Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C@:10]2([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:11](=[O:12])[C@@H:6]([C@:7]([CH3:28])([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:8]([O:18][CH2:19][O:20][CH3:21])[CH2:9]2)[C:5](=[O:29])[CH:4]=1>[Pd].CO>[CH2:13]([C@@:10]12[C:11](=[O:12])[C@@H:6]([C@:7]([CH3:28])([CH2:22][CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[C@@H:8]([O:18][CH2:19][O:20][CH3:21])[CH2:9]1)[C:5](=[O:29])[CH:4]=[C:3]2[O:2][CH3:1])[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C=C2OC)[C@]1(C)CCC=C(C)C
Agent: [Pd]
Solvent: CO
Product: COCO[C@H]1C[C@@]2(CCC(C)C)C(=O)[C@H](C(=O)C=C2OC)[C@]1(C)CCCC(C)C
Reaction time: 0.42 h
Yield: 95.9 %

Procedure:
A 1 dram vial equipped with a stir bar is charged with 14.9 mg (0.037 mmol, 1 equiv.) of starting material 50 followed by 370 μL of methanol. The vial was flushed with argon, and 8.5 mg of palladium (5 wt % on activated carbon, 0.004 mmol, 0.10 equiv.) was added. The vial was then flushed with hydrogen, and a balloon contained hydrogen was affixed to the vial through a rubber septum cap. The mixture was stirred for 25 min at which time the mixture was filtered through Celite®. The filter cake was rinsed with copious amounts of methanol, and the collected filtrate was concentrated. The crude product was purified by silica gel chromatography (Rf=0.25 in 9:1 hexane:ethyl acetate), affording 14.5 mg (92% yield) of 55 as a clear oil. 1H NMR (500 MHz, CDCl3) δ ppm 5.69 (s, 1H), 4.58 (dd, J=6.9, 52.4 Hz, 2H), 3.80 (s, 3H), 3.59 (dd, J=5.4, 11.3 Hz, 1H), 3.33 (s, 3H), 3.15 (s, 1H), 2.20 (dd, J=5.4, 13.4 Hz, 1H), 1.79 (dt, J=4.5, 12.6 Hz, 1H), 1.72 (dd, J=11.3, 13.3 Hz, 1H), 1.66-1.48 (m, 3H), 1.31-1.14 (m, 4H), 1.14-1.05 (m, 1H), 0.90-0.85 (m, 15H). HRMS-ESI (m/z): [M+K]+ calculated for C24H40O5, 447.2507. found 447.2511.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][C:7](=O)[NH:8][N:9]=1)[CH2:2][CH3:3].P(Br)(Br)([Br:13])=O.O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:13][C:7]1[N:8]=[N:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCCc1ccc(=O)[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1ccc(Br)nn1
Temperature: 80 °C
Yield: 48 %

