Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=O)[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>[Pt]=O.C(O)C>[CH:1]1([O:7][N:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH:11]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:26][CH:11]3[CH2:12][C:13]([CH3:15])([CH3:14])[N:8]([O:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:9]([CH3:18])([CH3:17])[CH2:10]3)[CH2:12][C:13]2([CH3:15])[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Reactant: NCCCCCCN
Agent: O=[Pt]
Solvent: CCO
Product: CC1(C)CC(NCCCCCCNC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Reaction time: 4 h
Yield: 55 %

Procedure:
A mixture of 15.0 g (59.1 mmol) of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one, 3.4 g (29.6 mmol) of 1,6-hexanediamine, 500 mg of platinum oxide, and 150 ml of ethanol is hydrogenated in a Paar apparatus for 4 hours. The catalyst is removed by filtration. The filtrate is concentrated to an oil which is purified by flash chromatography (silica gel:ethyl acetate, then ethyl acetate:methanol) to afford 9.7 g {55% yield) of the title compound, as a yellow oil.
Reaction SMILES: [C:1]([O:8][NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:32]([NH:34][C@H:35]([C:39]([NH:41][C@H:42]([C:51]([NH:53][C@H:54]([C:59]([NH:61][C@H:62]([C:69]([N:71]1[CH2:86][CH2:85][CH2:84][C@H:72]1[C:73]([NH:75][C@H:76]([C:81]([OH:83])=[O:82])[C@H:77]([CH2:79][CH3:80])[CH3:78])=[O:74])=[O:70])[CH2:63][C:64]1[N:68]=[CH:67][NH:66][CH:65]=1)=[O:60])[C@H:55]([CH2:57][CH3:58])[CH3:56])=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=1)=[O:40])[CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:31])[NH:20][S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.O1CCOC[CH2:89]1>>[C:1]([O:8][NH:9][C@H:10]([C:11]([NH:13][C@H:14]([C:32]([NH:34][C@H:35]([C:39]([NH:41][C@H:42]([C:51]([NH:53][C@H:54]([C:59]([NH:61][C@H:62]([C:69]([N:71]1[CH2:86][CH2:85][CH2:84][C@H:72]1[C:73]([NH:75][C@H:76]([C:81]([OH:83])=[O:82])[C@H:77]([CH2:79][CH3:80])[CH3:78])=[O:74])=[O:70])[CH2:63][C:64]1[N:68]=[CH:67][NH:66][CH:65]=1)=[O:60])[C@H:55]([CH2:57][CH3:58])[CH3:56])=[O:52])[CH2:43][C:44]1[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=1)=[O:40])[CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:31])[NH:20][S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:12])[CH3:89])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)CNOC(=O)OC(C)(C)C)C(C)C)[C@@H](C)CC)C(=O)O
Reactant: C1COCCO1
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@H](C)NOC(=O)OC(C)(C)C)C(C)C)[C@@H](C)CC)C(=O)O
Yield: 84 %

Procedure:
0.6 g. (0.5 mmoles) of Boc-Arg(Tos)-Val-Tyr-Ile-His-Pro-Ile-OH (prepared in Step 2 of Example 1) are dissolved in 5 ml. of a 8 M solution of hydrochloric acid in dioxane. The solution is allowed to stand for 20 minutes whereupon the free heptapeptide (Rf4 = 0.1) is precipitated with dry ether, filtered and washed with ether. It is immediately dissolved in 20 ml. of dimethyl formamide, the pH-value is adjusted to 8 with triethyl amine and 0.7 g. (1.9 mmoles) of Boc-OAla-OPFP are added. After 30 minutes the solution is evaporated and the residue is dissolved in 30 ml. of a 3:1 mixture of chloroform and dimethyl formamide. The solution is shaken with a 10% aqueous citric acid solution and subsequently with water. After drying and evaporation the residue is triturated with ethyl acetate, filtered and washed to give 0.55 g. (84%) of the title compound. Rf4 = 0.43; Rf5 = 0.80.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.[C:16]([O:20][C:21](=[O:26])[C:22](Br)([CH3:24])[CH3:23])([CH3:19])([CH3:18])[CH3:17].C(OC(=O)[C@@H](OC)CC1C=CC(C(OC(C)(C)C)=O)=CC=1OC)C>>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:22]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:26])([CH3:24])[CH3:23])[CH:7]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: COC(=O)C(Cc1cccc(O)c1)OC
Agent: CCOC(=O)[C@H](Cc1ccc(C(=O)OC(C)(C)C)cc1OC)OC
Product: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1)OC

