Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:36])=[C:5]([C:27]([O:34]C)=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][C:7]1[C:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(=O)([O-])O.[Na+]>C(#N)C.O>[CH3:31][O:30][C:29]1[C:3](=[O:2])[C:4]([CH3:36])=[C:5]([CH2:6][C:7]2[C:8]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[C:9]([CH:18]=[CH:19][CH:20]=2)[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[C:27](=[O:34])[C:28]=1[O:32][CH3:33]
Reactant: COc1c(C)c(Cc2cccc(C(=O)N3CCCCC3)c2-c2ccncc2)c(OC)c(OC)c1OC
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCCCC3)c2-c2ccncc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
N-[3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoyl]piperidine (74 mg, 0.1510 mmol) was dissolved in a mixed solvent of acetonitrile (9 ml) and water (3 ml), then CAN (206 mg, 0.3759 mmol) was added thereto at room temperature and the mixture was stirred for 1 hour. The reaction solution was poured into water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:5) to give the title compound (32 mg, 0.0695 mmol, 46%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[CH:4][C:5](Br)=[C:6]([CH:9]=1)[C:7]#[N:8].C1(N(C)C2CCCCC2)CCCCC1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.[CH2:48]([OH:52])[CH2:49][CH:50]=[CH2:51]>CC#N.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[NH2:1][C:2]1[C:3]([Cl:11])=[CH:4][C:5]([CH2:51][CH2:50][CH2:49][CH:48]=[O:52])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C=CCCO
Reactant: N#Cc1cc(N)c(Cl)cc1Br
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(N)c(Cl)cc1CCCC=O
Temperature: 60 °C
Yield: 23.4 %

Procedure:
5-amino-2-bromo-4-chlorobenzonitrile (4 g, 17.28 mmol) and N-cyclohexyl-N-methylcyclohexanamine (5.55 mL, 25.9 mmol) were combined in a 250 ml flask and 2 ml of DMF was added. The flask was evacuated and backfilled with Ar 4×. A suspension of Pd2 (dba)3 (0.316 g, 0.346 mmol) and di-tert-butyl(2′-methyl-[1,1′-biphenyl]-2-yl)phosphine (0.324 g, 1.037 mmol) in CH3CN (32 mL) was heated at 60° C. for 1 min until the solids dissolved and then cooled to room temperature. The solution was added to the flask by syringe, and then but-3-en-1-ol (1.933 mL, 22.46 mmol) was added. The reaction was heated at 90° C. for 45 min. The reaction was cooled to room temperature and diluted with H2O, extracting 3× with EtOAc. The organic layers were dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-70% EtOAc/Hex; 330 g column). 5-amino-4-chloro-2-(4-oxobutyl)benzonitrile (0.9 g) was obtained as yellow foam.
Reaction SMILES: S(Cl)(Cl)=O.C[N:6]([CH:8]=[O:9])C.[Cl:10][C:11]1[N:19]=[CH:18][C:17]([S:20](=[O:31])(=[O:30])[NH:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)=[CH:16][C:12]=1C(O)=O.[OH-].[NH4+]>C1(C)C=CC=CC=1>[Cl:10][C:11]1[N:19]=[CH:18][C:17]([S:20](=[O:30])(=[O:31])[NH:21][C:22]2[CH:23]=[C:24]([F:29])[CH:25]=[C:26]([F:28])[CH:27]=2)=[CH:16][C:12]=1[C:8]([NH2:6])=[O:9]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(S(=O)(=O)Nc2cc(F)cc(F)c2)cnc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(S(=O)(=O)Nc2cc(F)cc(F)c2)cnc1Cl
Yield: 72 %

