Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH2:24]2)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:52]1([CH3:75])[CH:57]=[CH:56][C:55]([S:58]([O:61][CH2:62][CH2:63]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:60])=[O:59])=[CH:54][CH:53]=1>CN(C)C=O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH:14]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]2)[CH2:24]1)=[O:22])[C:10]1[CH:11]=[N:12][CH:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][CH2:63][CH2:62][O:61][S:58]([C:55]2[CH:56]=[CH:57][C:52]([CH3:75])=[CH:53][CH:54]=2)(=[O:60])=[O:59])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2OCCOS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 68 h
Yield: 39.4 %

Procedure:
108.0 mg (0.17 mmol) Tert-butyl 4-{3-[(3R)-3-({1-[5-(2-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8d) were dissolved in 6.7 ml N,N-dimethylformamide. 170 mg (0.52 mmol) cesium carbonate and 96.4 mg (0.26 mmol) ethylene glycol bis-p-toluenesulfonate were added. The mixture was stirred at room temperature for 68 hours and concentrated. The remainder was taken up with saturated ammonium chloride solution and ethyl acetate. The aqueous phase was extracted with 3×20 ml ethyl acetate. The extracts were dried over sodium sulfate and concentrated. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 55 mg (37%) tert-butyl 4-{3-[(3R)-3-{[3-methoxy-1-{5-[2-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [C:1]1([CH:7]([CH:13]([N:15]([CH3:17])[CH3:16])[CH3:14])[C:8](OCC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]1([CH:7]([CH:13]([N:15]([CH3:17])[CH3:16])[CH3:14])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(c1ccccc1)C(C)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C(CO)c1ccccc1)N(C)C

Procedure:
The title compound is prepared according to the procedure of Example 2, from ethyl 2-phenyl-3-dimethylaminobutyrate and lithium aluminum hydride. B.p. 126°-129° C/0.2 mm Hg.
Reaction SMILES: C1C2C(C[O:15][C:16]([NH:18][C@H:19]([C:43]([OH:45])=O)[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.[NH2:47][CH2:48][CH2:49][C:50]1[CH:57]=[CH:56][C:54]([OH:55])=[C:52]([OH:53])[CH:51]=1>>[C:16]([NH:18][C@H:19]([C:43]([NH:47][CH2:48][CH2:49][C:50]1[CH:57]=[CH:56][C:54]([OH:55])=[C:52]([OH:53])[CH:51]=1)=[O:45])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:15])/[CH:48]=[CH:49]/[C:50]1[CH:57]=[CH:56][C:54]([OH:55])=[C:52]([OH:53])[CH:51]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: O=C(/C=C/c1ccc(O)c(O)c1)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCc1ccc(O)c(O)c1
Yield: 137 %

Procedure:
The title compound was prepared from Nα-(9-fluorenylmethoxycarbonyl)-Nγ-trityl-L-asparagine (2.0 g, 3.4 mmol) following the indications of general procedure F with dopamine hydrochloride (954 mg, 5 mmol). The crude material was purified by flash chromatography with a solvent gradient from 15% to 60% EtOAc/CH2Cl2 to give 2.3 g (95%) of the desired product as white crystals.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:7]2[CH:20]=[C:19]([OH:21])[C:10]3[C:11]4[CH2:18][CH2:17][S:16][C:12]=4[C:13](=O)[O:14][C:9]=3[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1.[CH2:22]([Mg]Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH:1]1([CH2:4][CH:5]([C:7]2[CH:20]=[C:19]([OH:21])[C:10]3[C:11]4[CH2:18][CH2:17][S:16][C:12]=4[C:13]([CH2:3][CH2:2][CH2:1][CH2:4][CH2:5][CH3:6])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:14][C:9]=3[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1
Reactant: CCCCCC[Mg]Br
Reactant: CC(CC1CC1)c1cc(O)c2c3c(c(=O)oc2c1)SCC3
Product: CCCCCCC1(CCCCCC)Oc2cc(C(C)CC3CC3)cc(O)c2C2=C1SCC2

