Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]N)#[N:2].C1N2CN3CN(C2)CN1C3.O.S(=O)(=O)(O)[OH:23]>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:23])#[N:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cccc(CN)c1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
7.9 g of m-cyanobenzylamine, 8.4 g of hexamethylenetetramine, 40 ml of water and 40 ml of acetic acid were mixed and reacted at 104° C. for 2 hours while stirring. The reaction solution was cooled to room temperature and thereto 12 g of concentrated sulfuric acid was added. The solvent was concentrated to dry in an evaporator with a water bath at 70° C. The concentration residue was separated by toluene/water and washed with water. The toluene layer obtained was concentrated until crystals were precipitated. The concentrated toluene solvent was placed in water and after removing toluene by azeotropic distillation, the residue was cooled to room temperature. The crystals precipitated were collected by filtration, washed with water and dried to obtain 5.9 g (yield: 74%) of m-cyanobenzaldehyde. The purity was 99% or more.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1>C(O)C>[CH2:2]([C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[N:20]=1)[CH3:1]
Reactant: COc1ccc(NN)cc1
Reactant: CCC(=O)CC(=O)CC
Agent: Cl
Solvent: CCO
Product: CCc1cc(CC)n(-c2ccc(OC)cc2)n1
Yield: 49.7 %

Procedure:
A solution of 3,5-heptanedione (1.06 mL, 7.80 mmol) and 4-methoxyphenylhydrazine hydrochloride (1.49 g, 8.58 mmol) in ethanol (25 mL) was stirred at 60° C. overnight. After the reaction was concentrated, the residue was partitioned between 1 N HCl and ethyl acetate. The ethyl acetate layer was washed two times with 1 N HCl. The organic layer was dried (MgSO4) and concentrated to give 893 mg of the title compound. LC-MS (C14H18N2O calculated 230) m/z 231 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=O.N[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[BH3-]C#[N:28].[Na+]>C(#N)C.[Cl-].[Cl-].[Zn+2]>[C:21]([O:20][C:19](=[O:25])[NH:18][CH2:17][CH:16]([NH:28][CH:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:1])[CH3:15])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(=O)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CC#N
Product: CC(CNC(=O)OC(C)(C)C)NC(C)c1cccc2ccccc12
Temperature: 80 °C
Yield: 70 %

Procedure:
To a solution of 1-acetonaphthone (152 μl, 1 mmol) in acetonitrile (2 ml) was added tert-butyl N-(3-aminopropyl)-carbamate (209 μl, 1.2 mmol), NaBH3CN (126 mg, 2 mmol) and anhydrous ZnCl2 (136 mg, 1 mmol). The reaction was heated for 70 hours at 80° C. in a screw cap vial with magnetic stirring. The precipitate was filtered off and the solution was evaporated. The residue was dissolved in 3 ml 0.1N HCl and extracted with methylenchloride (1×5 ml). The organic layer was dried (Na2SO4) and evaporated. The crude product was purified by silica gel flash chromatography using 1. CHCl2/MeOH (10/0.1) and 2. CH2Cl2/MeOH (10/1), as an eluent, to give an oily product 70%. The structure characterization of the products was made with 1HNMR; 13CNMR; MS (m/z): 329 (MH+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30](Cl)[C:31]([O:33]CC)=O)=[CH:25][CH:24]=1)([CH3:19])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[NH2:37][C:38]([NH2:40])=[S:39].S1(CCCC1)(=O)=O>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]3[S:39][C:38](=[NH:37])[NH:40][C:31]3=[O:33])=[CH:25][CH:24]=1)([CH3:19])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCCC2(C)CCc3cc(OC(C)=O)c(C(C)(C)C)cc3O2)cc1
Solvent: O=S1(=O)CCCC1
Product: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(CCOc1ccc(CC3SC(=N)NC3=O)cc1)CC2

