; 0.0165 M) in n-butanol (50 cm3). The reaction mixture was kept under dry nitrogen. After addition the mixture was heated under reflux for a further 2 hours and stood overnight at room temperature. TLC showed reaction half complete. The mixture was refluxed for a further 8 hours and stood over weekend at room temperature. TLC showed no further reaction was occurring. Insoluble material was filtered off, and solvent removed under vacuum. Residue taken up in 2 N-HCl (100 cm3) and washed with ether (50 ml). Aqueous layer basified with excess 10 N NaOH and extracted with chloroform (3×50 cm3). Combined extracts were dried over anhydrous MgSO4 and solvent removed under vacuum. Oily residue was run on a silica gel column and eluted with EtOAc/MeOH 9:1. 0.8 g of column product obtained and was distilled to give 0.28 g of pure product having b.p. 80° C. at 0.125 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][CH2:19][CH:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:29][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][F:18])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCC(O)CF
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC(CF)OC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 38.3 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (1.3 g) in methylene chloride (25 ml) was slowly added under ice cooling a solution of optically active 1-monofluoro-2-decanol (1.0g, [α]D20 =-7.2) and triethylamine (0.5 g) in methylene chloride (25 ml). The mixture was left to stand until it reached room temperature and stirred for 12 hours. The mixture was poured in ice water and extracted with methylene chloride. The extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water, in this order, and dehydrated over anhydrous magnesium sulfate. The solution was distilled under reduced pressure to remove the solvent until a crude product was obtained. The product was subjected to silica-gel column chromatography to obtain 1-monofluoro-2-decyl 4-benzyloxybenzoate (0.78 g). The benzoate and 10% palladium carried on carbon (0.13 g) were added to ethanol and then subjected to de-benzylation under a hydrogen atmosphere to obtain 1-monofluoro-2-decyl-4-hydroxybenzoate (0.6 g).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[CH:13]=[C:14]([C@:18]23[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:22][S:21][C:20]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:19]3)[CH:15]=[CH:16][CH:17]=1)([O-])=O.O>C(O)C>[NH2:9][C:12]1[CH:13]=[C:14]([C@:18]23[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:22][S:21][C:20]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[N:19]3)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc([N+](=O)[O-])c3)CCCC[C@H]2CS1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(N)c3)CCCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.2 %

Procedure:
A saturated solution of sodium dithionite (879 mg) was added to a solution of tert-butyl (−)-[(4aR*,8aS*)-8a-(3-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate (395 mg) in ethanol (20 mL) at room temperature. After stirring at room temperature for 10 minutes, ethanol (10 mL) was further added to the reaction solution. After stirring at room temperature for five minutes, water (10 mL) was further added. The reaction solution was warmed to 40° C. and stirred for 30 minutes. After confirming completion of the reaction, the reaction solution was cooled to room temperature. The excess of ethanol in the reaction solution was evaporated under reduced pressure and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (110 mg).
Reaction SMILES: [CH3:1][CH:2]([NH:10][CH2:11][C:12]#[CH:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Br[CH:17]([OH:19])[CH3:18]>CC#N>[C:4]1([CH2:3][C@H:2]([N:10]([CH2:11][C:12]#[CH:13])[CH2:18][CH2:17][OH:19])[CH3:1])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(O)Br
Reactant: C#CCNC(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: C#CCN(CCO)[C@H](C)Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of desmethyldeprenyl (Sigma, 150 mg, 0.72 mmol) and NaOH (60 mg, 1.5 mmol), in MeCN (5 ml) was stirred at room temperature for 30 min. To the stirred mixture 1-bromo ethanol (1.0 mmol) was added and the reaction mixture was refluxed for overnight. The reaction mixture was allowed to cool to room temperature and solvent was evaporated under reduced pressure. The residue was partitioned between CH2Cl2 (20 ml) and water (10 ml). The organic phase was separated and washed with saturated NaHCO3 (10 ml) and brine (10 ml). The organic layer was dried over MgSO4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as a light yellow liquid. The crude product was purified by silica-gel column chromatography (hexane/ether 8:2).