Procedure:
By reacting 7-(3-cyclopropyl-2-propyl)-1,2-dihydro9-hydroxy-4-oxo-4H-thieno[2,3-c][1]benzopyran with n-hexyl magnesium bromide, using the procedure described above in Example 8, there is obtained 7-(3-cyclopropyl-2-propyl)-4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-4H-thieno[2,3-c][1]benzopyran. The benzopyran is then reacted with morpholinoacetic acid and dicyclohexylcarbodiimide according to the method of Example 9 to yield the desired ester.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.O.[BH4-].[Na+].C[NH2:16]>CO>[NH2:16][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of aldehyde product from Step B (2.0 g, 14 mmol) in methanol (100 mL), 40% methylamine in water (2.27 mL, 27.6 mmol) was added at room temperature over a period of 10 min. The mixture was stirred at room temperature under nitrogen overnight and then was cooled down to 0° C. Sodium borohydride (1.05 g, 27.6 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 h. Most of methanol was removed in vacuo, and the residue was diluted with water and extracted (3×) with ether. The combined organic layers were extracted with 2 N HCl (100 mL). The HCl layer was made basic (pH˜11) with 2 N NaOH and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give crude 4-(aminomethyl)-indole as a white powder (1.95 g, 88%): 1H NMR (300 MHz, CDCl3) δ 8.29 (s, br, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.22 (t, J=2.7 Hz, 1H), 7.16 (t, J=8.0, 7.3 Hz, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.64 (t, J=2.0 Hz, 1H), 4.06 (s, 2H), 2.51 (s, 3H); CI MS m/z=160 [C10H12N2+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:39])([F:38])[C:13]([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])([OH:32])[CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:34]([CH2:35][CH2:36][CH3:37])[CH2:33][C:13]([CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)([OH:32])[C:12]([F:11])([F:39])[F:38])=[O:6]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1C

Procedure:
Prepared similarly to Example 1 from 2-methylbenzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][C:10]=1[F:27])#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][CH:42]=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1>>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[C:10]([F:27])[CH:11]=4)=[C:22]([CH2:23][CH2:24][CH3:25])[N:40]4[N:41]=[CH:42][N:43]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(F)c1)C(=O)OCC
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 250 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (3.3 g) and N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (1 g) was stirred at 250° C. for 1 hr under microwave irradiation. The reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (1.2 g, 50%).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH3:16])\[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([O:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH3:16])\[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])(=[O:26])[CH3:25]
Reactant: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C\CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C\COC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.5 g (0.0021 mol) of (6Z,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one dissolved in 5 ml of methylene chloride and 1.3 ml of pyridine is treated with 1 ml of acetic anhydride. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is taken up three times in toluene and freed from solvent each time on a rotary evaporator. The residue is chromatographed on silica gel with ether-hexane 1:5. There is obtained (2Z,6Z)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienyl acetate which has the following bands in the IR spectrum: 1742 cm-1, 1671 cm-1, 1634 cm-1, 1442 cm-1, 1367 cm-1, 951 cm-1.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:15]([CH3:16])=[N:14][N:13]=[N:12]1)(=[O:4])=[O:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]2[C:15]([CH3:16])=[N:14][N:13]=[N:12]2)(=[O:4])=[O:3])=[O:29])[N:22]=1
Reactant: Cc1nnnn1-c1ccccc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2-n2nnnc2C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To 0.48 g of 1-(2-aminosulfonylphenyl)-5-methyl 1H-tetrazole in 25 mL of acetonitrile was added at ambient temperature and pressure 0.54 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate and 0.3 mL of DBU. The reaction mixture was stirred for three hours, added to 25 g of ice and acidified to pH 3 with hydrochloric acid. The precipitate thus obtained was filtered, washed with water and dried to yield 0.74 g of the desired product, melting point at 213°-216° C. Infrared absorption spectra showed peaks at 1710, 1605 and 1570 cm-1, consistent for the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:13]=1[O:14][CH3:15])[CH2:10][C:9]([CH3:26])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[Li]CCCC.[Cl:39][Si:40](Cl)([CH3:42])[CH3:41]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11]([CH:10]=[C:9]([CH3:26])[CH:8]2[Si:40]([Cl:39])([CH3:42])[CH3:41])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:13]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)CC(C)=C2
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)C=C(C)C2[Si](C)(C)Cl
Temperature: -20 °C
Reaction time: 10 h
Yield: 99.7 %

