Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:28])[C@@H:19]([NH:23][C:24](=[O:27])[O:25][CH3:26])[CH:20]([CH3:22])[CH3:21])=[N:10][CH:9]=2)=[CH:4][C:3]=1OC(F)F.Br[C:34]1[CH:39]=[CH:38]C(C2NC([C@@H]3CCCN3C(OC(C)(C)C)=O)=NC=2)=[CH:36][C:35]=1OC(F)F>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:8]1[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:28])[C@@H:19]([NH:23][C:24](=[O:27])[O:25][CH3:26])[CH:20]([CH3:22])[CH3:21])=[N:10][C:9]=1[CH:36]=[C:35]2[C:34]#[C:39][CH3:38]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)c(OC(F)F)c2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)c(OC(F)F)c2)[nH]1
Product: CC#Cc1cc2nc([C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c2c2ccc(Br)cc12

Procedure:
Methyl (S)-1-((S)-2-(7-bromo-5-(prop-1-ynyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate was prepared according to the procedure described for the synthesis of methyl (S)-1-((S)-2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (S)-tert-butyl 2-(7-bromo-5-(prop-1-ynyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate for (S)-tert-Butyl 2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[Cl:11][C:12]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[Cl:11][C:12]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:13]=1[O:14][CH:15]1[CH2:16][CH2:17][N:18]([C:2]2[C:3](=[O:10])[NH:4][C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)[CH2:19][CH2:20]1.[Cl:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: Cn1nc(Br)c(=O)[nH]c1=O
Reactant: Clc1ccc(Cl)c(OC2CCNCC2)c1
Product: Clc1ccccc1OC1CCNCC1
Product: Cn1nc(N2CCC(Oc3cc(Cl)ccc3Cl)CC2)c(=O)[nH]c1=O

Procedure:
The compound 91 (white solid) is prepared from the triazine 2e and from 4-(2,5-dichlorophenoxy)piperidine (obtained as under the preparative methods of intermediate 8a) according to the synthesis method 1 in toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]=2[CH:22]=1.[C:23]([O:27][C:28]([NH:30][C@H:31]([CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1)[CH2:32][C:33](O)=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:33](=[O:34])[CH2:32][C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:38]=4)[CH2:12]3)[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccc(OC)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.3 %

Procedure:
(R)-6-Methoxy-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (41E) (2.82 mmol, 0.86 g) in DMF (16 mL) was added (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (3.10 mmol, 1.02 g) and N-methylmorpholine (11.28 mmol, 1.24 mL). The reaction mixture was stirred at rt for 5 min and then added HATU (3.10 mmol, 1.18 g) and kept stirring at rt overnight. The reaction mixture was poured into H2O, extracted with EtOAc. The extract was washed with H2O, NaHCO3, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by preparative LC/MS (40-90% CH3CN in H2O) to afford tert-butyl (R)-4-((R)-3-(6-methoxy-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (42F) (0.63 mmol, 0.387 g, three-step yield: 22.3%). ESI-MS: m/z 616.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([Cl:27])[CH:21]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[CH2:49]([NH2:52])[CH2:50][CH3:51]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:26]=[CH:25][C:23]([NH:24][C:41]([NH:52][CH2:49][CH2:50][CH3:51])=[O:47])=[C:22]([Cl:27])[CH:21]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2c(Oc3ccc(N)c(Cl)c3)ncnc2cc1OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCc4ccccc4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Yield: 63 %

Procedure:
