Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C1COCC1.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][S:13][CH2:12][CH2:11][NH:10]1.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1>O.CCOC(C)=O>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][N:10]1[C:9](=[O:8])[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:14][S:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CSCCN(Cc2ccc3ccccc3c2)C1=O
Yield: 191.2 %

Procedure:
81 mg of sodium hydride as a 60% suspension in oil (2.03 μmol) are introduced at room temperature into a 25 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of THF and 500 mg of 26 (2.03 mmol). The medium is stirred for 1 hour and 449 mg (2.03 mmol) of 2-(bromomethyl)naphthalene are then added. The medium is stirred for 16 hours, 20 ml of EtOAc and 20 ml of water are added to the reaction medium and, after separation of the phases by settling, the organic phase is washed with 10 ml of water. The organic phase is dried, filtered and then evaporated to dryness to give 1.5 g of crude product, which product is chromatographed on a silica cartridge (25 g) with a 90/10 heptane/EtOAc mixture. 510 mg of product 42 are recovered (yield=65%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>ClCCl.CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: O=C(Cc1ccc(O)cc1Br)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)OCc2ccccc2)c(Br)c1
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of benzyl (2-bromo-4-hydroxyphenyl)acetate (2.00 g) in dichloromethane (30.0 mL) were added tert-butyl (chloro)dimethylsilane (1.13 g) and N,N-dimethyl-4-aminopyridine (913 mg) under ice-cooling, followed by stirring for 2 hours under ice-cooling. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (2-bromo-4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)acetate (2.63 g).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([C:11]1[NH:12][C:13]([C:20]([O:22][CH3:23])=[O:21])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C>CCOCC>[CH3:3][N:15]1[C:14]([C:16]([O:18][CH3:19])=[O:17])=[C:13]([C:20]([O:22][CH3:23])=[O:21])[N:12]=[C:11]1[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1nc(Cc2ccccc2)[nH]c1C(=O)OC
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1nc(Cc2ccccc2)n(C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of diazomethane (1.5 g, 35.7 mmol) in ether (100 ml) was slowly added at 0° C. with stirring to a suspension of the above ester (18.59 mmol) in ether (100 mL). After the addition was completed, the solution was stirred at room temperature overnight. Excess diazomethane was decomposed by the slow and careful addition of dilute acetic acid and the mixture was concentrated in vacuo. Water (50 mL) was added and the mixture was thoroughly extracted with dichloromethane. The organic phase was washed with water, saturated sodium bicarbonate and again with water. The solution was dried and the solvent was removed in vacuo to give dimethyl 1-methyl-2-benzyl-4,5-imidazole dicarboxylate.
Reaction SMILES: O1CCOC[CH2:2]1.[OH-].[Li+].[CH:9]1([C:14]([N:16]2[CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:19][CH:18]([C:30]([O:32]CC)=[O:31])[CH2:17]2)=[O:15])[CH2:13]CC[CH2:10]1>O>[CH3:13][C:9]([CH3:2])([CH3:10])[C:14]([N:16]1[CH2:21][CH:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:19][CH:18]([C:30]([OH:32])=[O:31])[CH2:17]1)=[O:15]
Reactant: CCOC(=O)C1CC(c2ccc(OC)cc2)CN(C(=O)C2CCCC2)C1
Reactant: C1COCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C2CC(C(=O)O)CN(C(=O)C(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55 ml of dioxane, 28 ml of water and 0.77 g (32.2 mmol) of lithium hydroxide were added to 2.8 g (14.3 mmol) of ethyl 1-(cyclopentylcarbonyl)-5-[4-(methoxy)phenyl]piperidine-3-carboxylate. The mixture was stirred overnight at RT. For work-up, the dioxane was removed under reduced pressure, water was added and the reaction mixture was acidified using aqueous 1 N hydrochloric acid solution. The mixture was extracted with dichloromethane. The organic phase was dried with sodium sulphate and concentrated under reduced pressure. Yield: 2.44 g (95% of theory)
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]2[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7])(C)(C)C.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28]Br.[H-].[Na+]>CN(C=O)C>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:28][N:13]([C:14]1[N:15]=[CH:16][C:17]([Br:20])=[CH:18][N:19]=1)[C@@H:11]1[CH2:12][N:8]([C:6]([OH:5])=[O:7])[C@H:9]([CH2:21][CH3:22])[CH2:10]1
Reactant: CC[C@@H]1C[C@H](Nc2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (2R,4S)-4-(5-bromo-pyrimidin-2-ylamino)-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (13.0 mmol; 4.84 g), 3,5-bis(trifluoromethyl)benzyl bromide (26.0 mmol; 7.98 g) and sodium hydride (60% dispersion in mineral oil, 39.0 mmol; 1.56 g) in DMF (52 mL) is stirred for 1.5 hours at room temperature under nitrogen. The reaction mixture is quenched with water then saturated ammonium chloride solution. The product is extracted twice with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tent-butyl ester (5.57 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]2[C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:13][C:12]([C:22]3[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=3)=[N:11]2)=[CH:7][CH:6]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([C:22]3[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=3)=[N:11]2)=[CH:31][CH:32]=1)=[O:4]
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)cc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)cc2C(=O)O)cc1

