Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7]Cl.[C-:14]#[N:15].[Na+].ClCCl.CS(C)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7][C:14]#[N:15]
Reactant: [C-]#N
Reactant: COCOc1ccc(Br)cc1CCl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: COCOc1ccc(Br)cc1CC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
To a mixture of 5-bromo-2-methoxymethoxybenzyl chloride (21.6 g), sodium cyanide (8.33 g) and dichloromethane (10 ml) was added, at 15° to 20° C., DMSO (80 ml), followed by stirring for 3 hours at room temperature. The mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried (anhydrous magnesium sulfate) and concentrated to leave an oily product. The oily product was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 5-bromo-2-methoxymethoxybenzyl cyanide (20.4 g), whose spectrum data are shown below.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C@H:7]([CH2:12][OH:13])[CH2:8][CH2:9][CH2:10]Cl)=[N+:2]=[N-:3].[CH3:22]OS(OC)(=O)=O>CN(C=O)C>[N:1]([CH2:4][C@@H:5]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C@H:7]1[CH2:8][CH2:9][CH2:10][O:13][CH2:12]1)=[N+:2]=[N-:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@H](CO)CCCCl
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
The tert-butyl (2S,4R)-1-azido-7-chloro-4-(hydroxymethyl)heptan-2-ylcarbamate (1.59 g, 4.97 mmol, 1.0 equiv) was dissolved in 15 mL of DMF and the solution cooled to 0° C. A solution of NaNTMS2 (1.0 M, 14.9 mmol, 3.0 equiv) was added via syringe at such a rate that the internal reaction temperature remains below 5° C. After stirring for 2 h LC/MS analysis showed formation of the cyclised product. Dimethylsulfate (940 mg, 0.71 mL, 7.5 mmol, 1.5 equiv) was added and the reaction mixture stirred overnight with concomitant warming to ambient temperature. LC/MS analysis showed formation of the desired methylated carbamate. The reaction was quenched by addition of 10% K2CO3 solution (˜30 mL) and the mixture stirred for 0.5 h. The volatile materials were removed in vacuo and the residue partitioned between EtOAc/water. The layers were separated and the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. The product was purified by flash chromatography on silica (40 g), eluting with 0-7% EtOAc in hexanes. This afforded 1.21 g (82% yield) of the desired tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate as a colorless liquid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](=[O:39])[C:30]3[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:31]=3[F:38])[N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>C(Cl)Cl>[F:36][C:35]1[CH:34]=[C:33]([F:37])[CH:32]=[C:31]([F:38])[C:30]=1[C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)[N:23]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(OC2CCNCC2)n1)c1c(F)cc(F)cc1F
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
Add trifluoroacetic acid (20 mL) to a solution of 4-[6-(2,4,6-trifluoro-benzoylamino)-pyridin-2-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (preparation 92, 2.482 g, 5.5 mmol) in methylene dichloride (50 mL) and stir for 30 min. Remove volatiles, dissolve the residue in methylene dichloride, adjust pH>11 with 1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Recrystallization (ethanol-H2O) provides 1.625 g of the title compound as a white solid. Concentrate themother liquor and further purify by chromatography (silica gel, eluting with 5.5% 2M NH3-methanol in CH2Cl2) to provide another 200 mg (total yield 94%) of the title compound: mass spectrum (ion spray): m/z=352.0 (M+1); 1H NMR (CDCl3, ppm): 8.35 (br, 1H), 7.68 (d, br, 1H), 7.46 (t, 1H), 6.60 (m, 2H), 6.34 (d, 1H), 4.84 (m, 1H), 2.93 (m, 2H), 2.59 (m, 2H), 1.85 (m, 2H), 1.46 (m, 3H).
