Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16](O)=[O:17])=[N:9]2)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:27])=O.CN(C=O)C>ClCCl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([Cl:27])=[O:17])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nnc(-c3cccc(C(=O)O)c3)n2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2nnc(-c3cccc(C(=O)Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
The carboxylic acid intermediate (10 g, 0.032 mol) from Step (c) was suspended in dichloromethane followed by the addition of oxalyl chloride (20.4 g, 0.16 mol) and catalytic DMF. The reaction mixture was stirred at room temperature for 3 hours, at which time dissolution was nearly complete. The reaction mixture was filtered and concentrated in vacuo. The residue was triturated with petroleum ether and collected by filtration to give the title compound (9.5 g, 90%) as a white solid. 1H NMR (CDCl3) δ 8.9 (s, 1H), 8.5 (d, 1H), 8.2 (d, 1H), 8.6 (t, 1H), 7.4 (d, 2H), 6.9 (d, 2H), 3.8 (s, 3H) ppm. Mp 122–124° C.
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C@H:4]1[S:3]2.C(O)(=O)C>CN(C)C=O.[Zn]>[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:28])[CH:17]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Nc3ccccc3)[C@H]1S2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)Nc3ccccc3)[C@H]1S2
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(3-phenylureido)penam-3-carboxylate (1.12 g.) in dimethylformamide (7.5 ml.) were added acetic acid (2.3 ml.) and then zinc powder (1.8 g.) under ice-cooling, and the mixture was stirred for 1 hour. After the reaction, the reaction mixture was post-treated in the similar manner as described in Example 1 and residue obtained by distilling off ethyl acetate was crystallized by adding a small amount of acetonitrile to give colorless crystals of 2-methyl-2,3-methylene-6-(3-phenylureido)penam-3-carboxylic acid (0.72 g.), mp 108° to 110°C.
Reaction SMILES: ClC1C(=O)C2C(C(=[O:13])C=1Cl)=CC=CC=2.N([O-])=O.[Na+].[N+:19]([C:22]1[C:23](=[O:33])[C:24]2[C:29]([C:30](=[O:32])[CH:31]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)([O-:21])=[O:20]>CO.O>[OH:13][C:31]1[C:30](=[O:32])[C:29]2[C:24]([C:23](=[O:33])[C:22]=1[N+:19]([O-:21])=[O:20])=[CH:25][CH:26]=[CH:27][CH:28]=2
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: O=C1C=C([N+](=O)[O-])C(=O)c2ccccc21
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C(O)=C([N+](=O)[O-])C(=O)c2ccccc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A suspension of 2,3 -dichloro-1,4-naphthoquinone (6.83g; 0.03 mole) in methanol (40 ml) was stirred during the addition of a solution of sodium nitrite (6.9g; 0.1 mole) in water (50ml) and the mixture stirred at 80° C for 3 hours. Solution was attained after about 1 hr and the nitro naphthoquinone began to separate after 2 hrs. After cooling in ice and the yellow crystalline solid was filtered off, taken up in water (200ml), charcoalized and precipitated the product by addition of one-third the volume of concentrated hydrochloric acid, filtered off, washed well with 5N HCl and dried in vacuo over P2O5 /NaOH to give 5.30 g (81%) of material of m.p. 162°-163° C (d) which was identical to that prepared above.
Reaction SMILES: CS(C)=O.[H-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>C(OCC)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:15]#[N:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CC1(c2ccc(Cl)cc2)CCOCC1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Into a round-bottom flask under argon fitted with an addition funnel and thermometer was added anhydrous dimethylsulfoxide (60 mL) and sodium hydride (1.17 g, 48.8 mmol, 95%). Then a solution of (4-chlorophenyl)acetonitrile (G) (3.37 g, 22.2 mmol) and 2-bromoethyl ether (90%, 3.41 mL, 24.4 mmol) in diethyl ether (15 mL) was added slowly, while maintaining the reaction temperature at 20-30° C. The reaction mixture was maintained at room temperature for overnight. The reaction mixture was carefully quenched with water (50 mL) and then extracted with hexane (3×100 mL). The organic extracts were combined, washed with water (3×75 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to give a pale yellow oil. The oil was purified by column chromatography on silica gel using hexane/ethyl acetate (80:20) to give 4.7 g of 4-(4-chlorophenyl)tetrahydropyran-4-carbonitrile, H, as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 2.00-2.15 (m, 4H); 3.89 (dt, 2H, J1=12.6 Hz, J2=3 Hz); 4.05-4.11 (m, 2H); 7.37-7.45 (m, 4H); 13C NMR (CDCl3, 75 MHz): δ 36.66 (2C), 41.51, 64.98 (2C), 121.40,127.03, 129.37, 134.31, 138.46.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:43][C:44]1[S:45][CH:46]=[C:47]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[N:48]=1>>[CH2:53]([O:52][C:50]([CH2:49][C:47]1[N:48]=[C:44]([NH:43][C:17](=[O:19])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[S:45][CH:46]=1)=[O:51])[CH3:54]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: CCOC(=O)Cc1csc(NC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Yield: 84.1 %