Procedure:
To a solution of the intermediate from step C (1.3 g, 3 mmol) in dichloromethane (10 mL) was added TFA (10 mL). After stirring the reaction at room temperature for 18 hours, it was concentrated in vacuo, azeotroped with toluene (3×) and used in the next step without any further purification. 1H NMR (CD3OD, 500 MHz): 7.97 (d, J=8.2 Hz, 2H), 7.63 (dd, J=6.9, 9.0 Hz, 2H), 7.33 (s, 1H), 7.31 (d, J=8.3 Hz, 2H), 5.58 (s, 2H), 3.88 (s, 3H). LC-MS: 3.68 min; (M+H)=391.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)=[O:5])C.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][O:15][C:13]1[C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:14]=1
Reactant: CCOC(=O)c1cc(OCCc2ccc(Cl)cc2Cl)c2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(OCCc2ccc(Cl)cc2Cl)c2c(c1)OCO2
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.41 g (1.07 mmol) of 7-[2-(2,4-Dichloro-phenyl)-ethoxy]-benzo[1,3]dioxole-5-carboxylic acid ethyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1-2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [CH3:1][NH:2][NH2:3].CN([CH:7]=[C:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]1=O)C>CO>[CH3:1][N:2]1[C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[C:8]=2[CH:7]=[N:3]1
Reactant: CNN
Reactant: CN(C)C=C1C(=O)CCCC1=O
Solvent: CO
Product: Cn1ncc2c1CCCC2=O
Yield: 89.3 %