Procedure:
0.288 ml (3.87 mmol) of thionyl chloride and a drop of DMF are added successively to 0.450 g (1.29 mmol) of 2-chloro-5-(N-(3,5-difluorophenyl)sulfamoyl)nicotinic acid in 5 ml of anhydrous toluene. The mixture is placed under stirring, at reflux of toluene, for 2 hours. The acid chloride reaction mixture is then added drop by drop to an iced solution, under stirring, of 4.5 ml of 25% ammonium hydroxide. A release of gas is observed. The reaction medium is left under stirring at room temperature for 30 minutes. The reaction medium is extracted several times with ethyl acetate. The combined organic phases are dried on anhydrous sodium sulfate and then concentrated. 0.315 g of 2-chloro-5-(N-(3,5-difluorophenyl)sulfamoyl)nicotinamide in the form of a light brown solid is obtained (yield=72%).
Reaction SMILES: CC([O-])(C)C.[K+].Br[CH:8]([C:11]1([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:16][CH2:15][CH:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)[CH2:9]Br.O.Cl>C(O)(C)(C)C>[C:8]([C:11]1([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][CH2:13][CH:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]2)[CH2:15][CH2:16]1)#[CH:9]
Reactant: CCCCCC1CCC(C2CCC(CCCCC)(C(Br)CBr)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: C#CC1(CCCCC)CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
32.48 g of KOtBu are added at RT to 47.50 g of 4-(1,2-dibromoethyl)-4,4′-dipentylbicyclohexyl in 150 ml of tert-butanol. The mixture is heated to 60° C. and stirred at this temperature overnight. Water is subsequently added to the reaction mixture, which is acidified with dilute hydrochloric acid and subjected to conventional work-up, giving 4-ethynyl-4,4′-dipentylbicyclohexyl (C 16 N 35 I, Δε−1.96, Δn 0.021).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:20][CH2:19][C:10]3[N:11]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13][C:14](=O)[C:9]=3[C:7]=2[CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:20][CH2:19][CH:10]3[N:11]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH:14]=[C:9]3[C:7]=2[CH:8]=1
Reactant: CCCN1CCC(=O)C2=C1COc1ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN1CCC=C2c3cc(OC)ccc3OCC21

Procedure:
To a solution of 9.0 g of 9-methoxy-4-propyl-1,2,3,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridin-1-one in 90 ml of dry pyridine at 0° is added 0.90 g of lithium aluminium hydride. After 20 minutes at 30° the reaction is quenched with 1.8 ml of 10% sodium hydroxide, the reaction mixture is diluted with ethyl acetate, dried over magnesium sulfate and filtered. The filter cake is washed well with 10% methanol/methylene chloride and the solvent is removed in vacuo from the combined filtrates. The entire above reduction procedure is repeated on the residue using tetrahydrofuran instead of pyridine as the initial reaction solvent. The product is triturated with ether to afford a white powder which is treated with 28 ml of pyridine and 6.3 ml of phosphorus oxychloride at 65° for 30 minutes. The reaction mixture is poured onto a mixture of ice and sodium carbonate solution, and the product is extracted with ethyl acetate. After drying over magnesium sulfate, the solvent is removed in vacuo to afford, as an oil, 9-methoxy-4-propyl-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine; NMR: δ 0.90 (3H,t), 3.75 (3H,s).
Reaction SMILES: N1C=CC=C2C(N)CCC=12.[CH2:11]([CH:13]1[CH2:14][C:15]2[C:16](/[C:21]/1=[N:22]\O)=[N:17][CH:18]=[CH:19][CH:20]=2)[CH3:12]>>[CH2:11]([CH:13]1[CH:21]([NH2:22])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14]1)[CH3:12]
Reactant: CCC1Cc2cccnc2/C1=N\O
Agent: NC1CCc2ncccc21
Product: CCC1Cc2cccnc2C1N

Procedure:
Following the procedure for the preparation of 6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine but substituting (7Z)-6-ethyl-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one oxime and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.40, 7.51, 7.10, 4.30, 3.95, 3.07, 2.95, 2.74, 2.50, 2.38, 2.03-1.93, 1.75, 1.57, 1.40, 1.09-0.97; HRMS (FAB) calcd for C10H14N2+H 163.1235, found 163.1229.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)=O)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:16]([N:6]1[C:5]2=[N:4][N:3]3[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[NH:1][C:2]3=[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7]1=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCn1c(=O)c2c(N)n(CC(=O)c3cccc(OC)c3)nc2n(Cc2ccccc2)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCn1c(=O)c2c(nn3cc(-c4cccc(OC)c4)[nH]c23)n(Cc2ccccc2)c1=O
Yield: 74.6 %

Procedure:
3-Amino-7-benzyl-2-(3-methoxyphenacyl)-5-propyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (1.16 g) and p-toluenesulfonic acid (0.1 g) were dissolved in toluene (50 ml) and the solution was refluxed for 3 hours. The reaction solution was concentrated and to the concentrate was added methanol. Precipitating crystals were collected by filtration to obtain pale yellow crystals (0.83 g, 75%), m.p. 249°-250° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(I)cc2)nc1
Temperature: 200 °C
Yield: 84.7 %