Reaction SMILES: O[CH:2]([CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH:3]1[C:7](=[O:8])[C:6]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])=[C:5]([O:18]C)[CH2:4]1>CC(C)=O.Cl>[O:23]1[CH2:22][CH2:21][CH:20](/[CH:2]=[C:3]2/[C:7](=[O:8])[CH:6]([C:9]3[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=3[CH3:15])[C:5](=[O:18])[CH2:4]/2)[CH2:25][CH2:24]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CCOCC2)C1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(C)c(C2C(=O)C/C(=C\C3CCOCC3)C2=O)c(C)c1
Temperature: 130 °C
Yield: 81.9 %

Procedure:
To a solution of 5-[hydroxy-(tetrahydro-pyran-4-yl)-methyl]-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (408 mg, 1.18 mmol) in acetone (2 ml) is added a 2N solution of hydrochloric acid (2 ml) and the resulting solution is heated to 130° C. by microwave irradiation for 90 minutes. The reaction mixture was diluted with 2N hydrochloric acid (25 ml), and extracted with ethyl acetate (2×25 ml). The combined organics are washed with brine (25 ml), dried over magnesium sulphate, filtered and concentrated in vacuuo to give 4-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (302 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5].CCN(C(C)C)C(C)C.[CH2:27](Cl)[O:28][CH3:29]>C(Cl)Cl>[CH3:27][O:28][CH2:29][O:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5]
Reactant: COCCl
Reactant: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(OC2CCCCO2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.1 %

Procedure:
To a solution of 2-hydroxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (10.4 g, 44.0 mmol) in DCM (100 mL) at 0° C. was added DIPEA (11.5 mL, 66.0 mmol) followed by MOMCl (5.0 mL, 66.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography (hexane:EtOAc 70:30) to give 2-methoxymethoxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (10.0 g, 81%). 1H NMR (400 MHz, CDCl3): δ 10.52 (s, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.55 (d, J=1.6 Hz, 1H), 5.51 (t, J=3.2 Hz, 1H), 5.25 (q, J=6.8 Hz, 2H), 3.87-3.81 (m, 1H), 3.65-3.61 (m, 1H), 3.51 (s, 3H), 2.57 (s, 3H), 2.04-1.58 (m, 6H). MS (ESI) m/z=281 [M+H]+.
Reaction SMILES: Cl.C(O)(=O)C.[F:6][C:7]1[C:16]([CH3:17])=[C:15]([N+:18]([O-:20])=[O:19])[C:14]([F:21])=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10]>O>[F:6][C:7]1[C:16]([CH3:17])=[C:15]([N+:18]([O-:20])=[O:19])[C:14]([F:21])=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])c(C)c1F
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)c(C(=O)O)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.4 %

Procedure:
Concentrated hydrochloric acid (15 ml) and acetic acid (5 ml) were added to methyl 2,5-difluoro-3-methyl-4-nitrobenzoate (9.1 g), and the mixture was heated under reflux for 3 hours. After the reaction mixture was cooled back to room temperature, water was added to conduct extraction with diethyl ether. After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (6.1 g) as a brown oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:17])([F:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH3:19].Cl>ClCCl>[CH2:18]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[C:24]([CH:25]=1)[C:11]([C:10]1[CH:14]=[CH:15][C:7]([C:6]([F:17])([F:16])[F:5])=[CH:8][CH:9]=1)=[O:12])[CH3:19]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCc1ccc(OC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(OC)c(C(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Aluminium chloride (0.6 g, 0.004 mole) was stirred in dichloromethane (2 ml) and treated with 4-trifluoromethylbenzoyl chloride (1 g, 0.0048 mole) (ice-bath cooling) and then with 4-ethylanisole (0.6 g, 0.0044 mole) in dichloromethane (1 ml). The mixture was stirred at room temperature overnight and then poured into ice and concentrated hydrochloric acid and extracted with chloroform. The chloroform solution was washed with 10% NaHCO3 solution (100 ml), dried (MgSO4), filtered and evaporated to leave 5-ethyl-2-methoxy-4'-trifluoromethylbenzophenone (1.2 g) as a yellow oil. The latter was heated in 55% aqueous hydrogen bromide (27.5 ml) at 110°-120° C. for 5 hours. The mixture was evaporated to dryness to leave the required product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[CH:10]2)=[CH:5][CH:4]=1)[CH3:2]>ClCCl.