Procedure:
11.75 g of 6-propyl-3(2H)-pyridazinone were dissolved in 70 ml of absolute toluene while warming in a sulphonation flask under nitrogen, heated to 80° C. and treated dropwise while stirring well within 30 minutes with a solution of 24.4 g of phosphorus oxybromide in 24.4 g of absolute toluene. The mixture was subsequently stirred under reflux for a further 3 hours. After completion of the reaction, the mixture was poured into 200 ml of water and neutralized with solid sodium hydrogen carbonate. The phases were separated and the aqueous phase was back-extracted twice with 100 ml of tert.butyl methyl ether each time. The combined organic phases were washed with 100 ml of water and dried over sodium sulphate. After evaporation of the solvent, the dark brown crystalline residue (14.1 g) was sublimed at 40°-60° C. in a high vacuum, there being obtained 8.2 g (48%) of 3-bromo-6-propylpyridazine as white crystals of melting point 35°-36° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].Cl.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:13].[OH-].[Na+]>OS(O)(=O)=O>[Cl:6][C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[CH:10]=[CH:9][N+:8]=1[O-:13]
Reactant: [O-][n+]1ccccc1Cl
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of conc. H2SO4 (30 mL) and fuming HNO3 (54 mL) was added dropwise at 0° C. to a solution of 2-chloropyridine-N-oxide hydrochloride (15.2 g, 91.56 mmole) in conc. H2SO4 (30 mL). The reaction mixture was heated at 90° C. for 1 hr, then was cooled to RT and poured onto ice (500 g). The reaction mixture was kept at RT overnight, then was cooled in an ice bath, and 50% NaOH was added slowly to give a precipitate. This was collected and dried to give the title compound (5.88 g, 37%) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ8.42-8.37 (m, 2 H), 8.06-8.04 (m, 1 H).
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=C1CCCC1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O[C@H]2CCNC2)cc1
Solvent: CCOC(C)=O
Solvent: CO
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: C(N(CC)CC)C.[C:8]([O:12][C:13](ON=C(C1C=CC=CC=1)C#N)=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:26][C@@:27]1([C:47]([OH:49])=[O:48])[C@H:32]([CH2:33][S:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=2)[C@@H:31]([OH:43])[C@@H:30]2[C@H:28]1[C@H:29]2[C:44]([OH:46])=[O:45]>O1CCOCC1.O>[C:8]([O:12][C:13]([NH:26][C@@:27]1([C:47]([OH:49])=[O:48])[C@H:32]([CH2:33][S:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=2)[C@@H:31]([OH:43])[C@@H:30]2[C@H:28]1[C@H:29]2[C:44]([OH:46])=[O:45])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1CSc1ccc(F)c(F)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1CSc1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
Triethylamine (407.27 mL, 2.92 mol) and [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile] (308.39 g, 1.25 mol) are added to a suspension of (1S,2R,3S,4S,5R,6R)-2-amino-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid (300.00 g, 834.84 mmol) in 1,4-dioxane (500.9 mL) and water (500.9 mL) at 25° C. The mixture is warmed to 50° C. After 12 hours, the reaction is cooled to 25° C., diluted with water (2.5 L), and washed with methyl tert-butyl ether (6×1 L). Basify the aqueous phase with a solution of aqueous. 1N HCl until pH=2, and extract with ethyl acetate (3×2 L). The combined ethyl acetate extracts are washed with brine, dried over MgSO4, and concentrated in vacuo to yield the title compound (250 g, 65% yield). MS (m/z): 360 (M+-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:32])[C:5]([NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][C:7]=1[Cl:8].N[C:34](N)=[O:35].O>ClC(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:17][CH2:18]3)[C:34](=[O:35])[NH:32][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: NC(N)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 190 °C
Reaction time: 3 h

Procedure:
A mixture of 4 parts of 4,5-dichloro-N1 -{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,2-benzenediamine and 1.5 parts of urea is stirred for 3 hours in an oil-bath at 190° C. After cooling, water and trichloromethane are added. The layers are separated and the organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane, yielding 5,6-dichloro-1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 214.7° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.CO.Cl>[OH-].[Na+]>[ClH:2].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([OH:21])=[O:20])(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1
Reactant: CCOC(=O)C(C)(C)CNS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CNS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)O
Yield: 166.7 %

Procedure:
A solution of ethyl 3-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}-2,2-dimethylpropanoate hydrochloride (28 mg, 0.06 mmol) in NaOH solution (2N, 0.5 ml), and MeOH (1 ml), was stirred at 75° C. for 24 h. The cooled mixture was acidified to pH 6 using HCl (2N), concentrated in vacuo to remove the MeOH, and the resulting precipitate filtered, washed with water and dried. The solid was suspended in a MeOH/EtOAc solution, ethereal HCl added, and the mixture evaporated in vacuo to afford N-({4-chloro-1-guanidino-7-isoquinolinyl}sulphonyl)-2,2-dimethyl-β-alanine hydrochloride as a white solid (22 mg, 0.05 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[N:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:74]1([NH:77][CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([O:85][CH3:86])[C:80]=2[CH3:87])[CH2:76][CH2:75]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:41])([CH3:40])[CH3:42])([CH3:38])[CH3:37])=[N:29][CH:28]=3)=[C:13]2[C:24](=[O:25])[N:77]([CH:74]2[CH2:76][CH2:75]2)[CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([O:85][CH3:86])[C:80]=2[CH3:87])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cnc(CCCO[Si](C)(C)C(C)(C)C)s3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Reactant: COc1cccc(CNC2CC2)c1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN(C(=O)C2=C(c3cnc(CCCO[Si](C)(C)C(C)(C)C)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Reaction time: 144 h
Yield: 56.2 %