Procedure:
The title compound was prepared from 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (example 9, step 4) and 2-bromo-2-methyl-propionic acid tert-butyl ester via the same procedure used for the preparation of (2S)-3-(4-tert-butoxycarbonyl-methoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 1) to produce a yellow oil. 1H-NMR (CDCl3, 200.15 MHz): δ 7.13-7.09 (m, 1H), 6.84-6.69 (m, 3H), 3.95-3.89 (dd, 1H, J=6.5, 4.4), 3.7 (s, 3H), 3.34 (s, 3H), 2.94-2.90 (m, 2H), 1.50 (s, 6H), 1.43 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15].Cl.N>O.CO.CC(O)C>[CH3:9][NH:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[CH:3]=1
Reactant: N#Cc1cccc(N)c1
Reactant: CNc1cc(Cl)ncn1
Agent: Cl
Agent: N
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: CNc1cc(Nc2cccc(C#N)c2)ncn1
Temperature: 25 °C

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-methylamine (1.44 g, 10 mmol), 3-amino-benzonitrile. (1.18 g, 10 mmol), 2-propanol (10 mL) and conc. HCl (0.45 mL, ˜5 mmol) is stirred for 36 h at 90° C. After cooling to room temperature, CH3OH is added and the reaction mixture is basified with conc. aqueous ammonia solution. The precipitate which forms upon addition of H2O is filtered off, washed with H2O and dried in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][CH:2]1[O:7][S:6](=[O:8])[N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.I([O-])(=O)(=O)=[O:17].[Na+].Cl>C(#N)C.O>[CH3:1][CH:2]1[O:7][S:6](=[O:17])(=[O:8])[N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:4][CH2:3]1
Reactant: CC1CCN(C(=O)OC(C)(C)C)S(=O)O1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reaction time: 0.08 h
Yield: 60.6 %

Procedure:
To a solution of tert-butyl 6-methyl-1,2,3-oxathiazinane-3-carboxylate 2-oxide (2.52 g, 10.7 mmol) in acetonitrile (25 mL) and water (15 mL) cooled to 0° C. is added sodium periodate (3.4 g, 16.1 mmol) in one portion. After 5 min, the pH is adjusted to 7-8 by addition of saturated Na2HPO4 solution. A solution of RuCl3 (22 mg, 0.11 mmol) in water (0.5 mL) is added and the pH is kept between 6 and 9 by addition of Na2HPO4 solution. After 2 h, water (100 mL) is added and pH is adjusted to 6 by addition of 2M HCl solution. The reaction mixture is extracted with EtOAc and the organic layer is washed with NaHCO3 and brine and the washes are back-extracted once with EtOAc. Then the combined organic layers are dried (MgSO4), filtered and concentrated. The crude compound is purified by flash column chromatography to afford the title compound (1.63 g, 61%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([O:16][C:17]([NH:19][OH:20])=[O:18])([CH3:15])([CH3:14])[CH3:13].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NO
Reactant: OCCCCCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NOCCCCCCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
To a solution of 179 μL (183 mg, 1.2 mmol) of DBU in 1 mL of CH2Cl2 was added 133 mg (1.0 mmol) of N-(tert-butyloxycarbonyl)hydroxylamine (Aldrich Chemical Co.) and 157 μL (217 mg, 1.2 mmol) of 6-bromohexan-1-ol (Aldrich Chemical Co.), and the mixture was stirred for 18 hours at room temperature. The mixture was concentrated to give a yellow oil. Purification by silica gel chromatography (35/5/65 EtOAc/MeOH/hexanes) gave 180 mg (77%) of compound 27 as a colorless oil: 1H NMR (CDCl3) δ 1.39 (m, 4H), 1.48 (s, 9H), 1.59 (m, 4H), 3.63 (t, 2H), 3.85 (t, 2H), 7.42 (s, 1H); 13C NMR (CDCl3) δ 25.6, 25.8, 28.1, 28.4, 62.8, 76.8, 81.7, 157.2.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:10]([Cl:13])(=O)C>CO>[ClH:13].[NH2:1][C@@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@H](N)CC(C)C
Product: Cl
Reaction time: 18 h