[O-2].[Mn+4].[O-2]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-n2cncc2CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCc1ccc(-n2cncc2C=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of [1-(4-ethylphenyl)-1H-imidazol-5-yl]methanol (C18) (2.50 g, 12.4 mmol) in dichloromethane (15 mL) was treated with activated manganese(IV) oxide (96%, 11.1 g, 123 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then filtered through Celite and the filter pad was washed with dichloromethane. The combined filtrates were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification was carried out by chromatography on silica gel (Gradient: 30% to 80% ethyl acetate in heptane) to afford the product. Yield: 1.8 g, 9.0 mmol, 73%. LCMS m/z 201.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.31 (t, J=7.6 Hz, 3H), 2.75 (q, J=7.6 Hz, 2H), 7.26-7.30 (m, 2H, assumed; partially obscured by solvent peak), 7.32-7.36 (m, 2H), 7.77 (dd, J=0.8, 0.8 Hz, 1H), 7.94 (d, J=0.9 Hz, 1H), 9.76 (d, J=0.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]3[C:15]([NH2:16])=[N:14][NH:13][C:9]3=[N:10]2)=[CH:5][CH:4]=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]3[C:15]([NH2:16])=[N:14][N:13]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:9]3=[N:10]2)=[CH:5][CH:4]=1
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc2cc3c(N)n[nH]c3nc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc3c(N)nn(CCN4CCOCC4)c3nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
A mixture of 17.1 g 7-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine (Example 3d), 15.25 g 4-(2-chloroethyl)morpholine hydrochloride, 7.2 g sodium hydride and 500 ml dimethylformamide was stirred at room temperature for about 16 hours. The solvent was then removed by evaporation, and the residue dissolved in 1N hydrochloric acid and extracted with ethyl acetate. The aqueous layer was made basic with carbonate to pH 8 and extracted with chloroform. The chloroform extracts were washed with water, dried over magnesium sulfate and passed through a silica gel pad. The pad was eluted with warm ethyl acetate, the product isolated and recrystallized from ethyl acetate to give 9.2 g 7-methoxy-1-[2-(4-morpholinyl)ethyl]-1H-pyrazolo[3,4-b]quinolin-3-amine, orange solid, m.p. 166°-168° C.
Reaction SMILES: COC(=O)[NH:4][C:5]12[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:9][O:8][C:7]1[CH:15]=[CH:16][CH:17]=[CH:18][C:6]2=1.C[Si](C)(C)[O-].[K+].[ClH:26]>>[ClH:26].[CH:18]1[C:6]2[C:5]3([NH2:4])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]3[CH2:9][O:8][C:7]=2[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)NC12CCCCC1COc1ccccc12
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: NC12CCCCC1COc1ccccc12

Procedure:
A solution of the compound from Example 72 (0.3 g, 1.15 mmol) and potassium trimethylsilanolate (0.3 g, 2.34 mmol) was refluxed for 21 hours. Workup followed by treatment of the free amine with isopropanolic HCl gave the title compound (0.24 g), mp 230°-232° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O>[CH3:15][S:16]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])(=[O:18])=[O:17]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
24.11 G (0.2041 mol) of ethyl L-(+)-lactate and 50 ml of anydrous pyridine were stirred in an ice bath. 17.0 Ml (25.2 g, 0.220 mol) of methanesulfonyl chloride was added dropwise over a period of 20 minutes, and the mixture was stirred for 1 hour at the same temperature and for 1 hour at room temperature. 200 Ml of water was added, and extraction was performed with methylene chloride (50 ml, 3 times). The extract was washed with water (50 ml), then dried with anhydrous magnesium sulfate, and vacuum concentrated. The red-colored oily residue was vacuum distilled, and 32.20 g of ethyl (-)-2-methanesulfonyloxypropionate was obtained in the form of a colorless liquid with bp 97°-102° C./2 Torr. Yield 82.0%.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[CH2:2][CH2:3][CH3:4].[C:14](Cl)([Cl:16])=[O:15]>C1(C)C=CC=CC=1>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]([Cl:16])=[O:15]
