Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12].[CH2:23]([O:30][C:31](=[O:48])[C:32]([CH3:47])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]2[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]2)[CH:36]=1)[CH3:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C1(C)C=CC=CC=1.O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([N:43]2[CH2:44][CH2:45][CH2:46][CH:41]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([O:34][C:32]([C:31]([O:30][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:48])([CH3:33])[CH3:47])[CH:36]=3)[CH2:42]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)c1ccc(O)cc1
Reactant: CC(C)(Oc1cccc(C2CCCNC2)c1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(OC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.3 %

Procedure:
To a solution of 4-isopropylphenol (1.54 g, 11.32 mmol) in 10 mL toluene was added 1,1′-carbonyldiimidazole (1.84 g, 11.32 mmol). This solution was stirred 18 h at ambient temperature. 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester (Preparation 2, Method C; 2.0 g, 5.66 mmol) was added in 5 mL toluene and the resultant solution was stirred 18 h at ambient temperature. The reaction was diluted with water (200 mL), acidified with 1N aqueous hydrochloric acid and extracted with diethyl ether (2×150 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 10% ethyl acetate/hexanes to yield 1.76 g (60%) of the desired 3-[3-(1-benzyloxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-phenyl ester as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:20][C:21]([OH:23])=[O:22])([O-:3])=[O:2].OS(O)(=O)=O.[CH3:29][CH2:30]O>>[CH2:29]([O:22][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:4]=1[N+:1]([O-:3])=[O:2])[CH3:30]
Reactant: CCO
Reactant: O=C(O)Cc1cccc(Nc2cccc([N+](=O)[O-])c2)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(Nc2cccc([N+](=O)[O-])c2)c1[N+](=O)[O-]

Procedure:
[2-Nitro-3-(3-nitro-phenylamino)-phenyl]-acetic acid (0.79 g, 2.5 mmol) is refluxed in EtOH (50 ml) in the presence of 0.5 ml concentrated H2SO4 for 2 hours. It is then concentrated and to the residue is added saturated NaHCO3. The mixture is extracted with ethyl acetate (30 ml×3). The organic layers are combined and dried with Na2SO4 to give the desired compound after concentration: 1H NMR (CDCl3) δ 1.29 (t, 3H, J=7.2 Hz), 3.92 (s, 2H), 4.20 (q, 2H, J=7.2 Hz), 6.89 (d, 1H, J=6.0 Hz), 7.34-7.41 (m, 2H), 7.44-7.52 (m, 2H), 7.92 (d, 1H, J=7.6 Hz), 8.03 (s, 1H), 8.17 (s, 1H); LC-MS: 346.0 (MH+).
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:18]=[C:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C.O>[CH2:18]=[C:19]1[CH2:24][CH2:23][CH:22]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: C=C1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: C=C1CCC(N2CCN(c3ccc(C(=O)OCC)cc3)CC2)CC1
Yield: 49.6 %

Procedure:
To a mixture of ethyl 4-(piperazinyl)benzoate (2.00 g) and 4-methylenecyclohexan-1-one (0.98 g) in a mixture of methanol (40 ml) and acetic acid (1.47 ml) was portionwise added sodium cyanoborohydride (644 mg) with stirring under ice-cooling and the mixture was stirred at ambient temperature overnight. To the reaction mixture was added water (200 ml) and the mixture was adjusted to pH 8-9 with saturated aqueous sodium hydrogen carbonate. The resulting precipitates were collected and chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give ethyl 4-[4-(4-methylenecyclohexyl)-1-piperazinyl]benzoate (1.39 g).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C@H:30]3[CH2:34][CH2:33][NH:32][CH2:31]3)=[CH:25][CH:24]=2)[C:19](=[O:35])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)(=O)C>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:31]3)=[CH:25][CH:24]=2)[C:19](=[O:35])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O[C@H]2CCNC2)cc1
Reactant: O=C1CCCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O[C@H]2CCN(C3CCCC3)C2)cc1
Yield: 52.8 %

Procedure:
Cyclopentanone (0.017 mL, 0.186 mmol) and a 0.3 mol Zn[B(CN)H3]2 methanol solution (0.4 mL, 0.12 mmol, prepared from ZnCl2 and NaB(CN)H3) were added to a methanol solution (1 mL) of 4-benzyloxy-1-{4-[(3S)-3-pyrrolidinyloxy]phenyl}-1H-pyridin-2-one (45 mg, 0.124 mmol) and sired at room temperature for an hour. Ethyl acetate was added to the reaction liquid, which was then washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous potassium carbonate. The solvent was concentrated under reduced pressure and the resulting residue was purified on silica gel chromatography (C-300; methanol:chloroform=1:10) to provide the title compound (28.2 mg, 53%).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[F:23][C:24]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:25]=1[NH2:26]>>[NH2:26][C:25]1[CH:27]=[CH:28][C:29]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:30][C:24]=1[F:23]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)c(F)c3)c(F)cn2c1=O
Yield: 9.8 %