Procedure:
A solution of 46.1 g (1.0 mol) of methylhydrazine in 400 ml of methanol is slowly added dropwise at ambient temperature to a solution of 167.2 g (1.0 mol) of 2-(dimethylaminomethylene)-cyclohexane-1,3-dione in 2000 ml of methanol. The reaction mixture is then refluxed for 1.5 hours. It is evaporated dryness in vacuo and the crude product obtained is purified by chromatography on silica gel (made by Baker, 30-60 μm) with a mixture of ethyl acetate and cyclohexane=9:1.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:45][C:42]1[CH:41]=[CH:40][C:39]([C:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)=[C:33]2[CH2:38][CH2:37][N:36]([C:21](=[O:22])[CH2:20][N:3]3[CH2:4][CH2:5][CH2:6][C:7]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]3=[O:1])[CH2:35][CH2:34]2)=[CH:44][CH:43]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E) (0.144 g, 0.47 mmol) and 4-(bis(4-fluorophenyl)methylene)piperidine hydrochloride (European Journal of Medicinal Chemistry; 22, 1987; 243-250) (0.15 g, 0.47 mmol) in methylene chloride (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.177 g, 0.47 mmol) and diisopropylethylamine (0.4 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with methylene chloride, and washed with 1 N HCl, water, 1 N NaOH, and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by silica gel flash chromatography, eluting with 5% methanol/dichloromethane. 1H NMR (300 MHz, CDCl3) δ ppm 7.17-7.33 (m, 10H), 6.96-7.05 (m, 8H), 4.24 (s, 2H), 3.66 (t, J=5.5 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 3.42-3.48 (m, 2H), 2.62-2.67 (m, 2H), 2.29-2.42 (m, 4H), 1.75-1.89 (m, 2H); MS (ESI+) m/z 577 (M+H)+.
Reaction SMILES: [Cl-].[Li+].[BH4-].[Na+].[CH2:5]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C@@H:20]([NH:26][C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[S:28])[C:21](OCC)=[O:22])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-]>C(O)C.O1CCCC1.ClCCl.C(OCC)(=O)C>[C:30]([NH:29][C:27]([NH:26][CH:20]([CH2:21][OH:22])[CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[O:12][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[S:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)[C@@H](CCCCNC(=O)OCc1ccccc1)NC(=S)NC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)NC(=S)NC(CO)CCCCNC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
1.78 g of lithium chloride and then 1.6 g of sodium borohydride are added, under an inert atmosphere, to a stirred solution of 12.7 g of ethyl (2R)-6-{[(benzyloxy)-carbonyl]amino}-2-{[(tert-butylamino)carbothioyl]-amino}hexanoate in 130 cm3 of ethanol and 65 cm3 of tetrahydrofuran, cooled to between 0° C. and 5° C. After stirring for 16 hours at a temperature in the region of 20° C., a further 0.4 g of borohydride is added and the mixture is maintained at about 80° C. for 4 hours. The reaction medium is filtered and the filter cake is washed with ethanol. The filtrate is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and the residue obtained is taken up in a dichloromethane/ethyl acetate mixture (85/15 by volume) and left under cold conditions at about 5° C. The crystalline product is spin-filtered and purified by chromatography at atmospheric pressure on a column of silica gel (particle size 40-63μ; mass of silica: 600 g), eluting with a dichloromethane/ethyl acetate mixture (85/15 by volume). The fractions containing the expected product are collected. These fractions are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 6.9 g of benzyl (SR)-5-{[(tert-butylamino)carbothioyl]amino}-6-hydroxyhexylcarbamate are obtained in the form of a colorless oil. (αD20=+24.0±0.8 at a concentration of 0.5% in methanol).
Reaction SMILES: [CH:1]1[C:8]([CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])=[CH:7][C:5](=[O:6])[C:3](=[O:4])[CH:2]=1.[NH2:15][C@H:16]([C:19]([OH:21])=[O:20])[CH2:17][SH:18]>>[CH:7]1[C:5]([OH:6])=[C:3]([OH:4])[C:2]([S:18][CH2:17][CH:16]([NH2:15])[C:19]([OH:21])=[O:20])=[CH:1][C:8]=1[CH2:9][CH:10]([NH2:14])[C:11]([OH:13])=[O:12]
Reactant: N[C@@H](CC1=CC(=O)C(=O)C=C1)C(=O)O
Reactant: N[C@@H](CS)C(=O)O
Product: NC(CSc1cc(CC(N)C(=O)O)cc(O)c1O)C(=O)O

Procedure:
The other pathway from dopaquinone to melanin involves the addition of cysteine to dopaquinone to produce 5-S-cysteinyldopa, followed by the oxidation of 5-S-cysteinyldopa to 5-S-cysteinyldopaquinone. A ring closure of the 5-S-cysteinyldopaquinone then yields 7-alanyl-5-hydroxy-3-carboxy-2H-1,4-benzothiazine which is subsequently decarboxylated to yield 7-alanyl-5-hydroxy-2H-1,4-benzothiazine. At this point, the 7-alanyl-5-hydroxy-2H-1,4-benzothiazine is converted to melanin and pheomelanin. Tyrosinase does not play any additional role in this melanin production pathway.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][NH2:60])=[CH:54][CH:53]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:60][CH2:59][CH2:58][C:55]3[CH:56]=[CH:57][C:52]([Cl:51])=[CH:53][CH:54]=3)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: NCCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(Cl)cc1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (72.5 mg, 0.378 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol (51.1 mg, 0.378 mmol) were dissolved in DCM (Volume: 3.0 mL). The reaction was stirred for 10 minutes before 2-(4-chlorophenyl)ethanamine (0.053 mL, 0.378 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.066 mL, 0.378 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with water and ethyl acetate. The organic layer was washed with 1N HCl, saturated sodium bicarbonate solution, and finally saturated sodium chloride. the organic layer was then dried over magnesium sulfate, filtered and concentrated. The crude material was triturated in ethyl acetate to give the product as a white solid. (Yield: 60 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.85, 7.63, 7.54, 7.38-7.31, 7.24-7.18, 7.14-7.06, 6.71, 5.49, 4.37, 4.00, 3.26, 2.92, 2.69, 2.37-2.27, 1.76-1.22
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1.[OH-].[Na+].[C:14](Cl)(=[O:16])[CH3:15]>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH:9][C:14](=[O:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(CCN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(CCNC(C)=O)cc1
Reaction time: 8 h
Yield: 106.6 %

