Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[CH2:12]([O:19][C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1
Yield: 73.1 %

Procedure:
A solution of 6-aminocaproic acid (13.1 g, 0.10 mole) in 2.5 N NaOH (40 ml, 0.10 mole) was cooled to 0° and benzyloxycarbonyl chloride (18.7 g, 0.11 mole) in ether (25 ml and 2.5N NaOH (50 ml, 0.125 mole) were added simultaneously in several portions, with vigorous stirring, over a 1 hr period. The reaction mixture was extracted with ether (3 × 50 ml), cooled in an ice-bath and acidified with 6M HCl. The crystalline product was recrystallized from ether-pet ether to give 19.4 g of product (73.2%); mp 54°-55.5°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.[B:15](OC)([O:18]C)[O:16]C.Cl>C(OCC)C.CCCCCC>[Br:1][C:2]1[CH:7]=[C:6]([B:15]([OH:18])[OH:16])[CH:5]=[C:4]([Br:9])[CH:3]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To 9.44 g of 1,3,5-tribromobenzene in 200 mL of diethyl ether was added 19.4 mL of 1.55 M n-butyllithium in hexane at -78° under nitrogen. The suspension was stirred for 30 min, then added to 30 mL of trimethyl borate in 300 mL of diethyl ether at the same temperature. The now clear solution was stirred at -78° for 30 min then warmed to room temperature overnight. Fifty mL of 1 N hydrochloric acid were added and allowed to react for 2 h. The aqueous layer was discarded and the ether layer was extracted with 2 N sodium hydroxide solution (5 times with 100 mL). The extract was washed once with 50 mL of ether, then acidified with 6N HCl to pH 2 at 0°. A white precipitate was collected by filtration after the solution had been kept at 0° for 2 h. After air drying, 8.49 g (95%) of the title product was obtained. Melting point was >300° and the purity was confirmed by chromatography.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].[CH3:21][CH:22]([CH2:24][CH2:25][CH2:26][C@H:27]([C@@H:29]1[C@:46]2([CH3:47])[C@H:32]([C@H:33]3[C@H:43]([CH2:44][CH2:45]2)[C@:41]2([CH3:42])[C:36]([CH2:37][C@@H:38]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]I)[CH2:39][CH2:40]2)=[CH:35][CH2:34]3)[CH2:31][CH2:30]1)[CH3:28])[CH3:23].C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][O:48][C@H:38]1[CH2:39][CH2:40][C@@:41]2([CH3:42])[C:36](=[CH:35][CH2:34][C@@H:33]3[C@@H:43]2[CH2:44][CH2:45][C@@:46]2([CH3:47])[C@H:32]3[CH2:31][CH2:30][C@@H:29]2[C@H:27]([CH3:28])[CH2:26][CH2:25][CH2:24][CH:22]([CH3:23])[CH3:21])[CH2:37]1)(=[O:3])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@H]1OC(C)=O
Yield: 61 %