Procedure:
To a solution of 10.5 g (30.0 mmol) of 5-tert-butyl-7-(4-tert-butylphenyl)-6-methoxy-2-methyl-1H-indene in 200 ml of toluene 12.0 ml (30.0 mmol) of 2.5 M nBuLi in hexanes was added at room temperature. The resulting viscous solution was stirred for 10 h, and then 10 ml of THF was added. The formed mixture was stirred for 2 h at 60° C., then cooled to −20° C., and 19.4 g (150 mmol, 5 eq.) of dichlorodimethylsilane was added in one portion. The resulting solution was warmed to room temperature, refluxed for 1 h, and then filtered through glass frit (G3). The precipitate was additionally washed by 2×10 ml of toluene. The combined filtrate was evaporated to dryness to give 13.2 g (99%) of the title product as a yellowish oil which was further used without an additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:20][CH3:21])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CCO
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
4-Chloro-3-(trifluoromethyl)benzoic acid (1 g, 4.45 mmol) was dissolved in ethanol (3 ml) and concentrated sulfuric acid (0.15 ml) was added. The mixture was heated in the microwave at 100° C. for 5 minutes and then 120° C. for 15 minutes. The solvent was removed in vacuo and the residue partitioned between saturated aq. sodium bicarbonate (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with further EtOAc (50 ml) and the organic phases were combined, dried with a phase separator and concentrated in vacuo to give the title compound (1.026 g) as a colourless oil. δH (methanol-d4, 400 MHz) 1.40 (3H, t), 4.41 (2H, q), 7.76 (1H, d), 8.21 (1H, dd), 8.33 (1H, d).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Br:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27]Br)[O:26][C:22]=2[C:21]([O:29][CH3:30])=[CH:20][CH:19]=1>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:27][C:25]2[O:26][C:22]3[C:21]([O:29][CH3:30])=[CH:20][CH:19]=[C:18]([Br:17])[C:23]=3[CH:24]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1ccc(Br)c2cc(CBr)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c2cc(COC3CCN(C(=O)OC(C)(C)C)CC3)oc12
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Sodium hydride (72 mg of a 60% dispersion in oil) was added to a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (363 mg) in N,N-dimethylformamide (10 ml) under an inert atmosphere at ambient temperature. After stirring for 30 minutes 4-bromo-2-bromomethyl-7-methoxybenzofuran (526 mg) was added and the reaction stirred overnight. The reaction mixture was preadsorbed onto silica and purified by column chromatography eluting with 25% ethyl acetate in hexane to afford the desired product as a yellow oily solid (269 mg).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>CCO>[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Reactant: NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CCO
Product: O=c1c(NCCc2ccc(Oc3ccc(Cl)cc3)cc2)c(Nc2ccncc2)c1=O
Temperature: 150 °C

Procedure:
3-Ethoxy-4-(pyridine-4-yl-amino)-3-cyclobutene-1,2-dione (70 mg, 0.32 mmol) and 2-[4-(4-chlorophenoxy)-phenyl]-ethylamine (105 mg, 0.45 mmol) in EtOH (1.5 mL) were stirred and heated to 150° C. in a sealed vessel in a microwave synthesizer for 30 s. After cooling to r.t. the precipitate was filtered off, washed with EtOH (3×3 mL) and dried in vacuo.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=1)/[CH:10]=[CH:11]/[C@H:12]1[C@H:16]([O:17][Si](C(C)(C)C)(C)C)[CH2:15][C@H:14]([OH:25])[C@@H:13]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>C(O)(C)C>[OH:17][C@@H:16]1[CH2:15][C@H:14]([OH:25])[C@H:13]([CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[C@H:12]1/[CH:11]=[CH:10]/[C@@H:9]([OH:8])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=1
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](COc2cccc(C(F)(F)F)c2)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Yield: 99 %

Procedure:
A mixture of crude compound (11a) (10 g), 2N HCl (37 mL) and isopropanol (IPA) (100 mL) was stirred. The reaction solution was neutralized with saturated aqueous NaHCO3 and extracted twice with EtOAc (80 mL each), once with saturated aqueous NaCl (80 mL) and then the organic layer was concentrated under reduced pressure. The product was purified twice by column chromatography using mixtures of EtOAc and n-heptane to afford Travoprost (HPLC >99.0%).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([I:14])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20]C)[C@H:17]([O:22][C:23](=O)C)[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Na+]>O>[CH2:1]([C:8]1[C:13]([I:14])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:16][C@H:17]([O:22][CH3:23])[C@H:18]([OH:20])[CH2:19]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Yield: 98.5 %

