Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:26]3[CH:27]=[CH:28][C:23]([CH2:22][C:21]([O:20][CH3:19])=[O:30])=[CH:24][CH:25]=3)=[CH:9][C:8]=2[C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:6][CH2:5]1)[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC1(c2ccc(C#Cc3ccc(CC(=O)OC)cc3)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112, 95.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 108.0 mg, 0.39 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 0.13 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 100.0 mg (72%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[CH3:17])=[O:5])[CH3:2].[NH2:19][CH:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:19][CH:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[CH3:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(Cl)cc(C)c2nc1Cl
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Product: CCOC(=O)c1cc2cc(Cl)cc(C)c2nc1NC(Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloro-8-methyl-quinoline-3-carboxylic acid ethyl ester is reacted with DL-tryptophan to provide 2-[1-carboxy-2-(1H-indol-3-yl)-ethylamino]-6-chloro-8-methyl-quinoline-3-carboxylic acid ethyl ester. The ester (107 mg, 0.24 mmol) is dissolved in THF (2 mL), then 0.7M aqueous NaOH (1 mL) is added and the mixture is stirred at rt for 23 h. The mixture is concentrated under reduced pressure treated with water and filtered. The filtrate is acidified by addition of 3N HCl till pH 2-3, and stirred for 40 min. Precipitate is filtered off and washed with cold water to provide after drying the title compound (55 mg, 61%) as pale green powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[CH:40]2[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([O:50][CH3:51])[CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:40]2[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([O:50][CH3:51])[CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(NC2CCCc3ccc(OC)cc32)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2ccc(OC)cc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.51, 7.34, 7.10, 6.99, 6.83, 5.47, 4.68, 3.78, 2.85, 2.65, 2.53, 2.15, 2.01, 1.27, 1.21; 13C NMR (100 MHz, CDCl3) δ 173.14, 157.25, 150.37, 149.81, 139.28, 138.42, 136.72, 136.05, 134.21, 133.33, 131.82, 129.41, 129.26, 128.65, 126.39, 112.41, 54.61, 48.17, 28.92, 28.00, 26.49, 25.27, 19.52, 12.19, 10.54; HRMS (FAB) calcd for C25H27Cl2N3O+H 456.1609, found 456.1601.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]2[CH2:20][O:19]2)[CH:11]=1)(=O)C1C=CC=CC=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)[N:23]=1.C1C=CC(=O)C(O)=C(C2C=NC=NC=2)C=1>CC(O)C.CS(C)=O>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:30][CH2:31][CH:32]([NH:35][CH2:20][CH:18]([OH:19])[CH2:17][O:16][C:12]3[CH:11]=[C:10]([OH:9])[CH:15]=[CH:14][CH:13]=3)[CH2:33][CH2:34]2)[N:23]=1
Reactant: O=C(Oc1cccc(OCC2CO2)c1)c1ccccc1
Reactant: Cc1cc(C)nc(N2CCC(N)CC2)n1
Agent: O=c1ccccc(-c2cncnc2)c1O
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1cc(C)nc(N2CCC(NCC(O)COc3cccc(O)c3)CC2)n1
Yield: 14 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 120° C., 24 h), using 200 μmol 3-(oxiran-2-ylmethoxy)phenyl benzoate and 1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-amine to give O-benzoylated intermediate, which was directly treated according to SP10. Title product was obtained by purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) with 14% yield (LCMS: detected [M+1]=373.2).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]3([C:28]#[N:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[O:30][CH3:31])[C@@H:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)(C)(C)C.[ClH:38].Cl.COC1C=CC(C(C2SCCS2)(C)C)=CC=1CN[C@H]1CCCN[C@H]1C1C=CC=CC=1>>[ClH:38].[ClH:38].[C:28]([C:22]1([C:20]2[CH:19]=[CH:18][C:17]([O:30][CH3:31])=[C:16]([CH:21]=2)[CH2:15][NH:14][C@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)#[N:29]
Reactant: COc1ccc(C2(C#N)CCOCC2)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: COc1ccc(C(C)(C)C2SCCS2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccc(C2(C#N)CCOCC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 90 in the same manner of Compound 83.