Procedure:
4-Methoxyphenethylamine (50 g, 330 mmol) was added to dichloromethane (50 ml) and then 2N sodium hydroxide solution (25 ml) was added thereto. Acetyl chloride (26 ml, 364 mmol) was slowly added at 0° C. to the reaction mixture, which was then stirred overnight. The reaction mixture was diluted with dichloromethane, washed with water and a saturated sodium chloride solution, and then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 68 g of the titled compound as a white solid. The product was used in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.CC[CH2:18][CH:19]([C:21](NC1C=CC(C)=C(Cl)C=1)=[O:22])C>C1(C)C=CC=CC=1>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:18][CH:19]3[CH2:21][O:22]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: CCCC(C)C(=O)Nc1ccc(C)c(Cl)c1
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
At rt under an inert atmosphere, (±)-glycydol (0.129 g, 1.74 mmol, 120 uL) is added into a solution of 3,6-dibromo-9-H-carbazole (0.565 g, 1.74 mmol) in anhydrous toluene (10 mL). Then CMMP (which is prepared according to the protocol of Tetsuto, Tsunoda Tett. Lett. 1996, 37(14), 2459-2462) (0.20 g, 1.74 mmol) is added. The resulting mixture is allowed to stir at rt for 16 hours. The solvent is evaporated and the crude compound is purified via flash chromatography using Biotage device and Petroleum Ether/DCM (3/1) as eluant to give the title compound in a 60% yield as a white solid and 5% of (±)-3,6-dibromo-9-[(1E)-3-(3,6-dibromocarabazol-9-yl)propen-1-enyl]carbazole as a grey powder.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15](\[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])/[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1/[C:15](/[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[CH:14]\[CH:13]=[CH:12]\[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)=[O:10]
Reactant: NCCCCc1cccnc1
Reactant: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2OC)cc1
Product: COc1ccc(/C(=C/C=C/C(=O)NCCCCc2cccnc2)c2ccccc2OC)cc1
Yield: 96.3 %

Procedure:
As before in Example 134, a solution of (2E,4Z)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (0.82 g) and 3-pyridinebutanamine (0.33 g) in tetrahydrofruan (7 mL) was stirred overnight at room temperature. After the usual work up. the crude product was purified by HPLC (ethyl acetate) and lyophilized from benzene to give 0.81 g of (2E,4Z)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide as an amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH2:16])[C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH3:16])[C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=1)[CH3:2]
Reactant: C=C(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(C(C(N)=O)C(C)c2ccccc2N2CCCCC2)cc1
Temperature: 0 °C

Procedure:
An amount of 5.5 gm (0.014 mol) of 4-[(1-(2-piperidinophenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid ethyl ester in 110 ml of ethanol was hydrogenated in the presence of 1.5 gm of palladium/charcoal (10%) at 20° C. and a hydrogen pressure of 5 bar. After 30 minutes the catalyst was filtered off over celite, and the filtrate was evaporated in vacuo to a volume of 20 ml. One hundred milliliters of petroleum ether were added, and the mixture was cooled to 0° C.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.Cl.[NH2:12][CH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:17]([C:33]([O:35][CH3:36])=[O:34])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([NH:12][CH2:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:17]([C:33]([O:35][CH3:36])=[O:34])=[CH:16][CH:15]=1)=[O:2]
Reactant: O=CO
Reactant: COC(=O)c1ccc(CN)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(CNC=O)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 48 h
Yield: 99.6 %

Procedure:
Formic acid (2.2 mL, 58 mmol) and acetic anhydride (5.2 mL, 58 mmol) were stirred at room temperature for 1 hour. The mixture was added dropwise to a solution of tert-butyl 4-[6-(aminomethyl)-3-(methoxycarbonyl)pyridin-2-yl]piperazine-1-carboxylate hydrochloride (4.9 g, 13 mmol) in methylene chloride (90 mL) at 0° C. and stirred for 48 hours. Evaporation gave the crude material which was treated with sodium bicarbonate and extracted with methylene chloride to give the desired compound (4.9 g, 100%). LCMS calculated for C18H27N4O5 (M+H)+: m/z=379.2. found: 378.9.