Procedure:
To a stirred sol. of compound D6 (2.66 g, 4.26 mmol) in CH2Cl2 (45 mL) were added EDC.HCl (2.04 g, 10.6 mmol), HOBt (783 mg, 5.11 mmol), DMAP (13 mg, 0.107 mmol), and DIPEA (3.35 mL, 19.19 mmol). After 15 min cyclopropyl-(3-methoxy-2-methyl-benzyl)amine (prepared by reductive amination from 3-methoxy-2-methylbenzaldehyde, Comins, D. L.; Brown, J. D., J. Org. Chem., 1989, 54, 3730 and cyclopropylamine, 2.45 g, 12.80 mmol) was added and stirring was continued over 6 days. Three times were added cyclopropyl-(3-methoxy-2-methyl-benzyl)amine (817 mg, 4.27 mmol) and HOBt (392 mg, 2.55 mmol). The reaction mixture was partitioned between aq. 1M HCl and CH2Cl2, and the phases were separated. The org. layer was washed with aq. sat. NaHCO3, dried over MgSO4, filtered, and the solvents were removed in vacuo. Purification by FC (heptane/EtOAc 7/3→1/1) yielded the title product (1.91 g, 56%). LC-MS: tR=1.27 min, ES+: 797.59.
Reaction SMILES: CCCCCCCCCCCCCCCC([NH:18][C@@H:19]1[C:50](=[O:51])[NH:49][C@@H:48]([C@H:52]([OH:54])[CH3:53])[C:46](=[O:47])[N:45]2[C@@H:41]([CH2:42][C@@H:43]([OH:55])[CH2:44]2)[C:39](=[O:40])[NH:38][C@@H:37]([C@H:56]([OH:71])[C@@H:57]([OH:70])[C:58]2[CH:59]=[CH:60][C:61]([OH:69])=[C:62]([O:64][S:65]([OH:68])(=[O:67])=[O:66])[CH:63]=2)[C:35](=[O:36])[NH:34][C@@H:33]([C@H:72]([OH:77])[CH2:73][C:74]([NH2:76])=[O:75])[C:31](=[O:32])[N:30]2[C@@H:26]([C@@H:27]([OH:79])[C@@H:28]([CH3:78])[CH2:29]2)[C:24](=[O:25])[NH:23][C@@H:22]([OH:80])[C@H:21]([OH:81])[CH2:20]1)=O.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+].ClC(Cl)(Cl)C(O)=O>>[CH3:78][C@@H:28]1[C@H:27]([OH:79])[C@H:26]2[C:24]([NH:23][C@H:22]([OH:80])[C@H:21]([OH:81])[CH2:20][C@H:19]([NH2:18])[C:50]([NH:49][C@@H:48]([C@H:52]([OH:54])[CH3:53])[C:46]([N:45]3[C@H:41]([C:39]([NH:38][C@@H:37]([C@H:56]([OH:71])[C@@H:57]([OH:70])[C:58]4[CH:59]=[CH:60][C:61]([OH:69])=[C:62]([O:64][S:65]([OH:68])(=[O:67])=[O:66])[CH:63]=4)[C:35]([NH:34][C@@H:33]([C@H:72]([OH:77])[CH2:73][C:74]([NH2:76])=[O:75])[C:31](=[O:32])[N:30]2[CH2:29]1)=[O:36])=[O:40])[CH2:42][C@@H:43]([OH:55])[CH2:44]3)=[O:47])=[O:51])=[O:25]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@H](O)NC(=O)[C@@H]2[C@@H](O)[C@@H](C)CN2C(=O)[C@H]([C@H](O)CC(N)=O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)c(OS(=O)(=O)O)c2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Product: C[C@@H](O)[C@@H]1NC(=O)[C@@H](N)C[C@@H](O)[C@@H](O)NC(=O)[C@@H]2[C@@H](O)[C@@H](C)CN2C(=O)[C@H]([C@H](O)CC(N)=O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)c(OS(=O)(=O)O)c2)NC(=O)[C@@H]2C[C@@H](O)CN2C1=O
Reaction time: 3 h