Procedure:
Combine 4-iodophenol (6.31 g, 28.7 mmol), 6-chloro-nicotinamide (4.51 g, 28.8 mmol), potassium carbonate (10.0 g, 72.4 mmol), and dimethylacetamide (145 mL), stir and heat at 200° C. After 3 h. cool to ambient temperature and dilute with water (600 mL), filter, and dry in vacuo to provide 8.27 g (85%) of the title compound as a white/brown solid: mass spectrum (electrospray): m/z=341.0 (M+1); 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.4 Hz), 8.31 (dd, 1H, J=2.4, 8.3 Hz), 7.82-7.79 (m, 2H), 7.09 (d, 1H, J=8.8 Hz), 7.03-6.99 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].CCOC([CH:26]([N:35]1C(=O)[O:39][C:37](=[O:38])[CH:36]1[CH3:42])[CH2:27]CC1C=CC=CC=1)=O>>[CH3:2][CH2:1][O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:35]1[C@H:36]([C:37]([OH:39])=[O:38])[CH2:42][CH2:27][CH2:26]1)=[O:20])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5]
Reactant: CCOC(=O)C(CCc1ccccc1)N1C(=O)OC(=O)C1C
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 81.8 %

Procedure:
In the said patent in the activation reaction of the starting N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine neither the racemization on α-C atom of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride is specified nor possible side reactions (J. Org. Chem., 32, 11, 1967) are mentioned. In the optimum Example 4 the reaction yield up to enalapril (base) is 87%. The separation of enalapril maleate is carried out with a 81.8% yield.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1.[N+:25]([CH2:28][CH3:29])([O-:27])=[O:26].O>C1(C)C=CC=CC=1>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:1]=[C:28]([N+:25]([O-:27])=[O:26])[CH3:29])[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C=C(C)[N+](=O)[O-])cc1OC
Temperature: 40 °C

Procedure:
A mixture of veratraldehyde (200 g, 1.20 mol), ammonium acetate (94.0 g, 1.22 mol) nitroethane (400 ml, 418 g, 5.57 mol) and toluene (200 ml) is refluxed for 2 hours and thirty minutes, with ternary azeotrope toluene/nitro ethane/water being distilled off and formed water being separated. The red solution is cooled down to about 40° C. and is concentrated to residue at 40°-50° C./20 mbar.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:13])=[C:8]([CH2:10][C:11]#[N:12])[CH:9]=1)(=[O:3])[CH3:2].[Br-:14].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>O1CCCC1>[Br:14][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:13])=[C:8]([CH2:10][C:11]#[N:12])[CH:9]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(O)c(CC#N)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: N#CCc1cc(C(=O)CBr)ccc1O

Procedure:
To 5-acetyl-2-hydroxyphenylacetonitrile (3.5 g., 0.02 mole) in 100 ml. of tetrahydrofuran is added trimethylphenylammonium tribromide (7.6 g., 0.02 mole) portionwise over a 15 min. period with stirring. After stirring for an additional 18 hrs. at 25° C., the reaction mixture is concentrated to dryness under reduced pressure. Trituration of residual material with water affords 5.0 g. of brominated product, m.p. 187°-191° C. (dec.). Crystallization of this material from isopropanol affords 5-bromoacetyl-2-hydroxyphenylacetonitrile, m.p. 196°-198° C. (dec.).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=O.C([O:38][C:39](=O)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Br:47])[CH:42]=1)C>C(Cl)Cl.[Pd]>[Br:47][C:43]1[CH:42]=[C:41]([CH2:40][CH:39]=[O:38])[CH:46]=[CH:45][CH:44]=1
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)C[Al+]CC(C)C
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=CCc1cccc(Br)c1
Temperature: -78 °C

Procedure:
60 g (246 mmol) of ethyl(3-bromophenyl)acetate (Compound B1) was converted into the title compound (oil) using 255 ml (255 mmol) of diisobutyl aluminum hydride (DIBAL-H, 1M in hexane), 85.8 g (250 mmol) of (carbethoxy methylene)triphenylphosphorane and 1.7 g of 10% Pd/C. The procedure was as follows: To a cold solution (-78° C.) of Compound B1 in CH2Cl2 was added dropwise (over a span of 1 hour) the diisobutyl aluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at -78 ° C. for an additional hour. The reaction was quenched by the dropwise addition of methanol, followed by water and 10% HCl. The mixture was then warmed to 0° C., stirred for 10 minutes and then washed with water, 10% aqueous NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent distilled off at ambient temperature to give crude (3-bromophenyl)acetaldehyde. To a cold solution (0° C.) of this crude aldehyde in CH2Cl2 was added a solution of the (carbethoxy methylene)triphenylphosphorane reagent in CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(3-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in EtOAc and hydrogenated over 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: I[C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[NH2:8][C:5]1[C:4]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[CH:10][S:11][C:3]=2[C:2](/[CH:27]=[CH:26]/[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:7][N:6]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ncc(I)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12
Yield: 76 %