4-{[7-(Benzyloxy)-6-methoxy-4-quinazolinyl]oxy}-2-chloroaniline (12.2 g) was dissolved in anhydrous chloroform. Triethylamine (8.4 ml) was then added to the solution, and the mixture was stirred at room temperature. Separately, triphosgene (4.5 g) was dissolved in anhydrous chloroform (12 ml), and the solution was added dropwise to the mixed solution. The mixture was stirred at room temperature for 20 min, and n-propylamine (4.9 ml) was then added thereto, followed by stirring at room temperature for additional one hr to precipitate a white solid. This solid was collected by filtration and was then washed with chloroform to give rib 9.4 g (yield 63%) of the title compound.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:38]([NH2:40])=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[NH:51]([C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67])[C@H:52]([C:63]([OH:65])=O)[CH2:53][CH2:54][CH2:55][NH:56][C:57](=[NH:62])[NH:58][N+:59]([O-:61])=[O:60].[N+](C1C=C([N+]([O-])=O)C=CC=1O)([O-])=O.C1CCC(N=C=NC2CCCCC2)CC1>[Pd].O1CCCC1.CN(C=O)C>[NH:51]([C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67])[C@H:52]([C:63]([NH:1][CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:38]([NH2:40])=[O:39])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])=[O:65])[CH2:53][CH2:54][CH2:55][NH:56][C:57](=[NH:62])[NH:58][N+:59]([O-:61])=[O:60]
Reactant: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Reactant: NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O)N[N+](=O)[O-]
Reaction time: 6 h

Procedure:
In 30 ml. of DMF was dissolved 1.0 g. of Z-β-Ala-Phe-Phe-Tyr-NH2, and using Pd-black as a catalyst, catalytic reduction was carried out for 6 hours. The catalyst was filtered off. To the filtrate was added a solution of Z-Arg(NO2)-ODNP in tetrahydrofuran (the dinitrophenyl ester prepared from 0.52 g. of Z-Arg(NO2)-OH and 0.30 g. of 2,4-dinitrophenol in 10 ml. of tetrahydrofuran by the DCC process). The mixture was stirred for 13 hours and the solvent was distilled off. To the residue was added 50 ml. of water and the resulting powder was collected byy filtration and dried. Yield 1.01 g. (74.9 %); melting point: 192°-194°; [α]D22 -11.1° (c=1.02 %, DMF).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20]CC1C=CC=CC=1)=O)([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C(Cl)(=O)[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1>CO.C(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:28])[C:14]([NH:17][C:18](=[O:20])[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)([CH3:15])[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)C(C)(C)NC(=O)OCc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NC(C)(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To solution of 49 (1.00 g, 2.56 mmol) in MeOH (20 ml) was added 10% Pd/C (200 mg) and the mixture was stirred under H2 for 2 hours. The mixture was filtered through a 0.45 μm PTFE filter and the solvent removed in vacuo to yield a colorless oil. This oil was dissolved in CH2Cl2 (25 mL) and DIEA (660 μl, 3.79 mmol) and p-anisoyl chloride (480 mg, 2.8 mmol) were added. The solution was stirred at room temperature under N2 for 18 hours. The solvent was removed in vacuo and the oil dissolved in EtOAc. The organic phase was washed with 0.5N NaHSO4 (2×), water, saturated NaHCO3 (2×) and brine. The organic phase was dried over Na2SO4, filtered and evaporated to give a white solid which was purified by flash column chromatography, eluting with CH2Cl2/MeOH (99/1 to 98/2%) to give the title compound as a white solid (655 mg, 65% yield). 1H-NMR (500 MHz, CDCl3) δ 1.47 (s, 9H), 1.68-2.24 (m, 5H), 1.80 (d, 6H), 3.55-3.68 (m, 1H), 3.72-3.93 (m, 1H), 3.84 (s, 3H), 4.43-4.55 (m, 1H), 6.90 (d, 2H), 7.60 (br s, 1H), 7.77 (d, 2H) Analytical HPLC (C18 column) 8.98 min.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl[CH2:31][C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[C:12]([O:14][CH2:31][C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)OCC(=O)N(CC)CC)n1Cc1ccccc1Cl
Temperature: 70 °C
Yield: 78.1 %

Procedure:
A solution of (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(benzyl)-2-propenoic acid (Example 2) (2.05 g, 5 mmol) in dry dimethylformamide (10 mL) was treated with 2-chloro-N,N-diethylacetamide (0.825 g, 5.51 mmol) followed by powdered potassium carbonate. This mixture was heated at 70° C. for 7 hours, diluted with water and extracted with ethyl acetate. The water-washed, dried, concentrated product solidified and after trituration with ether/hexane afforded 2.04 g (78%) of the title ester; mp 76°-77° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][C:9]([CH3:11])=[O:10].[CH2:12](O)[CH3:13].[OH-].[Na+]>O>[S:1]1[CH:2]=[CH:3][C:12](/[CH:13]=[CH:8]/[C:9](=[O:10])/[CH:11]=[CH:6]/[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:5]1
Reactant: CCO
Reactant: CC(C)=O
Reactant: O=Cc1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(/C=C/c1ccsc1)/C=C/c1ccsc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
A mixture of 29.8 g (0.27 mol) of 3-thiophenecarboxaldehyde, 7.7 g (0.13 mol) of acetone, 80 mL of ethanol, 40 mL of water, and 2 mL of 10% aqueous sodium hydroxide was stirred for 15 hours at ambient temperature. The solid that crystallized from the mixture was collected by filtration, and is dried to give 29.2 g (46% yield) of E,E-1,5-di-(3-thienyl)-1,4-pentadien-3-one as a yellow solid. 1H NMR, IR, and FDMS analyses were consistent with the expected structure. Elemental analysis: Calcd for C13H10OS2 : C, 63.38; H, 4.09. Found: C, 63.10; H, 4.12.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][S:36]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)(=[O:38])=[O:37])[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)C(CS(=O)(=O)Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: c1ccc2c(c1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(CS(=O)(=O)N1CCc2ccccc2C1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 64 h
Yield: 83 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline (0.17 ml) was dissolved in dichloromethane (40 ml) at room temperature under nitrogen. Triethylamine (0.19 ml) was added, followed by 4-(1-tert-butoxycarbonyl-2-chlorosulfonyl-ethyl)-piperidine-1-carboxylic acid benzyl ester (500 mg) as a solution in dichloromethane (1.5 ml). The reaction was left to stir for 64 h then diluted with dichloromethane (60 ml), washed with 10% citric acid solution (2×50 ml), water (2×50 ml), saturated sodium bicarbonate solution (2×50 ml) and brine (50 ml). The organic layer was then dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound (506 mg, 83%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH3:14])=[CH:5][N:4]=1.[Li]CCCC.[S:20](Cl)([Cl:23])(=[O:22])=[O:21]>C1COCC1.C(OCC)C.C(OCC)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([S:20]([Cl:23])(=[O:22])=[O:21])=[CH:12][C:13]=2[CH3:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2sccc2C)cn1
Reactant: O=S(=O)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(-c2sc(S(=O)(=O)Cl)cc2C)cn1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
2-Methoxy-5-(3-methyl-thiophen-2-yl)-pyridine (0.32 g, 1.6 mmol) was dissolved in THF/diethyl ether (10 ml, 1:1 v/v) and cooled to −70° C. BuLi (1.6M hexanes, 1 ml, 1.6 ml) was added dropwise and after a further 15 min at −70° C. the reaction mixture was added via canula to a condensed solution of SO2 (5 ml) in diethyl ether (10 ml). The yellow colored reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue washed with diethyl ether and dried. The crude solid (0.31 g) was suspended in dry n-hexane (7 ml), cooled using an ice bath to 0° C. and treated with a solution of sulfuryl chloride (1 M, 1.2 ml, 1.2 mmol) in CH2Cl2. The reaction mixture was slowly warmed to room temperature and analyzed (TLC) showing no starting material. Solvent was removed under reduced pressure and the crude product was purified over silica gel (n-heptane/tert.butylmethyl ether 1:9 to 1:4 v/v) to yield a white solid: 0.19 g (38%), MS: m/e 304.0 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.B(Br)(Br)Br.[OH2:18]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:5][CH:6]=2)=[CH:4][C:3]([O:2][CH3:1])=[O:18])[CH:10]=[CH:11][CH:12]=1