Procedure:
The procedure described in Example 1(a) was repeated, except that 266 mg of ethyl 3-{4-[2-(6-acetoxy-7-t-butyl-2-methylchroman-2-yl)ethoxy]phenyl}-2-chloropropionate, 50 mg of thiourea and 4 ml of sulfolane were heated at 110°-120° C. for 4.5 hours. The product was treated as described in Example 1(a) except that the crude product was purified by column chromatography through silica gel eluted with a 1:1 by volume mixture of benzene and ethyl acetate, to give the title compound, melting at 175°-178° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:16]([CH2:17][OH:18])[C@@H:15]2[C@H:19]([OH:20])[C@H:12]1[C@H:13]([O:21][CH3:22])[O:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].[C:31](Cl)(=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@H:16]([CH2:17][O:18][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C@@H:15]2[C@H:19]([O:20][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:12]1[C@@H:13]([O:21][CH3:22])[O:14]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CO[C@@H]1O[C@H]2[C@H](O)[C@@H]1N(C(=O)OCc1ccccc1)[C@@H]2CO
Solvent: O
Solvent: c1ccncc1
Product: CO[C@H]1O[C@H]2[C@H](OCc3ccccc3)[C@@H]1N(C(=O)OCc1ccccc1)[C@@H]2CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
The compound (152 mg, 0.49 mmol) synthesized in Example 7 (7b) was dissolved in pyridine (4 mL) and t-butyldimethylsilyl chloride (82 mg, 0.54 mmol) was added thereto, followed by stirring of the mixture at 0° C. for 3 hours. After it was confirmed by TLC that the raw material was no longer present, benzoyl chloride (86 μL, 0.74 mmol) was added and the mixture was stirred at 0° C. for 1 hour. After water (20 mL) was added thereto at 0° C. and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine (20 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 10:1, V/V) to obtain the desired title compound (218 mg, yield 84%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[N:7]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]2=[O:22])[CH3:2].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+]>C(#N)C>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:47])[O:39][N:38]=3)=[CH:27][CH:26]=1)[C:8](=[O:13])[N:7]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]2=[O:22])[CH3:2]
Reactant: CCc1ccc2[nH]c(=O)n(CCc3ccccc3)c(=O)c2c1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1ccc2c(c1)c(=O)n(CCc1ccccc1)c(=O)n2Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A mixture of 6-ethyl-3-(2-phenylethyl)quinazoline-2,4(1H,3H)-dione (0.40 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.65 g), potassium carbonate (0.38 g) and acetonitrile (16 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL) and acetone (4 mL). 1N Aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and extracted with chloroform. The obtained chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.18 g, 24%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])[NH:11][N:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])[N:11]([CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([F:33])[CH:35]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1nc(-c2cc(F)ccc2F)n[nH]1)C(C)(C)C
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1)C(C)(C)C

Procedure:
To a stirred suspension of (R)-tert-butyl 1-(3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylcarbamate (5.89 g, 16.1 mmol) and Cs2CO3 (10.5 g, 32.2 mmol) in DMF (46 mL, 0.35 M) was added 3-fluorobenzyl bromide (2.17 mL, 17.7 mmol). Once the reaction was complete, the mixture was partitioned between EtOAc and H2O. The organic layer was separated and washed with H2O, brine, then dried over Na2SO4, filtered, and evaporated in vacuo to give (R)-tert-butyl 1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylcarbamate. The desired less polar regioisomer was obtained by silica gel column (0% to 100% EtOAc in Hexanes, 5.05 g, 66.2%).
Reaction SMILES: [C:1]([C:3]1([C:8](OC)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[BH4-].[Li+]>C1COCC1>[OH:9][CH2:8][C:3]1([C:1]#[N:2])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(C#N)CCCC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(CO)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.1 %

Procedure:
A mixture of methyl 1-cyanocyclopentanecarboxylate (prepared in Example 740, Step 1) (500 mg, 3.0 mmol) in THF (7 mL) was treated with lithium tetrahydroborate (100 mg, 6.0 mmol). The resulting solution was heated to reflux for 3 hours, then stirred at ambient temperature for 16 hours. The mixture was quenched by the addition of water, and was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, then filtered and the solvent was removed in vacuo to afford the product (387 mg, 95%). 1H NMR (300 MHz, CDCl3): δ 3.62 (s, 2H), 2.39-1.60 (m, 8H).
Reaction SMILES: [BH3:1].B#B.O1[CH2:8][CH2:7][CH2:6][CH2:5]1>>[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:5]([B:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:6][CH2:7][CH2:8][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: B
Reactant: C1CCOC1
Agent: B#B
Product: C=CCCCCCC
Product: CCCCCCCCB(CCCCCCCC)CCCCCCCC