Procedure:
D-Leucine (3.00 g, 22.9 mmol) was added to a solution of acetyl chloride (1.70 mL, 23.9 mmol) in methanol (30 mL). The reaction mixture was allowed to stir for 18 h and then concentrated under reduced pressure. This yielded 3.8 g (91%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 0.99 (dd, 6H), 1.63-1.87 (m, 3H), 4.10 (dd, 1H), 3.81 (s, 3H).
Reaction SMILES: ClC1C=C(C=CC=1Cl)C([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)=O.[CH3:30][O:31][C:32]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:30][O:31][C:32]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:33]=1[C:34]([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:9]1)=[O:36]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])ccc1C(=O)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A mixture of Intermediate 3′ (40 mg), 2-methoxy-4-nitro-benzoic acid (47 mg), triethylamine (0.07 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (121 mg) in dry tetrahydrofuran (3 ml) was stirred at 20° C. for 18 h under a nitrogen atmosphere. The mixture was then partitioned between potassium carbonate solution and dichloromethane. The organic phase was passed through a hydrophobic frit and evaporated. The residue was purified on a silica gel SPE cartridge. Elution with dichloromethane, then with dichloromethane:ethanol: 0.880 ammonia; 400 then 200:8:1 gave an oil which was triturated with diethyl ether giving the title compound as a colourless solid (51 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([NH:17][C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([CH:29]4[CH2:31][CH2:30]4)[N:27]=3)[N:22](COCC[Si](C)(C)C)[CH:21]=2)=[O:19])([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:16][C:13]([C:10]1([NH:17][C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([CH:29]4[CH2:30][CH2:31]4)[N:27]=3)[NH:22][CH:21]=2)=[O:19])[CH2:11][CH2:12][NH:8][CH2:9]1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(C4CC4)nc23)(C(C)(C)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C1(NC(=O)c2c[nH]c3ncc(C4CC4)nc23)CCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
In a 10 mL round-bottomed flask, 3-{[2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-3-(1-hydroxy-1-methyl-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (118 mg, 0.21 mmol) was dissolved in CH2Cl2 (1 mL). Trifluoroacetic acid (0.8 mL) was added and the light yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was taken up in toluene (3 mL), concentrated and then dried under high vacuum. The residue was dissolved in CH2Cl2 (1 mL) and ethylenediamine (1 mL) was added. The reaction mixture was stirred at room temperature for 1 h then H2O and EtOAc were added. The aqueous layer was extracted with EtOAc. The combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated. The residue was triturated with EtOAc to afford 37 mg (48%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [3-(1-hydroxy-1-methyl-ethyl)-pyrrolidin-3-yl]-amide as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.CCOCC.[O-]S([O-])(=O)=O.[Na+].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[NH:19]1[CH2:18][CH2:17][CH:16]([CH:15]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]3[CH:22]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc2c(c1)CCc1cccnc1C2C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution 66.27 g (0.21 mole) of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta(1,2-b]pyridin-11-ylidene)-piperidine (product from Preparative Example 1 Example, step G), in THF (1 L) was added LiAIH4 (24.32 g, 0.64 mole) and the reaction mixture was heated to reflux overnight. The reaction mixture was then cooled to room temperature and ~3 L of Et2O is added followed by dropwise addition of saturated Na2SO4 until a white gray precipitate forms. MgSO4 was then added to the separated organic layer and stirred for 30 minutes. All the volatiles were then removed and the resulting crude mixture was chromatographed on a silica gel column eluting with 10% MeOH saturated with NH4OH in CH2Cl2. The material obtained contained both the desired compound and the des-chloro compound. Separation on HPLC using reverse phase column and eluting with 40% MeOH-water afforded the desired compounds as white solids (Product A's mp=95.2-96.1° C., Product B's mp=145.1-145.7° C.).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:20][C:18](=[O:19])[CH2:17][C@@H:16]([OH:21])[C@H:15]([CH3:22])[C@@H:14]([O:23][C@@H:24]2[O:29][C@H:28]([CH3:30])[C@@H:27]([OH:31])[C@H:26]([N:32]([CH3:34])[CH3:33])[C@H:25]2[OH:35])[C@@H:13]([CH2:36]C=O)[CH2:12][C@@H:11]([CH3:39])[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH3:40])=[CH:5][C@@H:4]1[CH2:41][O:42][C@@H:43]1[O:48][C@H:47]([CH3:49])[C@@H:46]([OH:50])[C@@H:45]([O:51][CH3:52])[C@H:44]1[O:53][CH3:54]>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][CH2:2][CH:3]1[O:20][C:18](=[O:19])[CH2:17][CH:16]([OH:21])[CH:15]([CH3:22])[CH:14]([O:23][CH:24]2[O:29][CH:28]([CH3:30])[CH:27]([OH:31])[CH:26]([N:32]([CH3:33])[CH3:34])[CH:25]2[OH:35])[CH:13]([CH3:36])[CH2:12][CH:11]([CH3:39])[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH3:40])=[CH:5][CH:4]1[CH2:41][O:42][CH:43]1[O:48][CH:47]([CH3:49])[CH:46]([OH:50])[CH:45]([O:51][CH3:52])[CH:44]1[O:53][CH3:54]
Reactant: CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)C(=O)C=CC(C)=C[C@@H]1CO[C@@H]1O[C@H](C)[C@@H](O)[C@@H](OC)[C@H]1OC
Agent: CCC1OC(=O)CC(O)C(C)C(OC2OC(C)C(O)C(N(C)C)C2O)C(C)CC(C)C(=O)/C=C/C(C)=C\C1COC1OC(C)C(O)C(OC)C1OC
Agent: CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)C(=O)/C=C/C(C)=C/[C@@H]1CO[C@@H]1O[C@H](C)[C@@H](O)[C@@H](OC)[C@H]1OC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCC1OC(=O)CC(O)C(C)C(OC2OC(C)C(O)C(N(C)C)C2O)C(C)CC(C)C(=O)C=CC(C)=CC1COC1OC(C)C(O)C(OC)C1OC
Temperature: 90 °C