Reactant: COC1CCc2ccccc2C1=O
Reactant: O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C=C(c1ccccc1)c1cccc(OC)c1
Reaction time: 0.5 h

Procedure:
A solution of 11.39 g (0.0451 mol) of the methoxy tetralone from step 7 in 250 mL CH2Cl2 is cooled in ice and treated dropwise with 29 mL of BBr3. The purple solution is kept at 0° for 0.5 hour, then at room temperature overnight. The solution is poured into H2O and extracted twice with Et2O. The Et2O is washed twice with 5% NaOH and the NaOH back extracted with Et2O. The NaOH extract is acidified with dil. HCl and extracted twice with Et2O. The Et2O is washed with sat. NaCl, dried over Mg SO4, and the solvent removed leaving 10.82 g of a brown foam. Chromatography on silica gel, eluting with CHCl3/MeOH (98:2) gives 2.05 g (19.1% yield) of the product as a pink solid. The structure is confirmed by NMR and mass spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([CH2:24][CH3:25])=[C:17]3[N:22]([CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:27]#[C:28][C:29]([O-:31])=[O:30].[C:32]1(C)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([CH2:24][CH3:25])=[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[N:22]3[C:23]=2[CH:27]=[C:28]4[C:29]([O:31][CH3:32])=[O:30])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2ccccc12
Reactant: CC#CC(=O)[O-]
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(=O)OC)c3cccc1n32
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of 2-(4-benzyloxyphenyl)-1-ethylindolizine (6.55 g, 20 mmol) and methylpropiolate (10.4 g, 124 mmol) in 250 ml of dry toluene was heated to 100° C. under nitrogen atmosphere and stirred for 21/2 hour. The mixture was cooled to room temperature and 2,3-dichloro-5,6-dicyano-1,4-benzoequinone (1.84 g, 8.1 mmol) was added and stirring was continued for 1 our. The mixture was filtered through celite and the solvent removed. The crude product was purified by column chromatography over silica gel 60, using 20% of diethyl ether in hexane as the eluent to afford 4.82 g (58%) of methyl 3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1-carboxylate. M.p. 129-131° C. MS(SP): m/z 409 (M+). 1H-NMR (CDCl3, 200 MHz) δ: 1.47 (t, 3H); 3.22 (q, 2H); 4.01 (s, 3H); 5.16 (s, 2H); 7.15 (d, 2H); 7.32-7.52 (m, 5H); 7.72 (d, 2H); 7.75-7.90 (m, 2H); 8.03 (s, 1H); 8.33 (dd, 1H). Analysis: Calculated for C27H23N1O3 : C, 79.20; H, 5.66; N, 3.42%; Found: C, 79.10; H, 5.50; N, 3.20%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:14][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1cccs1
Reactant: COc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(NC(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
According to Scheme 1 Method A: A solution of thiophene-2-carbonyl chloride (2.92 mmol, 0.31 mL) in DCM (1 mL) was added to solution of 3-methoxyaniline (2.44 mmol, 0.27 mL) and DIEA (4.87 mmol, 0.87 mL) in DCM (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The organic phase was washed with HCl 1 M solution, then with a saturated solution of NaHCO3, was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield N-(3-methoxyphenyl)thiophene-2-carboxamide (1.71 mmol, 0.40 g, 70%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([F:14])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([F:15])[CH:4]=1.[Cl:16][C:17]1[CH:18]=[C:19]([OH:27])[CH:20]=[N:21][C:22]=1[O:23][CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([O:27][CH2:2][C:3]2[C:13]([F:14])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([F:15])[CH:4]=2)[CH:20]=[N:21][C:22]=1[O:23][CH:24]([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1cc(F)c(CBr)cc1F
Reactant: CC(C)Oc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(F)c(COc2cnc(OC(C)C)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 144 %