Procedure:
In the practice of the invention, borane adducts of N,N-diisopropylalkylamines are prepared by passing diborane into a neat amine until no more diborane is absorbed. The adduct with N,N-diisopropylisobutylamine is liquid above 0° C., 4.6M in borane, and is stable over prolonged periods at room temperature. The adduct with N,N-diisopropyl-sec-butylamine is a liquid 3.3M in borane when freshly prepared at 0° C., slowly losing borane at room temperature. All of the adducts of this invention hydroborate 1-octene in tetrahydrofuran at room temperature in less than 1 hour to give trioctylborane. They are also soluble in diethyl ether and dichloromethane. Alternatively, neat adducts can be used for hydroboration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][C:17](=[O:19])[CH2:16][CH2:15][C@@H:14]2[CH2:13][NH:12][CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[CH2:20](O)[CH2:21][OH:22].CS(O)(=O)=O.N>O.C1C=CC=CC=1>[CH2:21]1[O:22][C:17]2([CH2:16][CH2:15][C@H:14]3[C@:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)([CH2:10][CH2:11][NH:12][CH2:13]3)[CH2:18]2)[O:19][CH2:20]1
Reactant: OCCO
Reactant: COc1cccc([C@]23CCNC[C@H]2CCC(=O)C3)c1
Agent: CS(=O)(=O)O
Agent: N
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc([C@]23CCNC[C@H]2CCC2(C3)OCCO2)c1