Procedure:
Ethyl 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (149 mg, 0.46 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (134 mg, 0.58 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (18 mg, 10%). ESI-MS m/z: 399 (M+H)+.
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[C:9]1[S:13][C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:11][CH:10]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg]Br.[NH4+].[Cl-]>C(Cl)Cl>[C:17]([O:16][C:14]([C:12]1[S:13][C:9]([C@H:8]([NH:7][S@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])[CH3:21])=[CH:10][CH:11]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)c1ccc(/C=N/[S@@](=O)C(C)(C)C)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(=O)OC(C)(C)C)s1
Temperature: -45 °C
Reaction time: 4 h
Yield: 48.1 %

Procedure:
To an oven-dried 100-mL round-bottom flask was added (S,E)-tert-butyl 5-((tert-butylsulfinylimino)methyl)thiophene-2-carboxylate (1.00 g, 3.2 mmol) and DCM (15.8 mL). The solution was cooled to −45° C. under nitrogen, then methylmagnesium bromide (2.11 mL, 6.36 mmol, 3.0 M in ether) was slowly added via syringe. The resulting reaction mixture was stirred at −45° C. for 4 h, then gradually warmed to rt and stirred for 2 h. To the reaction was added DCM (50 mL) and sat. NH4Cl solution (10 mL). After separation, the aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. Purification via flash chromatography (20% EtOAc-hexanes to 50% EtOAc-hexanes) afforded major diastereomer tert-butyl-5-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]thiophene-2-carboxylate (0.51 g, 48%) as a white solid; 1H NMR (Methanol-d4, 400 MHz) δ 7.55 (d, J=3.8 Hz, 1H), 7.00 (d, J=3.8 Hz, 1H), 4.73 (q, J=6.5 Hz, 1H), 3.30 (br, 1H), 1.65 (d, J=6.8 Hz, 3H), 1.55 (s, 9H), 1.25 (s, 9H). Minor diastereomer tert-butyl-5-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]thiophene-2-carboxylate (0.061 g, 6%) was isolated as a white solid. 1H NMR (Methanol-d4, 400 MHz) δ 7.55 (d, J=3.5 Hz, 1H), 7.00 (d, J=3.5 Hz, 1H), 4.73 (q, J=6.8 Hz, 1H), 3.30 (br, 1H), 1.61 (d, J=6.8 Hz, 3H), 1.55 (s, 9H), 1.23 (s, 9H).
Reaction SMILES: [NH2:1][N:2]1[C:6](=O)[CH2:5][O:4][CH-:3]1.[OH2:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH2:16][CH2:15][C:14]2=O>C1C=CC=CC=1.Cl>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH2:16][CH2:15][C:14]2=[N:1][N:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:8]
Reactant: NN1[CH-]OCC1=O
Reactant: COc1ccc2c(c1)C(=O)CCO2
Reactant: O
Agent: Cl
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(=NN1CCOC1=O)CCO2
Reaction time: 8 h

Procedure:
A solution of 62 g (0.61 mole) of 3-amino-2-oxazolidone in 650 ml of benzene was treated with 15 drops of HCl (isopropanol) solution using mechanical stirring, and refluxed until all water was removed via a Dean-Stark trap. The solution was then treated with 107 g (0.60 mole) of 6-methoxy-4-chromanone and refluxed for 11.5 hr. A 9.6 ml portion of water (theory: 10.8 ml) was collected. The reaction mixture was stripped of benzene under the water pump. The residue was taken up in 200 ml of 1:1 isopropanol:ether, stored 24 hr at room temperature, refrigerated overnight and filtered. The resultant cream-colored solid was washed with 125 ml of isopropanol, ether, and dried. M.p. 54°-64°; yield: 115 g (73%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[CH2:7][Br:8].[CH3:9][N:10]1C=NN=C1CO.Cl.NCCS>Br>[BrH:8].[BrH:8].[NH2:10][CH2:9][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[N:5][N:4]=1
Reactant: Cn1cnnc1CO
Reactant: Cn1cnnc1CBr
Agent: Br
Agent: Cl
Agent: NCCS
Product: Cn1cnnc1CCN