Procedure:
To a solution of ethyl 4-(bromomethyl)-2,5-difluorobenzoate (Preparation 13, 200 mg, 0.72 mmol) in N,N-dimethylformamide (4 mL) at room temperature under nitrogen was added 5-chloro-6-isopropoxypyridin-3-ol (Preparation 6, 161 mg, 0.86 mmol) and potassium carbonate (198 mg, 1.43 mmol). The reaction was stirred at room temperature for 2 days, then partitioned between water and ethyl acetate (1:1 10 mL). The organic phase was washed with brine (10 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo to afford the title compound as a light yellow solid (400 mg, >100%). No further purification undertaken.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>>[O:14]=[C:12]1[C:11]2[C:10](=[CH:9][C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][CH:15]=2)[C:17](=[O:19])[N:20]1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: NCC(=O)O
Reactant: O=C(O)c1ccc(Sc2ccccc2)cc1C(=O)O
Product: O=C(O)CN1C(=O)c2ccc(Sc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
5.62 g of 4-phenylsulfanyl-phthalic acid (20.5 mmol) and 1.55 g of glycine (20.5 mmol) were ground thoroughly together in a mortar. Then the mixture was heated to 210° C. to 220° C. in an oil bath. The molten mass was stirred with a spatula at this temperature for 15 min before it was allowed to cool to ambient temperature in vacuo. 6.30 g of the title compound were obtained; MS-(−)-ion: M−1=311.8; 1H NMR (DMSO-d6): δ=7.82 (d, 1H), 7.46 to 7.62 (m, 7H), 4.26 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[C:9]([O:13][CH3:14])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([OH:16])=[C:4]2[C:17](=[O:37])[C@:18]3([C:32]4[C:31]([OH:33])=[C:30]5[C:25]([CH:26]=[C:27]([CH:35]=O)[NH:28][C:29]5=[O:34])=[CH:24][C:23]=4[CH2:22][CH2:21]3)[C:19](=[O:20])[C:3]=12.[Cl-].[CH2:39]([O:46][NH3+:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.N1C=CC=CC=1.O>CN(C=O)C>[CH2:39]([O:46][N:47]=[CH:35][C:27]1[NH:28][C:29](=[O:34])[C:30]2[C:25]([CH:26]=1)=[CH:24][C:23]1[CH2:22][CH2:21][C@@:18]3([C:17](=[O:37])[C:4]4=[C:5]([OH:16])[C:6]5[C:7](=[O:15])[CH:8]=[C:9]([O:13][CH3:14])[C:10](=[O:12])[C:11]=5[C:2]([OH:1])=[C:3]4[C:19]3=[O:20])[C:32]=1[C:31]=2[OH:33])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: [NH3+]OCc1ccccc1
Reactant: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C=O)[nH]c(=O)c4c(O)c21)C3=O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C=NOCc5ccccc5)[nH]c(=O)c4c(O)c21)C3=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ten (10) mg (19.4 μmol) fredericamycin aldehyde (4) are dissolved in 2 mL DMF. After addition of 6.4 mg (43.2 μmol) O-benzylhydroxylammonium chloride and 3.2 μl pyridine, the reaction mixture is stirred for 2 h at room temperature. Then, it is added to 50 ml water, and the supernatant is sucked off from the red precipitate (HPLC clean).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Na+]>CO.O>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:19])=[O:20])=[CH:14][CH:13]=2)[C:4]([OH:25])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)CC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of the title C compound, 3-cyclopentyl-2-[4-(2-oxo-propylsulfonyl)-phenyl]-propionic acid ethyl ester (5 g, 0.013 mol) in 40 mL of methanol and 60 mL of water is treated with 1 g (0.027 mol) of sodium hydroxide and the reaction is stirred at 25° C. for 6 h. The reaction mixture is concentrated under vacuum, and the residue is re-dissolved in water and extracted with diethyl ether (50 mL). The aqueous layer is then acidified to pH 1 with 1 N aqueous hydrochloric acid solution. This solution is extracted with ethyl acetate (2×100 mL). The organic layer is washed with water and brine, dried over sodium sulfate and then filtered and evaporated under vacuum to give 3-cyclopentyl-2-[4-(2-oxo-propylsulfonyl)-phenyl]-propionic acid as a white solid.