Reaction SMILES: CN(C1C=CC=CN=1)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH:32]1[CH2:35][CH:34]([CH2:36][C:37]2[S:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)[N:41]=2)[CH2:33]1.[F:49][C:50]([F:66])([F:65])[C:51]1[O:55][N:54]=[C:53]([C:56]2[CH:57]=[C:58]([CH:62]=[CH:63][CH:64]=2)[C:59](O)=[O:60])[N:52]=1>CN(C=O)C>[F:48][C:45]1[CH:46]=[CH:47][C:42]([C:40]2[N:41]=[C:37]([CH2:36][CH:34]3[CH2:35][N:32]([C:59]([C:58]4[CH:62]=[CH:63][CH:64]=[C:56]([C:53]5[N:52]=[C:51]([C:50]([F:65])([F:49])[F:66])[O:55][N:54]=5)[CH:57]=4)=[O:60])[CH2:33]3)[S:38][CH:39]=2)=[CH:43][CH:44]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: Fc1ccc(-c2csc(CC3CNC3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CC(Cc2nc(-c3ccc(F)cc3)cs2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
Dimethylaminopyridine (0.151 g, 1.24 mmol), EDCl (0.142 g, 0.744 mmol), and HOBt (0.095 g, 0.620 mmol) were added to a solution of 2-(azetidin-3-ylmethyl)-4-(4-fluorophenyl)thiazole (0.170 g, 0.682 mmol) in DMF (10.0 mL), followed by 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (0.160 g, 0.62 mmol). The reaction was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield the crude product which was purified by preparative thin layer chromatography using (40% EtOAc/Hexane) to provide (3-((4-(4-fluorophenyl)thiazol-2-yl)methyl)azetidin-1-yl)(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanone (0.140 g, 42.04%) 1H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 8.15-8.17 (d, 1H), 7.94-7.95 (d, 1H), 7.90-7.92 (m, 2H), 7.86-7.88 (d, 1H), 7.66-7.78 (t, 1H), 7.19-7.23 (t, 2H), 4.48-4.52 (t, 1H), 4.17-4.25 (m, 2H), 3.91-3.95 (m, 1H), 3.42-3.43 (m, 2H), 3.10-3.17 (m, 1H). MS (ESI) m/z: Calculated for C23H16F4N4O2S: 488.09. found: 489.0 (M+H)+
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[Si:7]([CH2:14][CH2:15][SH:16])([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9].[OH-].[K+]>O>[Si:7]([CH2:14][CH2:15][S:16][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CO[Si](CCS)(OC)OC
Reactant: C=CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)CCSCC[Si](OC)(OC)OC
Temperature: 60 °C
Yield: 87 %

Procedure:
A mixture of 26 gms of methyl acrylate (0.3 mols) and 36.4 gms of (CH3O)3SiCH2CH2SH was catalyzed by adding 1 ml. of N/2 alcoholic KOH into a 250 ml., round bottomed glass flask, with stirring. An exothermic reaction raised the temperature to 60° C. The mixture was refluxed for 30 minutes and then distilled under vacuum to recover 46 gms of water-white product with a boiling point at 0.7 mm Hg pressure of 115°-125° C. for an 87 percent yield of (CH3O)3Si(CH2)2S(CH2)2COOCH3.d420 =1.115, ND25 =1.4546. One tenth gram mol (26.8 gms) of this product was saponified by refluxing for one hour with 4 grams of NaOH (0.1 mol) in 80 gms of H2O. Methanol and other volatiles were taken off until the temperature, with auxiliary heating, reached 100° C. The residue was diluted to 100 gms with water to give a 1 molal solution of (Na)O1.5 Si(CH2)2S(CH2)2COONa.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[O:11].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].CN([CH:30]=[O:31])C>>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:10]([C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH:30]=[O:31])=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])[CH2:17][CH2:16]1
Reactant: CN(C)C=O
Reactant: CN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C(=O)c2[nH]c3ccccc3c2C=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 4, 0.206 g) in DMF (1.5 mL) at 0° C. was treated with phosphorus oxychloride (0.1 mL) over 10 min. The reaction mixture was warmed to ambient temperature and stirred for 16 h. The reaction mixture was poured into water and adjusted to neutral pH by addition of 1 M sodium hydroxide. The mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane afforded the title compound (0.108 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:5][C:6]1[C:7]2[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][C:8]=2[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[CH2:34][N:35]1[CH2:36][CH2:37][CH2:38][CH2:39]1)[CH2:5][C:6]1[C:7]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:8]=2[S:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[CH:15][CH:16]=1