Procedure:
To a mixture of 7.5 g of 2-benzyl-3-iodo-6-[(3R,4S)-3-acetoxy-4-methoxypyrrolidin-1-yl]pyridine and 30 ml of methanol was added 0.33 ml of 28% methanol solution of sodium methoxide and the resultant mixture was stirred under nitrogen atmosphere at room temperature for 30 minutes. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (20–50% ethyl acetate/hexane), to give 6.7 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([CH3:23])[C:15](=[O:24])[C:14]2[CH:25]=[N:26][CH:27]=[N:28][C:13]1=2)=[O:11].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH3:23][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:12]([C:10](=[O:11])[CH2:9][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[C:13]2[N:28]=[CH:27][N:26]=[CH:25][C:14]=2[C:15]1=[O:24]
Reactant: CN1CCNCC1
Reactant: CN1C(=O)c2cncnc2N(C(=O)CCl)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CN1CCN(CC(=O)N2c3ccccc3N(C)C(=O)c3cncnc32)CC1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
2.6 g (0.0266 mol) of N-methylpiperazine are added dropwise at 50° C., in the course of 15 minutes, to a suspension of 4.0 g (0.0133 mol) of 11-chloroacetyl-6-methyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 30 ml of absolute benzene, and the mixture is stirred for a further 1.5 hours at 70° C. After cooling, the mixture is poured into 100 ml of saturated sodium bicarbonate solution and is extracted once with 50 ml of ethyl acetate and twice with 100 ml, each time, of chloroform. After drying, the organic phase is concentrated in vacuo, and the liquid residue is induced to crystallize by means of ether. It is purified by filtering through neutral silica gel (elution with chloroform) and evaporating the filtrate; yield: 2.7 g, m.p. 183° to 185° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22]>>[CH3:19][N:20]([CH3:24])[C:21](=[S:22])[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=S)Cl
Reactant: O=C(c1ccc(O)cc1)c1cccc([N+](=O)[O-])c1
Product: CN(C)C(=S)Oc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Yield: 83.8 %

Procedure:
Following the procedure described in Preparation I and starting from 18 g (0.07407 mol) of 4-hydroxyphenyl 3-nitrophenyl methanone and 12.3 g (0.0992 mol) of dimethylthiocarbamoyl chloride, 20.5 g (yield: 84%) of O-4-(3-nitrobenzoyl)phenyl dimethylthiocarbamate are obtained.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>O1CCCC1>[CH2:1]([NH:5][C:6]([NH:14][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=O
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Product: CCCCNC(=O)NC1CCCCC1
Reaction time: 1 h

Procedure:
One hundred mL of tetrahydrofuran (THF) was added to a dry 500 mL round bottom 3-neck flask equipped with a thermometer, pressure equalizing addition funnel capped with a drying tube, nitrogen inlet and magnetic stirrer. Then 17.24 mL (0.15 moles) of 98% n-butyl isocyanate was added under nitrogen. A solution of 17.33 mL (0.15 moles) of 99% cyclohexylamine in 46 mL of THF was added to the addition funnel and slowly dropped into the stirred solution of n-butyl isocyanate at a rate (about 20 min.) which maintained the temperature below 40° C. The reaction mixture was stirred for one hour after completion of the addition. The solvent was removed by rotary evaporation. The white residue was vacuum dried for 12 hours at room temperature. The yield of dried, crystalline white product was quantitative. The product melted sharply at 107°-108° C. (uncorrected).
Reaction SMILES: Br/[C:2](/[F:16])=[C:3](/[F:15])\[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26].C([O-])([O-])=O.[Na+].[Na+].CC(C)=O>C1(C)C=CC=CC=1.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>[F:16]/[C:2](/[C:21]1[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=1)=[C:3](\[F:15])/[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: COc1ccc(/C(F)=C(/F)Br)cc1[N+](=O)[O-]
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: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(/C(F)=C(/F)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 90 mg (0.31 mmol; 1 eq.) of (9), 198 mg (0.93 mmol; 3 eq.) of 3,4,5-trimethoxyphenyl-boronic acid, 0.6 mL of Na2CO3 2M aqueous solution and 19 mg (0.0016 mmol; 0.05 eq.) of Pd(Ph3P)4 in 4 mL toluene was refluxed for 2.5 h. The solution was then cooled down to room temperature, dried over anhydrous sodium sulfate and the crude mixture was passed through a short silica gel column to remove catalyst. The crude product was purified by chromatography on silica gel with Hexane/Acetone 8:2 to give 57 mg (0.15 mmol; 48%) of a yellow oil. Rf=0.17 in Hex./Acetone 8:2.