Reactant: CCCCNc1c(C)cccc1C
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCN(C(=O)Cl)c1c(C)cccc1C

Procedure:
To a suspension of 31.5 g. of N-butyl-2,6-dimethylaniline in 400 ml. of toluene is added 50 ml. of phosgene. The solution is heated to reflux and refluxed for 30 minutes. The solvent is then allowed to distill off (ca 350 ml.) and then cooled. The solution is evaporated in vacuo to a light oil which is then dissolved into hexane, filtered and the hexane evaporated off in vacuo to give a milky oil which is then distilled to give 2,6-dimethyl-N-butylphenylcarbamoyl chloride (b.p. 105° C./0.1 mm)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:30](=[O:33])[CH:31]=[CH2:32])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of 1.26 g (4.27 mmol) of the resulting compound (9) and 1.8 ml (24.8 mmol) of anhydrous triethylamine dissolved in 20 ml of tetrahydrofuran under argon atmosphere was added dropwise 5 ml of an tetrahydrofuran solution containing 0.38 ml (4.08 mmol) of acryloyl chloride. The whole was stirred at room temperature overnight, thereby a salt precipitated. After addition of water to the reaction mixture, the whole was extracted with diethyl ether. The extract was purified by silica gel column chromatography. The resulting pale yellow solid was recrystallized from methanol to obtain 1.01 g of 4-cyano-4'-(6-acryloxyhexyloxy)biphenyl (10) (yield: 67.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:28])=[C:12]([CH2:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18][N:17]=3)[CH:13]=2)[NH:8][C:7]=1[CH3:29])=[O:5])[CH3:2].N1C=CC=CC=1.[C:36](OC=O)(=[O:41])C(C)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:28])=[C:12]([CH:15]=[C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18][N:17]3[CH:36]=[O:41])[CH:13]=2)[NH:8][C:7]=1[CH3:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2cc(Br)c(CC3=NCCc4cc(OC)ccc43)cc12
Reactant: CC(C)(C)C(=O)OC=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C)[nH]c2cc(Br)c(C=C3c4ccc(OC)cc4CCN3C=O)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a solution of 6-bromo-5-(6-methoxy-3,4-dihydro-isoquinoline-1-ylmethyl)-2-methyl-1H-indole-3-carboxylic acid ethyl ester (2.03 g, 4.5 mmol) in CH2Cl2 (50 mL) is added pyridine (2.3 g, 30 mmol) and 3N formic pivalic anhydride (5 mL; 14.5 mmol) at 0° C., and the reaction is stirred at room temperature for 3 hours. CH2Cl2 (50 mL) is then added to the reaction mixture and the organic layer is washed with water (2×50 mL), IN HCl (50 mL), 1N NaOH (50 mL), and brine (50 mL). The solution is dried (Na2SO4), filtered, and concentrated in vacuo to give the desired product (1.3 g, 60%). MS: 483, 485 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21]C(OCC2C=CC=CC=2)=O)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H][H].C(Cl)Cl.C1COCC1>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH2:21])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCCN)cc1
Yield: 76.2 %

Procedure:
{4-[4-(2-Benzyloxycarbonylaminoethoxy)phenyl]butyl}carbamic acid tert-butyl ester 15 (61.8 g) was stirred in ethanol (500 ml) with 10% palladium on carbon (6 g, wet), under one atmosphere of hydrogen. After stirring for more than 6 h, TLC (silica gel, methylene chloride/THF, 20:1) indicated reaction completion. The complete reaction was flushed with nitrogen, and suction filtered through a pad of Celite, and the pad washed with methylene chloride. The residue (41 g) after evaporation of the methylene chloride was applied to an 800 g pad of silica gel, and sequentially eluted with a mixture of THF and methylene chloride (1.4 L, 2:1), and a mixture of methylene chloride, methanol, and concentrated ammonium:hydroxide (30:10:1, 2 L). The fraction containing the product was collected. Evaporation afforded the pure product 16 (32.8 g, 74% over 2 steps). 