Reactant: COc1ccc2c(Cc3ccc(CN4CCCC4)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCS
Solvent: CC(Cl)Cl
Solvent: O
Product: Oc1ccc2c(Cc3ccc(CN4CCCC4)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
3-[3-Bromo-4-[(1-pyrrolidinyl)methyl]benzyl]-6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (0.32 g; 0.53 mmol)(Part A) was dissolved in 9.0 mL of dichloroethane under an argon atmosphere and cooled in an ice-water bath. To this was added ethanethiol (0.78 mL; 10.56 mmol) and 0.70 g (5.28 mmol) of aluminum chloride, and the mixture was stirred in the cold bath for 1 h. Brine (80 mL) was added to the mixture, and stirring was continued while warming to room temperature for 1 h. Extraction was carried out with dichloromethane (4×75 mL). The combined organics were dried by passage through sodium sulfate. The title compound (0.23 g; 74% yield) was isolated as a white crystalline solid by flash chromatography on silica gel eluting with a gradient of EtOAc(100-85%)/Et3N(0-5%)/MeOH(0-10%).
Reaction SMILES: C([O:4][C:5]1[C:6]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:7][C:8]2[O:12][C:11]([CH2:14][NH:15][C:16]([NH2:18])=[S:17])([CH3:13])[CH2:10][C:9]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=O)C.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1>[C:20]([C:19]1[C:9]2[CH2:10][C:11]([CH2:14][NH:15][C:16]([NH2:18])=[S:17])([CH3:13])[O:12][C:8]=2[CH:7]=[C:6]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]=1[OH:4])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CNC(N)=S)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC1(CNC(N)=S)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
Under a nitrogen atmosphere, 1.0 g of 1-[(5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methyl]thiourea was dissolved in 30 ml of toluene. To the solution was added 10.2 ml of diisobutyl aluminum hydride (1.0 M in toluene) and the mixture was stirred at room temperature for 1 hour. After reaction, the mixture was combined with a saturated aqueous ammonium chloride solution and 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 33% ethyl acetate to give 0.89 g of 1-[(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)methyl]thiourea as a white crystal (yield 100%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[C:21]2[C:22]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[C:23]3[C:28](=[CH:29][C:30]=2[CH:31]([CH3:33])[CH3:32])[O:27][C:26]([CH3:35])([CH3:34])[CH2:25][C:24]3=[O:36])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].O>ClCCl>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([F:7])[C:21]2[C:22]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[C:23]3[C:28](=[CH:29][C:30]=2[CH:31]([CH3:32])[CH3:33])[O:27][C:26]([CH3:35])([CH3:34])[CH2:25][C:24]3=[O:36])=[CH:16][CH:15]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Reaction time: 2.5 h

Procedure:
At −78° C., a solution of 46 μl (350 μmol) of diethylaminosulfur trifluoride in 1 ml of dichloromethane is slowly added dropwise to a solution of 150 mg (320 μmol) of rac-6-[(4-tert-butylphenyl)(hydroxy)methyl]-5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 27A) in 4.5 ml of dichloromethane, and the mixture is stirred at this temperature for 2.5 h. The mixture is then allowed to thaw slowly to −15° C. Water is then added, and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1→5:1) gives the target compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:15][C@@H:14]2[C@@H:5]([C@@H:6]3[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C@@:9]2([CH3:20])[C:16](=[O:19])[CH2:17][CH2:18][C@@H:8]2[CH2:7]3)[CH2:4][CH2:3]1.[I-].[CH3:22][S+](C)C.CC(C)([O-])C.[K+]>O>[CH3:20][C@:9]12[C@@:16]3([CH2:22][O:19]3)[CH2:17][CH2:18][C@@H:8]1[CH2:7][C@H:6]1[C@@H:11]([CH2:12][CH2:13][C@H:14]3[C@@H:5]1[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:15]3)[CH2:10]2