Procedure:
Alternatively, by working in a way similar to that above reported and by using N-tert-butoxycarbonyl-L-phenylalanine (10 g; 37.7 mmoles), N-hydroxysuccinimide (4.78 g; 41.5 mmoles), dicyclohexylcarbodiimide (8.56 g; 41.5 mmoles) and ethyl (2-amino-4-thiazolyl)acetate (7 g; 37.7 mmoles), a crude was obtained which, chromatographed on silica gel (eluent ligroin:ethyl acetate 6:4) and further crystallized from ligroin, afforded N-(4-ethoxycarbonylmethyl-2-thiazolyl)-3-phenyl-2-(tert-butoxycarbonyl)amino-propanamide (13.74 g; 84.14% yield).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5].[CH3:25][Mg]Br.CCOCC>O1CCCC1>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:25]
Reactant: CON(C)C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (1-(4-(methoxy(methyl)carbamoyl)phenyl)cyclobutyl)carbamate (0.5 g, 1 eq.) in tetrahydrofuran (THF) (5 mL) cooled to 0° C. was slowly added a 1 M solution of methylmagnesium bromide in ether (4.5 mL, 3 eq.). The reaction mixture was stirred at room temperature overnight then quenched by the addition of saturated aqueous ammonium chloride (15 mL). The mixture was extracted with dichloromethane (2×25 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (15% ethyl acetate in dichloromethane), giving tert-butyl (1-(4-acetylphenyl)cyclobutyl)carbamate as a colorless oil which solidified upon standing (261 mg, 60%). 1H NMR (DMSO-d6) 400 MHz δ 7.91 (d, J=8.0 Hz, 2H), 7.74 (br. s, 1 H), 7.50 (d, J=8.4 Hz, 2H), 2.56 (s, 3H), 2.45-2.32 (m, 4H), 2.06-1.94 (m, 1H), 1.86-1.75 (m, 1H), 1.33 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH3:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50]Br.[I-].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH3:38])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Reactant: COCCOCCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCOCCOCCOCCOC)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 73.7 %

Procedure:
A mixture of 2.0 g (3.83 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 4.15 g (15.3 mmol) of 2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethyl bromide, 1.2 g (7.66 mmol) ofsodium iodide and 1.6 g (11.5 mmol) of potassium carbonate in 60 ml of acetone and 30 ml of DMF was stirred at reflux for 48 hours. The solvents were removed at reduced pressure and the residual oil was purified by HPLCusing 60% ethyl acetate-hexane to give 2.01 g (73% yield) of N-[3-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C.Cl>COCCOC>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(NC(N)=O)ccc1Cl
Reactant: CCOC=CC(=O)OCC
Agent: Cl
Solvent: COCCOC
Product: CCOC(=O)C=CNC(=O)Nc1ccc(Cl)c(C(=O)OCC)c1