Procedure:
25.93 g (0.1 mol) of octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone (see Example 1), 100 ml of benzene, 11.2 ml (0.2 mol) of ethylene glycol and 8.1 ml (125 mmol) of methanesulphonic acid are boiled for 3 hours in a water separator. The mixture is cooled, made basic with aqueous ammonia and extracted with methylene chloride. The organic phase is evaporated to dryness to yield octahydro-4a-(3-methoxyphenyl)-cis-6(2H)-isoquinolinone ethylene ketal. The ketal is dissolved in 50 ml of absolute methanol, cooled to 0° C., and 13.91 ml (0.1 mol) of triethylamine and 7.46 ml (0.12 mol) of methyl iodide are added thereto. The mixture is kept at 22° for 1 hour. The mixture, containing octahydro-4a-(3-methoxyphenyl)-2-methyl-cis-6(2H)-isoquinolinone ethylene ketal, is mixed with 20 ml of dioxane and concentrated by evaporation. 100 ml of dioxane and 100 ml of 2 N aqueous hydrochloric acid are added to the residual oil. The resultant mixture is stirred for 2 hours at 40°, made basic with aqueous ammonia, and extracted with toluene. The extracts are concentrated by evaporation to yield the title compound as an oil, which is crystallized as the hydrogen fumarate from ethanol.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=1[F:53]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=3[F:53])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(C#N)cc3F)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-3-fluoro-benzonitrile according to procedure B followed by deprotection yielded the title compound as an off-white foam. MS (ESI): m/z=398.2 [M+H]+.
Reaction SMILES: [Cl-].C[CH:3]=[N+:4]=[CH:5]C.[CH3:7][N:8]([CH3:19])[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[C:20](#N)C>>[CH3:19][N:8]([CH3:7])[CH2:9][CH:10]([C:11](=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][N:4]([CH3:5])[CH3:20]
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: CC=[N+]=CC
Reactant: CC#N
Agent: [Cl-]
Product: CN(C)CC(CN(C)C)C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
The compound N,N,N',N'-tetramethyl-2-benzoyl-1,3-propanediamine (VIII) was synthesized by the method of Kinast and Tietze, Angew. Chemie. Int. Ed. 15 239-240 (1976). A mixture of 500 parts of N,N-dimethylmethylene ammonium chloride, 2600 parts of dry acetonitrile and 1035 parts of compound VII, described above, was heated to reflux under nitrogen for 15 minutes. The mixture was allowe to cool to room temperature andd then placed in the refrigerator overnight. A total of 800 parts of the hydrochloride salt of VI was isolated by filtration. The mother liquor was made basic with 10% NaOH solution and extracted with ether, the ether solution dried with anhydrous potassium carbonate and the ether evaporated under reduced pressure to yield 479 parts of a light yellow, low melting solid identified as VIII by NMR spectroscopy. The total yield of VIII was thus 93%.
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([OH:9])(=O)[CH3:7].[O:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C#C.C#C.[Zn]>[CH:12]([C@@H:11]1[O:10][C@H:7]1[CH2:6][OH:9])=[C:13]=[CH:14][C:11]#[C:12][C:13]#[CH:14]
Reactant: CC(=O)O
Reactant: C1CCOC1
Agent: C#C
Agent: CS(=O)(=O)Cl
Agent: [Zn]
Product: C#CC#CC=C=C[C@@H]1O[C@H]1CO
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
In a separate flask, the mesylate of 6-[(tetrahydro-2H-pyran-2-yl)oxy]-4-hexen-1-yn-3-ol was prepared via the following procedure. To a stirred solution of 6-[(tetrahydro-2H-pyran-2-yl)oxy]-4-hexen-1-yn-3-ol (98 mg, 0.5 mmole), anhydrous lithium bromide (43 mg, 0.5 mmole) and a few milligrams of 1,10-phenanthroline in 5 ml of tetrahydrofuran at -78° C. was added n-butyllithium dropwise until a brown color was obtained (ca. 0.5 mmole of n-butyllithium). The mixture was stirred for one-half hour whereupon mesyl chloride (38 μl, 0.5 mmole) was added dropwise. The brown color discharged to yellow. The solution was stirred for 10 minutes at -78° C. and was then added all at once (via short teflon cannula and argon pressure) to the above stirred -20° C. solution of zinc diacetylene. The resultant mixture was stirred at -20° C. for 15 minutes and was then acidified by the addition of a solution of acetic acid in tetrahydrofuran. The mixture was then concentrated to ca. 1/4 volume and 30 ml of a mixture of ether-hexane 1:1 was added with stirring whereupon a gum separated. The supernatant was then filtered through a pad of silica gel. The filtrate was concentrated to dryness and immediately redissolved in a few ml of ether-hexane 1:5 (some solid did not dissolve). This solution of crude product was then purified via flash chromatography (LPS-1 silica gel, ether-hexane 1:10) to afford pure title compound (30 mg). This allene was stored in solution in ether-hexane in the freezer.
Reaction SMILES: C([NH:11][C@H:12]([C:16]([N:18]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:19][C:20]([OH:22])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])(OCC1C=CC=CC=1)=O.[C:30]([OH:35])(=[O:34])[C:31]([CH3:33])=[O:32]>C(O)C.[Pd]>[C:30]([OH:35])(=[O:34])[C:31]([CH3:33])=[O:32].[C:30]([CH:31]([NH:11][C@H:12]([C:16]([N:18]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:19][C:20]([OH:22])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])[CH3:33])([OH:35])=[O:34]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)Cc1ccccc1
Agent: [Pd]
Agent: CC(=O)C(=O)O
Solvent: CCO
Product: CC(N[C@H](C(=O)N(CC(=O)O)Cc1ccccc1)C(C)C)C(=O)O
Reaction time: 4 h

Procedure:
To a solution of N-carbobenzoxy-L-valyl-N-benzyl glycine (17.2 g, 44.6 mmol) and pyruvic acid (19.6 g, 0.223 mol) in 400 ml absolute ethanol was added 10% palladium on carbon (1.5 g). The mixture was hydrogenated at 50 psi for 4 hours. Filtration and concentration in vacuo provided an oily product which was purified as in example 7D.
Reaction SMILES: C([NH:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(OC(C)(C)C)=O.C(Cl)Cl>CN(C)C=O>[NH2:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 0.17 h