Reactant: C[S+](C)C
Reactant: C[C@@]12C[C@@H]3CC[C@@H]4CC(O)CC[C@@H]4[C@H]3C[C@H]1CCC2=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: C[C@@]12C[C@@H]3CC[C@@H]4C[C@H](O)CC[C@@H]4[C@H]3C[C@H]1CC[C@]21CO1
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a solution of compound 55 (40 mg, 0.144 mmol) in DSMO (3 mL) was added trimethylsulfonium iodide (204 mg, 1.0 mmol) and potassium tert-butoxide (112 mg, 1.0 mmol) at room temperature. After 3 h, water (20 mL) was added and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to give compound 56 (27 mg, 65%) as a white solid: mp 163-165° C.; [α]D25 +16.7 (c 0.12, CHCl3); 1H NMR (CDCl3) δ 3.64-3.60 (m, 1H), 2.90 (d, J=15.0 Hz, 1H), 2.61 (d, J=15.2 Hz, 1H), 0.86 (s, 3H); 13C NMR (CDCl3) δ 71.7, 70.5, 53.6, 47.1, 41.6, 40.7, 39.1, 38.6, 38.1, 36.2, 35.1, 35.0, 33.6, 33.0, 30.4, 29.8, 28.9, 25.6, 14.5; IR νmax 3379, 1443, 1375 cm−1. MS (FAB) for [C19H30O2]+: 290.2246. Found: 290.2243.
Reaction SMILES: [CH:1]([NH2:3])=O.[NH2:4][C:5]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH3:19])[C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:11][C:6]=1[C:7](OC)=[O:8]>CN1CCCC1=O>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:12]1[CH:11]=[C:6]2[C:5](=[CH:14][C:13]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])[N:4]=[CH:1][NH:3][C:7]2=[O:8]
Reactant: NC=O
Reactant: COCCOc1cc(N)c(C(=O)OC)cc1OCCOC
Solvent: CN1CCCC1=O
Product: COCCOc1cc2nc[nH]c(=O)c2cc1OCCOC
Temperature: 167.5 °C
Reaction time: 8 h

Procedure:
Formamide (130 mL) was added to a solution of compound 21 (13.0 g, 43.43 mmol) in N-methyl-2-pyrrolidone (130 mL) and the reaction mixture was heated to 165-170° C. under N2 for 12 h. Reaction was monitored by TLC. After 8.0 h TLC indicated no starting material. The reaction mixture was poured in to ice cold water and solids were filtered. The crude product was purified by column chromatography to give compound 22 as light yellow solid.
Reaction SMILES: I/[CH:2]=[CH:3]/[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I>[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]([O:4]/[CH:3]=[CH:2]/[N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[CH:6][CH:7]=1
Reactant: I/C=C/Oc1ccc(-c2ccccc2)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C(=C/n1ccc2ccccc21)\Oc1ccc(-c2ccccc2)cc1
Yield: 86.7 %

Procedure:
The compound 9 was prepared following the procedure described for 5 with 4 (0.32 g, 1 mmol, 1 eq), indole (0.14 g, 1.2 mmol, 1.2 eq), Cs2CO3 (0.81 g, 2.5 mmol, 2.5 eq), CuI (0.095 g, 0.5 mmol, 0.5 eq) and L2 (0.097 g, 0.5 mmol, 0.5 eq) at 70° C. for 12 h to give crude product which were purified by silica gel column chromatography using ethyl acetate-hexane (9:95) to afford compound 9 as white crystals (0.27 g, 87%): mp 140-142° C. 1H NMR (300 MHz, CDCl3): 7.58-7.46 (m, 6H, HAr), 7.40-7.32 (m, 3H, HAr), 7.25-7.21 (m, 1H, HAr), 7.20-7.14 (m, 2H, HAr), 7.12-7.02 (m, 4H, HAr and H(O)C═(N)CH), 6.55 (d, H, J=3.1 Hz, HAr). 13C NMR (75 MHz, CDCl3): 156.8, 140.4, 136.5, 136.4, 128.9, 128.8, 128.5, 127.1, 126.9, 125.7, 125.6, 121.2, 120.5, 116.5, 115.2, 109.8, 104.0 ppm; IR (cm−1): 3034, 2358, 2338, 1682, 1606, 1515, 1485, 1475, 1462, 1358, 1333, 1322, 1301, 1232, 1202, 1186, 1174, 1134, 1115, 1088, 1031, 1007, 907, 865, 834; HRMS (ESI), Calculated for C22H17NO [M+H]+ 312.1388. Found 312.1381; Elemental analysis Calculated for C22H17NO.0.25H2O: C, 83.65; H, 5.58; N, 4.43. found: C, 83.61; H, 5.65; N, 4.01.