Procedure:
To 7 ml of the fermentation broth of Oidiodendron sp. No. 30084 obtained in Example 1-1 was added 1 ml of an aqueous solution (20 mg/ml) of FR901379 Substance (20 mg as FR901379 Substance; 16.7 μmol) as well as 2 ml of a buffer (0.2 M sodium citrate buffer, pH 4.0), and the reaction was carried out at 30° C. for 3 hours. The reaction was hen stopped by adding 0.4 M trichloroacetic acid and centrifuged at low speed to remove precipitated high molecular weight protein and other impurities. The FR179642 Substance produced was subjected to HPLC and monitored at 210 nm to determine the acylase activity.
Reaction SMILES: [O-]CC.[Na+].[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[CH:13]2.Cl[CH2:23][CH2:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])=[O:26]>C(O)C>[CH3:20][N:16]1[C:17]2[C:12](=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:23][CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]1=[O:21]
Reactant: Cn1c(=O)ccc2cc(OCCCN)ccc21
Reactant: Cc1ccccc1NC(=O)CCCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1NC(=O)CCNCCCOc1ccc2c(ccc(=O)n2C)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 58.5 %

Procedure:
Sodium ethoxide (34 mg) was added to an ethanol solution (5 ml) of 6-(3-amino-propoxy)-1-methyl-1H-quinolin-2-one (116 mg) and 3-chloro-N-o-tolyl-propionamide (148 mg). The mixture was stirred at 60° C. for 5 hours. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was condensed under reduced pressure to give the title compound (115 mg) as a white powder.
Reaction SMILES: N=[C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[C:5](=[O:19])[NH:4][C:3]1([CH2:28][O:29]C1CCCCO1)[CH2:20][O:21]C1CCCCO1.CO.Cl.C(=O)(O)[O-:40]>C(OCC)(=O)C>[OH:21][CH2:20][C:3]1([CH2:28][OH:29])[C:2](=[O:40])[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:17])([F:16])[F:18])[CH:8]=2)[C:5](=[O:19])[NH:4]1
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(N2C(=N)C(COC3CCCCO3)(COC3CCCCO3)NC2=O)cc1C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(N2C(=O)NC(CO)(CO)C2=O)cc1C(F)(F)F

Procedure:
300 mg of the product obtained in Stage 3 above is introduced into 3 ml of methanol and 1.5 ml of 2N hydrochloric acid and the whole is taken to reflux for one hour 30 minutes. It is returned to ambient temperature, poured into 5 ml of bicarbonate, extraction is carried out 4 times with ethyl acetate then the extracts are washed with a saturated sodium chloride solution and dried. 5 ml of methanol is added and purification is carried out on silica eluting with methylene chloride-methanol: 9-1. The residue is taken up in 20 ml of isopropanol under reflux then concentration is carried out and 225 mg of expected product (white crystals) is obtained. M.p.=207-208° C.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Na+].[CH2:10]=[CH:11][C:12](=[CH2:14])[CH3:13].[C:15]([O:18][CH:19]=[CH2:20])(=[O:17])[CH3:16].O>CO>[C:15]([O:18][CH:19]=[CH:20][CH2:13][CH:12]([CH3:14])[CH:11]=[CH2:10])(=[O:17])[CH3:16]
Reactant: C=COC(C)=O
Reactant: C=CC(=C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CC(C)CC=COC(C)=O
Temperature: 100 °C