Procedure:
While maintaining the nitrogen gas atmosphere, 3 fold molar excess of Boc-L-Tryptophan (Peninsula, supra.) dissolved in dimethylformamide and adjusted to 15 ml. with the addition of methylene chloride is added to the product of Step (F) above and the resulting mixture shaken. After about 10 minutes, 3 fold molar excess of N,N-dicyclohexylcarbodiimide is added and the resulting mixture is shaken for 4.5 to 5 hours at room temperature. At the end of this period, the reaction mixture is filtered and the residue washed with dimethylformamide. The washed residue is dried.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].C(N(CC)CC)C.[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCOC(CN)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(CNC(=O)c1ccc(Br)cc1)OCC
Reaction time: 6 h
Yield: 66.1 %

Procedure:
To a stirred solution of aminoacetaldehyde diethyl acetal (6.66 g, 50.0 mmol) in CH2Cl2 (100 ml) was added triethylamine (5.06 g, 50.0 mmol), 4-bromobenzoyl chloride (10.97 g, 50.0 mmol), and the mixture was stirred for 6 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate. The solution was washed with 0.5N HCl aqueous solution, water, saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized with ethyl acetate-hexane to give title compound (10.45 g, 66% yield). 1H-NMR (CDCl3) δ: 7.65 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz, 2H), 6.35 (s, 1H), 4.61 (t, J=5 Hz, 1H), 3.81-3.69 (m, 2H), 3.64-3.53 (m, 4H), 1.24 (t, J=7 Hz, 6H).
Reaction SMILES: O=[C:2]1[O:7][CH:6]=[C:5]([C:8]([O:10]C)=[O:9])[CH:4]=[CH:3]1.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([NH2:19])[CH2:14]1.CO.[Li+].[OH-]>C1COCC1>[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]2[C:2](=[O:7])[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6]2)[CH2:14]1
Reactant: CC1CCCC(N)C1
Reactant: COC(=O)c1ccc(=O)oc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CCCC(n2cc(C(=O)O)ccc2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
A solution of methyl 6-oxo-6H-pyran-3-carboxylate (620 mg, 4.0 mmol, Aldrich) and 3-methylcyclohexanamine (900 mg, 8.0 mmol, Pfaltz and Bauer) was heated in the Emry's optimizer microwave at 150° C. for 15 min. The resulting solution was transferred to a 50 mL round bottom flask with THF, then diluted with THF:MeOH to give approximately 40 mL of a 3:1 THF:MeOH solution. Add 1 M LiOH (6 mL, 6 mmol) and stir at RT overnight. The solution was concentrated in vacuo and the residue taken up in H2O. The aqueous solution was extracted with ether (30 mL). 2 N HCl was added to acidify the aqueous solution to pH 2. The aqueous solution was extracted with EtOAc (3×) and the combined EtOAc layers dried over MgSO4, and concentrated in vacuo to give 200 mg (21%) of the desired product as a light brown residue. MS m/z: 612.5 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[CH:12]([CH3:14])[CH3:13].CN(C)C1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>ClCCl.O>[CH:12]([C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH:8]([CH3:9])[CH3:10])[C:2]=1[NH:1][C:25](=[O:26])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1cc(O)cc(C(C)C)c1N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)Oc1ccccc1
Yield: 76.9 %

Procedure:
To a solution of 4-amino-3,5-diisopropylphenol (1.02 g, 5.27 mmol) in dichloromethane (10 ml) was added N,N-dimethylaniline (770 mg, 6.34 mmol), then a solution of phenyl chloroformate (910 mg, 5.81 mmol) in dichloromethane (2 ml) was dropped thereinto with ice-cooling and stirring, and the mixture was stirred for 30 minutes. The reaction solution was diluted with water and extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 34 g, developing solvent; hexane:acetone=5:1) to provide 1.27 g (77%) of phenyl N-(2,6-diisopropyl-4-hydroxyphenyl)carbamate as colorless oil.