Procedure:
6.0 g of ethyl 2-chloro-5-ureidobenzoate and 6.4 g of ethyl 3-ethoxyacrylate are heated at reflux temperature in 100 ml of 1,2-dimethoxyethane and subsequently heated at this temperature with 12 ml of 2N hydrochloric acid for 5 minutes. The reaction mixture is evaporated to dryness under reduced pressure and the residue is purified by chromatography on 300 g of silica gel using ethyl acetate/n-hexane (1:3) as the eluent. There is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)vinyl]ureido}-benzoate, m.p. 116°-117° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([N:15]([CH:29]([CH3:31])[CH3:30])[C@@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)=[O:14])[CH:11]=2)[C:6]([CH3:33])([CH3:32])[C:5]1=[O:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:56][CH:57]([F:61])[C:58](O)=[O:59]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:56][CH:57]([F:61])[C:58]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([N:15]([CH:29]([CH3:30])[CH3:31])[C@@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17]3)=[O:14])[CH:11]=2)[C:6]([CH3:32])([CH3:33])[C:5]1=[O:34])=[O:59]
Reactant: CC(C)N(C(=O)c1ccc2c(c1)N(CCN)C(=O)C2(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)c1ccc2c(c1)N(CCNC(=O)C(F)F)C(=O)C2(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To tert-butyl (3R)-3-[{[1-(2-aminoethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]-carbonyl}(isopropyl)amino]piperidine-1-carboxylate (300 mg) were added WSC (210 mg), HOBt (150 mg), triethylamine (0.30 ml), chloroform (5 ml), and difluoroacetic acid (79 mg), and the mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (170 mg) as colorless amorphous.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][CH:6]=1.[H-].[Na+].[CH3:15][O:16][CH2:17]Cl.O>CN(C=O)C>[CH3:15][O:16][CH2:17][N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[C:4]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1c[nH]c(-c2ccccc2)n1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1cc(C)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.8 %

Procedure:
To a solution of 1.0 g (6.32 mmol) of 4-methyl-2-phenylimidazole in 25 mL of DMF at 0° C. was added 278 mg (6.95 mmol, 60% in oil) of NaH. After stirring for 5 min, 0.528 mL (6.95 mmol) of chloromethyl methyl ether was added, and the reaction was warmed to 25° C. and stirred 4 h. The reaction was poured into H2O, and the product was extracted with hexanes/EtOAc (1:1). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel flash column chromatography using hexanes/EtOAc (5:95) as eluent provided 816 mg (64%) of title compound: low resolution MS (ES) m/e 225 (MNa+), 203 (MH+).
Reaction SMILES: [C:1]([Cl:4])(Cl)=O.[CH2:5]([O:12][C:13]1[CH:24]=[CH:23][C:16]([C:17]([NH:19][CH2:20]CO)=[O:18])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCOCC1>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:1][Cl:4])=[O:18])=[CH:23][CH:24]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(NCCO)c1ccc(OCc2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C(NCCCl)c1ccc(OCc2ccccc2)cc1
Yield: 68 %

Procedure:
Phosgene was bubbled through a suspension of 4-benzyloxy-N-(2-hydroxy-ethyl)-benzamide (22.49 g, 82.8 mmol) in dioxane (130 ml) until all the insoluble material had dissolved. Excess phosgene was removed by a stream of carbon dioxide. The solvent was removed at reduced pressure, and the residue was dried for 1 h. at 100° C. The crude product was recrystallized from ethyl acetate to yield 4-benzyloxy-N-(2-chloro-ethyl)-benzamide (16.3 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:19])[CH2:17][Cl:16])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CCl)Nc1ccc(F)c(F)c1
Reaction time: 8 h
Yield: 418.3 %