Procedure:
(p-Cymene)ruthenium dichloride dimer (27.8 mg, 0.091 mmol Ru) and sodium triflate (80 mg, 0.464 mmol) were dissolved in 10 ml of methanol. To the mixed solution were added isoprene (3 ml) and vinyl acetate (5 ml) and the mixture was stirred under heat at 100° C. for 14 hours. The resulting product was poured into water and extracted using toluene and the extract was subjected to a GLC analysis. As a result, it was confirmed that a co-dimer was produced with the conversion rate being 10% and the ratio of an isomer being 17:3.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:17][CH3:18])[CH:8]=2)[N:3]=1.[CH2:19]([Mg]Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:19]([C:2]1[C:11]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:17][CH3:18])[CH:8]=2)[N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc2nc(Cl)c(C3OCCO3)cc2c1
Reactant: CCCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(OC)cc2cc1C1OCCO1
Temperature: 70 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
To a solution of 2-chloro-3-(1,3-dioxolan-2-yl)-6-methoxyquinoline SMA 44002 (1.41 g, 5.31 mmol) in dry THF (27 mL) at 0° C. under N2 in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added Fe(acac)3 (197 mg, 0.547 mmol) followed by dropwise addition of n-butylmagnesium chloride (2.0 M in THF, 12.4 mL, 24.8 mmol). After complete addition, the mixture was stirred for 5 h at 70° C. then cooled to RT and quenched with water (10 mL). THF was then removed at 40° C. under vacuum and the resulting mixture was extracted with CH2Cl2 (50 mL). The organic phase was isolated, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:EtOAc=100:0 to 95:5) gave 2-butyl-3-(1,3-dioxolan-2-yl)-6-methoxyquinoline SMA 44042 as an orange oil (867 mg, 57% yield).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH:6](O)[CH2:5][C:4]1=[O:58])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH:6]=[CH:5][C:4]1=[O:58])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C=CC1=O)C(C)CC2OC
Yield: 87.6 %

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (210 mg) and a catalytic amount of p-toluenesulfonic acid in 40 ml of benzene was refluxed for 4 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and the dark residue was purified by chromatography (silica gel, 7% i-propanol/CH2Cl2)to give 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone (180 mg) as a white solid. This material was dissolved in ethanol (20 ml) and treated with 5% Rh/C (40 mg). Hydrogen was introduced via balloon for 30 min. and the mixture was filtered through celite. Removal of solvent followed by chromatography (silica gel) gave 172 mg of the title compound. Mass Spectrum, 1H and 13C NMR data were consistant with the title structure.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][CH:8]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].BrBr.[F:19][C:20]([F:25])([F:24])[C:21]([NH2:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CC(C)=O.O>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:16])[CH:14]([NH:23][C:21](=[O:22])[C:20]([F:25])([F:24])[F:19])[CH3:15])=[CH:11][CH:12]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: NC(=O)C(F)(F)F
Reactant: CCC(=O)c1ccc(OCCC(C)C)cc1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)CCOc1ccc(C(=O)C(C)NC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4'-Isoamyloxypropiophenone (100 g, 45.5 mmol) was dissolved in chloroform (100 ml), and bromine (7.63 g, 47.7 mmol) was dropwise added thereto under ice-cooling. The mixture was stirred for 3 hours, and poured into water after disappearance of bromine colour. The aqueous mixture was extracted with dichloromethane, and the extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated off, which gave a crude intermediate product. The product was dissolved, without purification, in acetone (100 ml) followed by the addition of trifluoroacetamide (10.2 g, 90 mmol) and anhydrous potassium carbonate (12.4 g, 90 mmol). After 1.5 hours heating under reflux, the mixture was cooled to room temperature, and the acetone was evaporated off. The residue was taken in dichloromethane, and the organic solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Evaporation of the organic solvent provided a crude product which was purified by silica gel chromatography. The title compound was thus obtained. Yield: 4.44 g (29%).