Procedure:
Desmycosin (Merck Index, Tenth Edition p. 1405) (18.9 o) was dissolved in degassed benzene (580 mL) and tris(triphenYlphospbine)rhodium chloride (29.5 g.) was added. The mixture was heated under dry nitrogen at 90° C. for 16 h. The mixture was diluted with ethyl acetate and extracted twice with 0.2N hydrochloric acid. The aqueous acid layer was adjusted to pH 10 and extracted with dichloromethane. The latter was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (60×5 cm.) using 5% methanol in chloroform (v/v) as the eluant to give 19deformyldesmycosin (13.2 g., 73%) as a colorless amorphous solid (Anal.: found: C, 57.05; H, 7.99; N, 1.62%. C38H65NO13. 0.5 CHCl3 requires C, 56.79; H, 8.15; N, 1.74%); MS: m/z 744 (MH+); Rotation: [α]D26 0° (CHCl3); UV: λmax (CH3OH) 282 nm (ε20,676); IR: νmax (CDCl3) 3540, 3450, 1705, 1670, 1590, 1185, 1163, 1055 cm-1 ; 1H-NMR: δH (CDCl3) 0.92 (3H,tJ16,17-CH3 7 Hz, 17-CH3), 1.02 (3H,d,J 7 Hz, CH3), 1.03 (3 H,d,J 7 Hz, CH3), 1.18 (3H,d,J 7 Hz, CH3), 1.26 (3H,d,J 7 Hz, CH3), 1.30 (3H,d,J 7 Hz, CH3), 1.78 (3H,d,J12 -CH3,13 1 Hz, 12-CH3), 2.53 (6H,s,3'-N(CH3)2), 3.48 (3H,s,2"-OCH3), 3.60 (3H,s,3"-OCH3), 4.28 (1H,d,J1'ax,2'ax 8 Hz, H1'ax), 4.55 (1H,d,J1"ax,2"ax 8 Hz, H1"ax), 4.97 (1H,m,H15), 5.82 (1H,dc,J12-CH3,13 1 Hz, J13,14 10 Hz, H13), 6.24 (1H,d,J10,11 16 Hz, H10), and 7.24 (1H,d,J10,11 16 Hz, H11)
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:19]([OH:21])=O)[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1C=C2N=NN(O)C2=CC=1.O.C1CCC(N=C=NC2CCCCC2)CC1.[C:48]1([CH2:54][O:55][CH2:56][CH2:57][NH:58][C:59](=[O:77])[CH2:60][NH:61][CH2:62][C:63]2[CH:68]=[CH:67][C:66]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)=[CH:65][CH:64]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[C:5]1([CH2:4][O:3][C:1]([NH:11][C@@H:12]([C:19]([N:61]([CH2:62][C:63]2[CH:64]=[CH:65][C:66]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)=[CH:67][CH:68]=2)[CH2:60][C:59]([NH:58][CH2:57][CH2:56][O:55][CH2:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:77])=[O:21])[CH2:13][C:14]2[N:18]=[CH:17][NH:16][CH:15]=2)=[O:2])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(N[C@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: O=C(CNCc1ccc(OCc2ccccc2)cc1)NCCOCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a suspension of CBZ-D-histidine (0.093 g, 0.32 mmol) in DMF (2 mL) was added HOBT hydrate (0.059 g, 0.39 mmol) followed by DCC (0.080 g, 0.39 mmol). A solution of the compound from Step 3 above (0.13 g, 0.32 mmol) in DMF (2 mL) was added and the mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was diluted with CHCl3, washed twice with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated. Flash chromatography (2-5% MeOH/CHCl3) gave 0.10 g (45%) of the title compound as a white powder; ES-MS 676 (m+1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:13]=1[CH:14]=[O:15].C(OC=O)=O>C1COCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:12]([NH:11][CH:1]=[O:3])=[C:13]([CH:14]=[O:15])[CH:16]=1
Reactant: Nc1ccc(Br)cc1C=O
Reactant: CC(=O)OC(C)=O
Agent: O=COC=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CNc1ccc(Br)cc1C=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To acetic acid anhydride (34.8 ml) was added formic acid (17.0 ml) at 0° C., and the mixture was stirred at 60° C. for 2 hours, cooled and diluted with THF (200 ml). In THF (100 ml) was dissolved 2-amino-5-bromobenzaldehyde (16.40 g), and the mixture was added dropwise to the previously prepared solution of formic acid anhydride in THF at 0° C. The mixture was stirred at 0° C. for 2 hours, and the solvent was evaporated under reduced pressure. The residue was washed with hexane and filtered to give 4-bromo-2-formylphenylformamide (15.24 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:12])=O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: ClCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of (5-bromopyridin-3-yl)methanol (3 g, 16.0 mmol) in DCM (15 mL) cooled to 0° C. was added thionylchloride (7.59 g, 63.8 mmol) dropwise and the reaction mixture was stirred at room temperature overnight. The mixture was poured onto ice/water (20 mL), basified with NaOH conc. (8 mL) and extracted with EtOAc (2×50 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 40% EtOAc-heptane gradient to give the title compound (3.08 g, 93%) as a white solid. MS: 206.0, 207.9 (M+H+).
Reaction SMILES: [CH:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16].CC(=CCC/C(=[CH:26]\[CH:27]=[O:28])/C)C.[CH3:29][C:30](=O)CCCCC.CC1C=CC(S(O)(=O)=O)=CC=1>[NH4+].[Cl-]>[CH2:29]([O:17][CH:1]([O:28][CH2:27][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16])[CH3:30]
Reactant: CC(C)=CCC/C(C)=C\C=O
Reactant: CCCCCC(C)=O
Reactant: CCCC/C=C\CCCCCCCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: CCCC/C=C\CCCCCCCCCC(OCC)OCC
Yield: 61.5 %