Procedure:
The method of Cervena et al.3 was followed. To a stirred solution of 3,4-difluoroaniline (10 mmol) in toluene (5 mL) and pyridine (10 mmol) maintained at 5-10 deg C was added chloroacetyl chloride (10 mmol) in toluene (5 mL) dropwise. The mixture was allowed to stand overnight at room temperature. The organic layer was then separated and the residue was mixed with water (60 mL). The separated solid product was recrystallized from toluene to give N-(3,4-difluorophenyl) chloroacetamide (8.6 g, 84.3% yield). 1HNMR (300 MHz, CDCl3) δ 8.24 (s, 1H, NH), 7.63 (td, J=8.1 Hz, 1H, Ar—H), 7.16-7.12 (m, 2H, Ar—H), 4.19 (s, 2H, COCH2Cl).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:13][C:14]([C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)=[CH:21][CH:20]=2)=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH:38]1([CH2:43]O)[CH2:42][CH2:41][CH2:40][CH2:39]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:13][C:14]([C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([CH3:34])([CH3:36])[CH3:35])=[CH:31][CH:32]=1)=[CH:21][CH:20]=2)=[O:15])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:43][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:10][CH:11]=1
Reactant: OCC1CCCC1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCC2CCCC2)cc1)NC(=O)c1cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2cn1
Yield: 46.5 %

Procedure:
To a solution of 50 mg (0.1 mmol) of (2S)-{[6-(4-tert-butyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-3-(4-hydroxy-phenyl)-propionic acid methyl ester (Example 298) in dry THF (1 mL) was added cyclopentanemethanol (1.5 eq., 0.15 mmol, 0.016 mL), triphenylphosphine (1.5 eq., 0.15 mmol, 39 mg) and DIAD (1.5 eq., 0.15 mmol, 0.030 mL) according to the procedure M. Chromatography on silica using 20-30% ethyl acetate in hexanes afforded 27 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C[O-].[Na+].CO>C(Cl)Cl.CO>[CH3:17][N:18]1[CH2:23][CH2:22][C:21]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([S:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH:9]=3)[NH:13][CH:12]=2)=[CH:20][CH2:19]1
Reactant: c1ccc(Sc2ccc3[nH]ccc3c2)nc1
Reactant: CN1CCC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CC=C(c2c[nH]c3ccc(Sc4ccccn4)cc23)CC1

Procedure:
5-(Pyrid-2-ylthio)indole (0.347 g, 1.53 mmol), 1-methylpiperid-4-one (0.347 g, 0.38 mL, 3.06 mmol), sodium methoxide (0.497 g) and some finely ground molecular sieves were heated in refluxing MeOH (20 mL) for 24 hr. After work-up and chromatography (silica gel; CH2Cl2 /MeOH; 0-15%), 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole was obtained as a yellow solid (0.35 g). This was treated with fumaric acid (0.189 g, 1.6 mmol) in MeOH/Et2O to give, as a pale yellow crystalline solid: 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole fumarate, 0.227 g (34%), m.p. 226°-28° C.
Reaction SMILES: [CH2:1]([Li])CCC.O=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:11]([O:12][CH3:13])[C:9]=1[OH:10]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:13][O:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:8]([CH:7]=[CH2:1])[C:9]=1[OH:10]
Reactant: COc1cccc(C=O)c1O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc(OC)c1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (19.7 g, 55.0 mmol) in anhydrous tetrahydrofuran (200 mL) was cooled to 0° C. and n-butyllithium (2.5 M in hexanes, 24.0 mL, 60.0 mmol) was added during 5–10 minutes with stirring. The resulting clear, orange solution was stirred at 0° C. for an additional 30 minutes and then was added via cannula to a solution of o-vanillin (3.80 g, 25.0 mmol) in tetrahydrofuran (100 mL) at 23° C. After 3 hours, the reaction was quenched with saturated aqueous ammonium chloride solution (100 mL), diluted with water (300 mL), and the aqueous phase was extracted with ether (3×200 mL). The organic phase was washed with water (300 mL) and brine (300 mL), dried over magnesium sulfate and filtered through a plug of silica gel (10 cm diam×5–6 cm H). Concentration under reduced pressure provided crude 2-methoxy-6-vinyl-phenol as a clear, colorless oil (4.20 g) that was used without further purification. 1H NMR (DMSO): δ3.79 (s, 3 H, OCH3), 5.19 (dd, 1H, CH═CHH), 5.74 (dd, 1H, CH═CHH), 6.74 (t, 1H, ArH), δ6.86 (dd, 1H, ArH), 6.96 (dd, 1H, CH═CHH), 7.04 (dd, 1H, ArH), and 8.74 (s, 1H, ArOH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O-:10])=[O:9].[Na+].Br[C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[CH2:23][CH:24]4[NH:28][CH:27]([C:16]=3[C:15]=2[C:14]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]4>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[CH2:23][CH:24]4[NH:28][CH:27]([C:16]=3[C:15]=2[C:14]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]4)(=[O:10])=[O:9]
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: Cc1ccccc1S(=O)[O-]
Agent: [Na+]
Product: Cc1ccccc1S(=O)(=O)c1ccc2c(c1C(=O)OC(C)(C)C)c1c(n2C)CC2CCC1N2
Yield: 17 %