Procedure:
A mixture of Example 221A (2 g, 4.5 mmol), tert-butyl acrylate (1.3 mL, 8.8 mmol), Pd(OAc)2 (100 mg, 0.44 mmol), PPh3 (236 mg, 0.89 mmol), Na2CO3 (0.95 g, 8.9 mmol), and DMF (40 mL) was stirred for 18 hours at 80° C. under a nitrogen atmosphere. The mixture was concentrated to half its original volume and poured into 10% NaCl (300 mL). The product was extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was dissolved in dichloromethane (300 mL), treated with silica gel (25 g), and concentrated. The preabsorbed silica gel was subsequently transferred to a silica gel (200 g) column and chromatographed with ethyl acetate/heptane (1:6) to provide 1.52 g (76%) of the desired product. 1H NMR (CD2Cl2, 400 MHz) δ 8.13 (s, 1H), 7.78 (d, 1H), 7.49–7.43 (m, 4H), 7.32 (s, 1H), 7.22 (t, 1H), 7.15 (d, 4H), 6.46 (d, 1H), 5.18 (br s, 2H), 1.59 (s, 9H); 13C NMR (CD2Cl2, 100 MHz) δ 166.8, 158.5, 156.8, 155.5, 147.1, 146.9, 139.8, 137.5, 131.3, 130.7, 130.4, 124.4, 123.8, 119.9, 119.7, 118.8, 118.7, 117.2, 80.6, 28.4.
Reaction SMILES: [C:1]1([N:7]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC>[Pd].CN(C)C=O>[NH2:12][C:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[C:10]([C:14](=[O:13])[CH3:15])[C:8]([N:7]([CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)N(CCN(C)C)c1ccccc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(=O)C(C(=O)N(CCN(C)C)c1ccccc1)=C(N)c1ccccc1