Procedure:
The thione (44 g.) was desulphurised by slow addition to a solution prepared from nitric acid (75 ml.), water (150 ml.) and sodium nitrite (1.5 g.) at 15°-20°. Following subsequent basification with sodium carbonate and concentration, the residue was extracted with ethanol-ether 1:1 and distilled to afford 3-ethoxymethyl-4-methyl 1,2,4-triazole (30 g.), b.p. 154°-156°/0.05 mm. The above compound (15 g.) dissolved in 48% aqueous hydrobromic acid (150 ml.) was heated under reflux for 24 hours, concentrated to dryness and the residue obtained (a mixture of 4-methyl-3-bromomethyl-1,2,4-triazole and 4-methyl-3-hydroxymethyl-1,2,4-triazole) was used directly in the reaction with cysteamine hydrochloride and hydrobromic acid as described in Example 1 (i)(a) to give 3-(2-aminoethyl)-4-methyl-1,2,4-triazole dihydrobromide, m.p. 175°-177°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7](C(O)=O)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.C([N:17](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:17])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2cn1
Reactant: CCN(CC)CC
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: Nc1cc2ccc(Cl)cc2cn1
Temperature: 25 °C
Yield: 20 %

Procedure:
7-Chloroisoquinoline-3-carboxylic acid (3.1 g, 14 mmol) was dissolved in 6 N HCl (50 mL), and the mixture was heated under reflux for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in tert-butanol (100 mL), and triethylamine (2.8 g, 28 mmol) and diphenylphosphoryl azide (5.6 mL, 26 mmol) were added. The mixture was heated under reflux overnight. After cooled to room temperature, the solvent was distilled off under reduced pressure. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1/1) and afforded the title compound (500 mg, 20% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): 8.62 (s, 1H), 7.66 (d, J=9 Hz, 1H), 6.86 (d, J=2.4, 1H), 6.75 (dd, J=2.4 and 9 Hz, 1H), 6.52 (s, 1H), 5.83 (s, 1H), 3.83 (s, 3H); MS: m/z 174.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][N:22]=[CH:21][C:20]=2[CH2:24][CH2:25][C:26](O)=[O:27])=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH:11][C:26](=[O:27])[CH2:25][CH2:24][C:20]2[CH:21]=[N:22][O:23][C:19]=2[C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)N)c1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(C)NC(=O)CCc2cnoc2-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of 1-(3-methoxyphenyl)ethylamine (0.32 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.45 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.33 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[1-(3-methoxyphenyl)ethyl]-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.61 g, yield 88%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 89–90° C.
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([F:13])[C:3]=1[O:4][CH2:5][CH2:6][OH:7].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:12][C:11]1[C:2]2[O:7][CH2:6][CH2:5][O:4][C:3]=2[C:8]([F:13])=[CH:9][CH:10]=1
Reactant: OCCOc1c(F)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(F)c2c1OCCO2

Procedure:
2-(2,3,6-Trifluorophenoxy) ethanol (48.8 g, 0.254 mole) and 24 g of anhydrous potassium carbonate in 800 ml of dimethylformamide was refluxed for 20 hours and then poured into water. This was extracted with ether, washed with water, and dried to give 5,8-difluoro-1,4-benzodioxane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[F:8].BrBr.C(=O)([O-])[O-:13].[Ca+2]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH:9]=[O:13]
Reactant: Cc1ccc(F)c(F)c1
Reactant: O=C([O-])[O-]
Agent: BrBr
Agent: [Ca+2]
Solvent: O
Product: O=Cc1ccc(F)c(F)c1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
3,4-difluorotoluene (25.6 g, 0.2 mol) is heated to 105° C. in a 250 ml 3-necked flask equipped with a magnetic stirrer, thermometer, condenser, and dropping funnel, and is illuminated as bromine (67 g, 0.42 mol) is added slowly. The temperature is kept between 105-110° C. while the first half of the bromine is added over a period of one hour. The rest of the bromine is added over approximately a two-hour period, and the temperature is raised to 150° C., and is kept there for 5 minutes. The reaction mixture is cooled and is transferred to a 1 liter 3-necked flask with a motor-driven stirrer and condenser. H2O (120 ml) and calcium carbonate (90 g) are added, and the mixture is refluxed for 20 hours with good stirring. The reaction mixture is steam distilled until no further oil is collected. The oil is taken up in methylene chloride and dried over MgSO4. Evaporation of the solvent yields 3,4-difluorobenzaldehyde that is used without further purification.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:9]([NH2:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>>[CH2:9]([NH:20][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCCC(=O)O
Reactant: C=CCCCCCCCCCN
Product: C=CCCCCCCCCCNC(=O)CCCC=C