Reaction SMILES: [CH3:1][C:2]([C:9]#[CH:10])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[Cl:11][CH2:12][C:13]([CH2:15]Cl)=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C.CCOCC>[Cl:11][CH2:12][C:13](=[CH2:14])[CH2:15][C:10]#[C:9][C:2]([CH3:1])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: C=C(CCl)CCl
Reactant: C#CC(C)=CCCC(C)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Solvent: CCOCC
Product: C=C(CCl)CC#CC(C)=CCCC(C)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 74 %

Procedure:
A mixture of 120 mg (0.88 mmole) of 6-methyl-5-octen-7-yn-2-one (produced in accordance with Example II), 2.00 mL (19 mmoles, the excess of which can be quantitatively recovered by distillation at reduced pressure after the reaction is complete) of 3-chloro-2-chloromethyl-1-propene (purchased from Aldrich Chemical Co., Milwaukee, Wis.), 193 mg (1.4 mmoles) of anhydrous potassium carbonate, 20 mg (0.20 mmole) of cuprous chloride, and 20 mg (0.087 mmole) of benzyltriethylammonium chloride in 2.00 mL of acetonitrile (HPLC-grade, purchased from Aldrich Chemical Co., Milwaukee, Wis.) was stirred vigorously at room temperature for 22 hours, during which time the mixture was maintained under an atmosphere of nitrogen. The mixture was then diluted with 40 mL of 1:1 (v/v) ether:hexane and filtered through a small pad of Hyflo Super-Cel® filtering aid. The filtrate was washed with 20 mL of 5% aqueous sodium chloride, then dried over anhydrous magnesium sulfate, and re-filtered. Removal of the volatile organic material by evaporation at reduced pressure (50 mm) and recovery of unreacted 3-chloro-2-chloromethyl-1-propene by evaporative fractional distillation at reduced pressure (2.5 mm) afforded 146 mg (74% yield) of the named ketone after distillation in the presence of a small amount of calcium carbonate: boiling point 122°-130° C. (bath temperature, 0.20 mm). Proton NMR analysis indicated the presence of a minor impurity, subsequently found to have been present as a contaminant in 3-chloro-2-chloromethyl-1-propene. The named ketone was characterized by a singlet at δ1.78 (CH3 bonded to C-6), a singlet at δ2.12 (CH3C=O), a singlet at δ3.15 (2 hydrogens bonded to C-9), and a singlet at δ4.05 (CH2Cl).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH:12]=O)=[CH:4][CH:3]=1.[Cl-].[CH2:15]([N:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20](=[O:22])[CH3:21])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([NH:19][C:20](=[O:22])/[CH:21]=[CH:12]/[CH2:11][CH2:10][C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(=O)N(CC(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCC#Cc1ccc(Br)cc1
Agent: [Cl-]
Product: CC(C)CNC(=O)/C=C/CCC#Cc1ccc(Br)cc1

Procedure:
N-isobutyl 7-(4'-bromophenyl)-(2E)-hepten-6-ynamide was prepared from 5-(4'-bromophenyl)-4-pentyn-1-al and N-isobutyl acetamidotriphenyl-phosphonium chloride as in Example 9 and semi-hydrogenated as in Example 9 to give N-isobutyl 7-(4'-bromophenyl)-(2E,6Z)-hepta-dienamide.