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.50 (br s, 2H), 1.55 (m, 4H), 2.56 (t, 2H), 3.12 (m, 2H), 3.50 (m, 2H), 3.98 (t, 2H), 4.75 (br s, 1H), 5.00 (br s, 1H), 5.09 (s, 2H), 6.80 (d, 2H), 7.06 (d, 2H), 7.34 (m, 5H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=O)C2C=CC=CC=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C:39]#[CH:40]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([NH:37][CH2:38][C:39]#[CH:40])=[O:33])[C:15]2[CH:24]=[CH:23][CH:22]=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: C#CCN
Product: C#CCNC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 183 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 49 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 536 [M+H]+.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])([O:4][CH2:5][CH3:6])[CH2:2][CH3:3].N1C=CC=CC=1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl>[CH2:11]([O:10][C:1]([O:4][CH2:5][CH3:6])([O:7][CH2:8][CH3:9])[CH:2]([Br:19])[CH3:3])[CH3:12]
Reactant: CCOC(CC)(OCC)OCC
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(OCC)(OCC)C(C)Br
Reaction time: 24 h
Yield: 80.7 %

Procedure:
A solution of 176 g (1 mole) of triethyl orthopropionate and 96 g (1.2 moles) of pyridine in 1 l of carbon tetrachloride was placed in a 2 l flask and 160 g (1 mole) of bromine was slowly added over two hours to the solution under ice-cooling. The resultant reaction mixture was allowed to stand at room temperature for one day to form a precipitate, which was then filtered off. The filtrate was concentrated by evaporation of the solvent and the residue was subjected to distillation under reduced pressure to afford 206 g (81%) of 1,1,1-triethoxy-2-bromopropane with a boiling point of 85° C./13 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:13]=[C:12]2[CH:26]=[C:27]1[S:31][C:30](=[O:32])[NH:29][C:28]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:13]=[C:12]2[CH2:26][CH:27]1[S:31][C:30](=[O:32])[NH:29][C:28]1=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cn(-c3ccc(Cl)c(Cl)c3)c3ccc(OCc4ccccc4)cc23)S1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(Cc2cn(-c3ccc(Cl)c(Cl)c3)c3ccc(OCc4ccccc4)cc23)S1

Procedure:
To oven-dried SiO2(150 mg) in toluene (2 mL) was added 50 mg of the thiazolidinylidene olefin (Example 1) with diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (25 mg). The mixture was stirred and heated at 70-90° for 3 days. Mass spectral monitoring indicated the reaction was complete. Silica was filtered and washed with EtOAc and combined volatiles were removed under reduced pressure to a residue. The solid dissolved in ether and solids were filtered and discarded. Ether was evaporated and residue was washed with hexanes and air-dried to afford the reduction product; ms: m/e 512 (M+1); HPLC ˜70% pure.
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH2:12][CH2:13][C:7]=2[C:6]([O:26]C)=[C:5]([O:28][CH3:29])[C:4]=1[O:30][CH3:31].N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.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+]>O>[CH3:29][O:28][C:5]1[C:6](=[O:26])[C:7]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:24][CH:25]=3)[CH2:10][CH2:9][C:8]=2[C:3](=[O:2])[C:4]=1[O:30][CH3:31]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccc(C(=O)O)cc1)CC2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(C(=O)O)cc3)CC2)C1=O
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a mixture of 4-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethoxy]benzoic acid (1.00 g), 2,6-pyridinedicarboxylic acid (1.16 g), THF (40 ml), and water (10 ml) was dropwise added a solution of CAN (5.09 g) in water (10 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with combined solvent of ethyl acetate and THF. The organic layer was washed with water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo. The residue was recrystallized from THF-ethyl acetate to yield the entitled compound (400 mg) as crystals.