Procedure:
Following the aforementioned procedure, diene was prepared from hex-5-enoic acid and undec-10-en-1-amine. The resulting yellow solid was purified by silica gel chromatography (5:1 hexanes: ethyl acetate) to afford the desired product as a white solid. IR (neat): 3291 (br, s), 3078 (m), 2924 (s), 2853 (s), 1640 (s), 1550 (s), 1438 (s), 1369 (m), 1257 (m), 991 (s), 908 (s), 722 (m), 634 (m); 1H NMR (400 MHz, CDCl3): δ 5.86-5.73 (2H, m), 5.39 (1H, s, br), 5.05-4.91 (4H, m), 3.23 (2H, dt, J=13.2, 7.2, 6.6 Hz), 2.16 (2H, t, J=7.4 Hz), 2.12-2.00 (4H, m), 1.78-1.70 (2H, m), 1.50-1.46 (2H, m), 1.38-1.27 (12H, m); 13C NMR (100 MHz, CDCl3): δ 172.8, 139.3, 138.1, 115.4, 114.3, 39.6, 36.2, 33.9, 33.3, 29.8, 29.6, 29.5, 29.4, 29.2, 29.1, 27.1, 24.9; HRMS (ESI+) [M+H]+ calcd for C17H32N1O1: 266.2484. found: 266.2491.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH:18]([CH3:20])[CH3:19])(=[O:15])[CH2:13][CH3:14]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:16][CH:17]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH:18]([CH3:19])[CH3:20])(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (250 mg, 1.6 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl propanoate (230 mg, 0.80 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 41 (70 mg, 21% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.85-0.92 (m, 8H), 1.08 (t, J=7.2 Hz, 3H), 1.17-1.32 (br. m, 3H), 1.68 (d, J=12 Hz, 2H), 1.85-1.96 (br. m, 3H), 2.05-2.12 (m, 1H), 2.25-2.36 (br. m, 2H), 2.80 (t, J=6.4 Hz, 2H), 6.42 (d, J=5.2 Hz, 1H), 7.38 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 352.12 (M+Na)+; 328.14 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:39][C:40]1[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=1)[C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C>[CH3:46][O:45][C:43](=[O:44])[C:42]1[CH:47]=[CH:48][CH:49]=[C:40]([CH2:39][O:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([N:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][C@@H:14]3[CH3:31])=[O:30])=[CH:28][CH:27]=2)[CH:41]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(COc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (150 mg, 0.35 mmol) was dissolved in DMF (5 mL) at room temperature. Cs2CO3 (283 mg, 0.87 mmol) was added followed by methyl 3-(bromomethyl)benzoate (119 mg, 0.52 mmol) and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate (15 mL). The reaction mixture was washed with sat. aq. NaHCO3 (15 mL), water (15 mL) and brine (15 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5/95 ethyl acetate/hexane-50/50 ethyl acetate/hexane gradient) to afford slightly yellow solid product (111 mg, 54%).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]([OH:12])=O)[CH2:6][CH2:7][S:8][CH3:9])(=[O:3])[CH3:2].ClC(OCC(C)C)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:33]=[C:32]([OH:34])[C:31]([C:35]([OH:37])=[O:36])=[CH:30][N:29]=2)=[CH:24][CH:23]=1.CC(N(C)C)=O>C(N(CC)CC)C.ClCCl>[C:1]([NH:4][CH:5]([C:10]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:33]=[C:32]([OH:34])[C:31]([C:35]([OH:37])=[O:36])=[CH:30][N:29]=2)=[CH:26][CH:27]=1)=[O:12])[CH2:6][CH2:7][S:8][CH3:9])(=[O:3])[CH3:2]
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reactant: CSCCC(NC(C)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CSCCC(NC(C)=O)C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Yield: 57.1 %

Procedure:
A suspension of 14.34 g (75 mmol) of N-acetyl-DL-methionine and 150 ml of dichloromethane is stirred at -15° and 10.5 ml (75 mmol) of triethylamine is added followed by 9.75 ml (75 mmol) of isobutyl chloroformate. After stirring for 20 minutes at -15° C., a solution of 11.6 g (50 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid in 200 ml of dimethylacetamide containing 7.7 ml (55 mmol) of triethylamine is added at -15° C. The mixture is stirred at 0° C. for 3 hrs and overnight at room temperature. The mixture is evaporated and the residue triturated with water. The aqueous suspension, after adjusting the pH to 2.5 with dilute HCl is filtered, washed with water, and dried to give 11.54 g of 2-[4-(N-acetyl-DL-methionylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid; mp 259° C. dec.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].O>CN(C)C=O>[O:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCCCCBr
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCCOc1ccccc1
Yield: 93.4 %

Procedure:
60% Sodium hydride (1.4 g) was suspended in dimethylformamide (40 ml), and phenol (3 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and 1-bromo-5-chloropentane (5.9 g) was added, which was followed by stirring at room temperature for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 5.9 g of 5-phenoxypentyl chloride.