Procedure:
Intermediate 19 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(2-methylphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (45 mg, 17%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.18 (dd, J=7.4, 1.5 Hz, 1H), 7.95 (dd, J=7.8, 1.8 Hz, 1H), 7.16-7.71 (m, 5H), 5.24 (br s, 1H), 4.70 (br s, 1H), 3.60 (s, 3H), 3.38 (br s, 1H), 2.50 (d, J=15.9 Hz, 1H), 2.49 (s, 3H), 2.26-2.47 (m, 1H), 2.13-2.26 (m, 1H), 1.88-1.99 (m, 1H), 1.59-1.67 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:13][O:14][C:15](=[O:37])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:33]=[C:32]([Br:34])[CH:31]=[C:30](Br)[CH:29]=2)=[CH:20][C:19]=1[CH3:36]>CN(C=O)C.C(N(CC)CC)C.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.[Cu]I>[CH3:13][O:14][C:15](=[O:37])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:29]=[C:30]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][CH:4]=3)[CH:31]=[C:32]([Br:34])[CH:33]=2)=[CH:20][C:19]=1[CH3:36]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(Br)c2)cc1C
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 75 °C

Procedure:
A mixture of 1-ethynyl-4-trifluoromethyl-benzene (149 mg, 0.88 mmol), {4-[3-(3,5-dibromo-phenyl)-prop-2-ynyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (412 mg, 0.88 mmol, intermediate 2), Pd(PPh3)2Cl2 (101 mg, 0.088 mmol), CuI (46 mg, 0.246 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 20 min. at 75° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using methylene chloride/heptanes mixtures to give (4-{3-[3-bromo-5-(4-trifluoromethyl-phenylethynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 94 mg (19%) yield.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=3[OH:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:21][O:22][CH2:23]Cl>CN(C=O)C>[C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=3[O:18][CH2:21][O:22][CH3:23])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a mixture of 2-(1-adamantyl)-4-bromophenol (10.00 g, 32.57 mmol) in DMF (90 mL) cooled to 0° C. was added NaH (1.08 g, 80% in mineral oil, 35.83 mmol) under an atmosphere of argon. The mixture was allowed to warm to room temperature and subsequently stirred for 30 minutes. The resulting mixture was cooled to 0° C. and chloromethyl methyl ether (2.72 mL, 35.83 mmol) was added dropwise. After 14 hours at room temperature and the reaction mixture was poured into ice water and extracted with EtOAc (2×150 mL). The combined organic layers were washed water (100 mL), brine (100 mL), dried (MgSO4) and filtered. The solvent was removed under reduced pressure and the resulting solid was purified on silica gel (hexane:ethyl acetate 99:1 to 97:3) to give 8.6 g (76%) of 3-(1-adamantyl)-4-methoxymethoxy-bromobenzene. 1H NMR (300 MHz; CDCl3): δ 1.77 (s, 6H), 2.08 (s, 9H), 3.50 (s, 3H), 5.19 (s, 2H), 6.98 (d, J=8.7 Hz, 1H), 7.24 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H).