Procedure:
The diethyl acetal or ketal is prepared by the above general procedure from (Z)-11-hexadecenal, (E)-and (Z)-citral in admixture and heptan-2-one using NH4Cl as catalyst in the first two cases and TsOH in the last. (Z)-1,1-Diethoxyhexadec-11-ene is obtained in 61.5% yield and has a b.p. 118°-120°C./0.05 mm, nD20 1.4475; (E)-and (Z)-1,1-diethoxy-3,7-dimethoxyocta-2,6-diene in admixture are obtained in 83.6% yield and have b.p. 68°-70°C./0.2 mm, nD20 1.4511; 2,2-diethoxyheptane is obtained in 71% yield and has b.p. 88°-92°C./18 mm.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][NH:28][CH3:29]>>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([N:28]([CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([O:23][CH2:22][O:21][CH3:20])[CH:25]=3)[CH3:29])=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CNCc1cccc(OCOC)c1
Product: COCOc1cccc(CN(C)c2cnc(-c3ccccc3)c(-c3ccccc3)n2)c1

Procedure:
In the same manner as in the step 1 of Example 9, except that 2-chloro-5,6-diphenylpyrazine was used in place of 2-chloro-5,6-di-p-tolylpyrazine and 3-(methoxymethoxy)-N-methylbenzylamine was used in place of 4-(methylamino)-1-butanol, the desired compound was prepared as a colorless crystal having a melting point of 109 to 111° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]([F:28])[F:27])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C[O-].[Na+].CO.[C:34](OCC)(=[O:36])C>CO.CCCCCC>[F:28][CH:26]([F:27])[CH2:25][O:24][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([O:36][CH3:34])[CH:3]=1)[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:21])[F:23])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: CCOC(C)=O
Reactant: O=C1c2c(Cl)cc(OCC(F)F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(OCC(F)F)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of 7-chloro-5-(2,2-Difluoro-ethoxy)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.057 g, 0.14 mmol), and 30% sodium methoxide-methanol (0.12 mL) in methanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-(2,2-Difluoro-ethoxy)-7-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.030 g, 51%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.96 (s, 3H), 4.22 (m, 4H), 4.73 (s, 2H), 5.94-6.32 (m, 1H), 6.45 (d, 2H), 7.17 (d, 2H), 7.35 (d, 2H). GC-MS: m/z 417 (M)+, 399 (M−18)+.