Procedure:
A mixture of 35 grams (0.1 mole) of N-phenyl-N-(2-dimethylaminoethyl)-5-methyl-3-phenyl-4-isoxazole carboxamide and 3.8 grams of 10% palladium on carbon in 200 milliliters of dimethylformamide is hydrogenated at 50 psi and 50°-60° C. overnight. The mixture is cooled, filtered, and the filtrate evaporated in vacuo. The residue obtained is then treated with hexane and the resulting crystals triturated with ether to give 2-(aminophenylmethylene)-N-(2-dimethylaminoethyl)-N-phenyl-3-oxobutanamide; M.P. 81°-83° C.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C:18]3[C:13](=[C:14]([OH:28])[C:15]([C:20]([NH:22][C@@H:23]([C:25]([OH:27])=[O:26])[CH3:24])=[O:21])=[C:16]([CH3:19])[CH:17]=3)[C:12]3[C:29]([OH:46])=[C:30]4[C:41](=[O:42])[C:40]5[C:35](=[C:36]([OH:45])[CH:37]=[C:38]([O:43][CH3:44])[CH:39]=5)[C:33](=[O:34])[C:31]4=[CH:32][C:11]=3[C@@H:10]2[OH:47])[C@H:5]([OH:48])[C@@H:4]([O:49][C@@H:50]2[O:55][CH2:54][C@@H:53]([OH:56])[C@H:52]([OH:57])[C@H:51]2[OH:58])[C@H:3]1[NH2:59].Cl.[C:61](OC(=O)C)(=[O:63])[CH3:62].Cl.C[C@H]1O[C@@H](O[C@H]2C3C(=C(O)C(C(NC(C(O)=O)C)=O)=C(C)C=3)C3C(O)=C4C(=O)C5C(=C(O)C=C(OC)C=5)C(=O)C4=CC=3[C@@H]2O)[C@H](O)[C@@H](O[C@@H]2OC[C@@H](O)[C@H](O)[C@H]2O)[C@H]1N>C(=O)([O-])[O-].[Na+].[Na+].CO>[CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C:18]3[C:13](=[C:14]([OH:28])[C:15]([C:20]([NH:22][C@@H:23]([C:25]([OH:27])=[O:26])[CH3:24])=[O:21])=[C:16]([CH3:19])[CH:17]=3)[C:12]3[C:29]([OH:46])=[C:30]4[C:41](=[O:42])[C:40]5[C:35](=[C:36]([OH:45])[CH:37]=[C:38]([O:43][CH3:44])[CH:39]=5)[C:33](=[O:34])[C:31]4=[CH:32][C:11]=3[C@@H:10]2[OH:47])[C@H:5]([OH:48])[C@@H:4]([O:49][C@@H:50]2[O:55][CH2:54][C@@H:53]([OH:56])[C@H:52]([OH:57])[C@H:51]2[OH:58])[C@H:3]1[NH:59][C:61]([CH3:62])=[O:63]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(O)c2c(c1)C(=O)c1c(cc3c(c1O)-c1c(cc(C)c(C(=O)N[C@H](C)C(=O)O)c1O)[C@H](O[C@@H]1O[C@H](C)[C@H](N)[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@H]1O)[C@H]3O)C2=O
Agent: COc1cc(O)c2c(c1)C(=O)c1c(cc3c(c1O)-c1c(cc(C)c(C(=O)NC(C)C(=O)O)c1O)[C@H](O[C@@H]1O[C@H](C)[C@H](N)[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@H]1O)[C@H]3O)C2=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COc1cc(O)c2c(c1)C(=O)c1c(cc3c(c1O)-c1c(cc(C)c(C(=O)N[C@H](C)C(=O)O)c1O)[C@H](O[C@@H]1O[C@H](C)[C@H](NC(C)=O)[C@H](O[C@@H]4OC[C@@H](O)[C@H](O)[C@H]4O)[C@H]1O)[C@H]3O)C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Benanomicin B hydrochloride (125 mg) was dissolved in 10 ml of an aqueous solution of 0.1 M sodium carbonate, and to the resulting solution was added 0.1 ml of acetic anhydride. The mixture obtained was stirred at ambient temperature for 20 minutes. The resultant reaction solution was then adjusted to pH 4.0 by addition of 1 M hydrochloric acid and subsequently passed through a column of 20 ml of a non-ionic microporous adsorbent resin, "Diaion" HP-20 (a product of Mitsubishi Kasei Co., Japan) to adsorb the acetylation product of benanomicin B by the resin. The resin column was washed with water and developed with aqueous 80% acetone. The red colored fractions of the eluate were combined together and concentrated to dryness. The residue obtained was dissolved in methanol and the methanolic solution was passed through a column of a molecule-sieve agent, "Sephadex" LH-20 (a product of Pharmacia Co., Sweden), followed by developement with methanol. The eluate which showed a single spot of red color on a thin layer chromatography on a silica gel plate was concentrated to dryness. N-acetylbenanomicin B (118 mg) was obtained as a reddish brown colored powder which showed a melting point of higher than 200° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])CCC.I[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1>O1CCCC1.CCCCCC.[Cl-].[Cl-].[Zn+2]>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 533.9 mg (2.6389 mmol) of 4,4-dimethyl-6-ethynylthiochroman (from Example 4) in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.7 ml of 1.6M (2.72 mmol) n-butyl lithium in hexane. This was stirred at 0° C. for 10 minutes and at room temperature for 15 minutes, cooled again to 0° C. and then treated with a solution of 410 mg (3.005 mmol) of fused ZnCl2 in 4 ml dry tetrahydrofuran using a double ended needle. Thereafter, the solution was stirred at 0° C. for 45 minutes, then at room temperature for 20 minutes. A solution of 724.4 mg (2.6243 mmol) of ethyl 4-iodobenzoate (from Example 5) in 4 ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 520 mg (0.45 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and stirred at room temperature for 20 minutes, then treated by double ended needle with the solution of the alkynyl zinc chloride prepared above. This mixture was stirred at room temperature for 18 hours, then quenched with ice and 30 ml 3N hydrogen chloride. Product was recovered by extraction with 3×75 ml ether. Ether fractions were combined and washed successively with saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl acetate in hexane) to give the title compound as a colorless oil. PMR (CDCl3) :δ 1.36 (6H), 1.42 (3H, t, J~7 Hz), 1.93-1.99 (2H, m), 3.03-3.08 (2H, m), 4.40 (2H, q, J~7 Hz), 7.09 (1H, d, J~8.4 Hz), 7.22 (1H, dd, J~8.4 Hz, 2.1 Hz), 7.56 (1H, d, J~2.11 Hz), 7.59 (2H, d, J~7.8 Hz), 8.04 (2H, d, J~7.8 Hz).