Procedure:
2,3,4-Tri-O-acetyl-1-thio-β-L-fucopyranose (10 mmol) is treated with 6-(5-cholesten-3β-yloxy)hexyl iodide (10 mmol) in dichloromethane (30 ml) containing triethylamine (10 mmol). The reaction takes place in 1 day at room temperature under nitrogen. The resulting solution is washed with distilled water (20 ml) and dried with anhydrous sodium sulfate. The filtered solution is concentrated to form a syrup which is put on a silica gel column and eluted with chloroform followed by 1.0% ethanol in chloroform. The fractions containing the title compound, as determined by thin layer chromatography, are pooled and evaporated to give the title compound in 61% yield [α]D -4° (c 1.5, chloroform).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH2:20][SH:21])[NH:5][CH2:6][C:7]([S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:9])[CH3:8].[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>C(Cl)(Cl)Cl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][S:10][C:7]([CH3:9])([CH3:8])[CH2:6][N:5]2[C@H:4]([C:3]([O:2][CH3:1])=[O:22])[CH2:20][S:21][C:23]2=[S:24])=[CH:17][CH:16]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](CS)NCC(C)(C)SCc1ccc(OC)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CSC(=S)N1CC(C)(C)SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
To a solution of N-[2-(4-methoxybenzylthio)-2-methylpropyl]-L-cysteine methyl ester (5.0 g) in chloroform (90ml), thiocarbonyldiimidazole (3.0 g) was added and the mixture was stirred for 1.5 hr at room temperature. The reaction mixture was washed with 3N hydrochloric acid, water and then saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 5.10 g(91%) of (4R)-3-[2-(4-methoxy-benzylthio)-2-methylpropyl]-4-methoxycarbonylthiazolidine-2-thione.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:5]([F:18])[CH:4]=1.[C-:19]#[N:20].[Na+]>CO>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:19]#[N:20])=[CH:4][C:5]=1[F:18]
Reactant: Fc1cc(CBr)ccc1-c1nc2ccccc2o1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Product: N#CCc1ccc(-c2nc3ccccc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1.0 gm. of 2-(4-bromomethyl-2-fluorophenyl)benzoxazole in 50 cc. of dry methanol which has been cooled in an ice-water bath is added 1.5 gm. of sodium cyanide. The reaction mixture is stirred cold for 10 minutes, allowed to warm to room temperature and finally heated on the steam bath. Solution of the starting material occurs and after 5 minutes reflux the reaction mixture is cooled, concentrated to about 25 cc., and poured into 100 cc. of ice cold 2.5 N hydrochloric acid. The resulting precipitate is filtered and air dried to give crude 4-(benzoxazol-2-yl)-3-fluorophenylacetonitrile.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]([OH:21])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(Cl)(Cl)=O.[NH:44]([CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH2:45][C:46]([O:48][CH3:49])=[O:47].C(N(CC)CC)C>C(Cl)Cl>[CH3:54][O:53][C:51](=[O:52])[CH2:50][N:44]([CH2:45][C:46]([O:48][CH3:49])=[O:47])[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCCCCCCCCC
Reactant: COC(=O)CNCC(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(CC(=O)OC)CC(=O)OC)cc1OCCCCCCCCCCCCCC
Reaction time: 18 h
Yield: 89.8 %

Procedure:
A solution of 0.8 g (1.46 mmol) of 3,4-bis(tetradecyloxy)benzoic acid and 20 ml of thionyl chloride was stirred at reflux for 3 hours. The excess thionyl chloride was removed at reduced pressure and the resultant acid chloride was dissolved in 10 ml of methylene chloride and 10 ml of anhydrous THF. This solution was added dropwise to a stirred, ice cooled mixture of 0.3 ml (1.86 mmol) of dimethyl iminodiacetate and 0.41 ml (2.9 mmol) of triethylamine in 10 ml of anhydrous methylene chloride. The cooling bath was removed after 30 minutes and the mixture was left at room temperature for 18 hours. The solvents were removed at reduced pressure and the residue was extracted with ethyl acetate. The extract was washed successively with 1N HCl, with NaHCO3 solution, dried and concentrated. Crystallization from ethyl acetate-hexane gave 0.905 g (90% yield, mp 70°-71°) of N-(2-methoxy-2-oxoethyl)-N-[3,4-bis(tetradecyloxy)benzoyl]glycine methyl ester.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14](O)=O)[CH2:4][S:3]1.C1(N=C=N[CH:26]2[CH2:31]CCCC2)CCCCC1.C([SH:34])C>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:31]([C:14]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[S:34])[CH3:26]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCS
Reactant: O=C(O)[C@@H]1CSC(=O)N1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCC(=S)[C@@H]1CSC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 200 ml of acetonitrile was dissolved 10 g of (4R)-2-oxo-3-benzylthiazolidin-4-carboxylic acid, and 9.2 g of dicyclohexylcarbodiimide was added to the solution under room temperature. Subsequently, to the solution were added 3.3 ml of ethanethiol, and 670 mg of 4-dimethylaminopyridine in this order under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=10:1) to give 10.8 g of (4S)-4-ethylthiocarbonyl-3-benzylthiazolidin-2-one as oily product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]#[N:10].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH2:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH:4]=1)[C:9]#[N:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-bromo-3-cyanophenol (1 g, 5.05 mmol) was dissolved in DMF (10 ml) and K2CO3 (1.40 g, 10.10 mmol) and benzyl bromide (0.66 ml, 5.56 mmol) added. The mixture was stirred under N2 for 1 hr at RT. The mixture was diluted with water (15 mL) and extracted with EtOAc (2×10 mL). The organic fractions were combined, washed with brine (saturated, 1×8 mL), dried over MgSO4, filtered and the volatiles removed in vacuo. The residue was purified by chromatography on silica gel Biotage 25M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 289 (M+H)+.
Reaction SMILES: O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]=[C:19]([CH2:25][OH:26])[C:18]2=[O:27].O>C(O)(=O)C>[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]=[C:19]([CH:25]=[O:26])[C:18]2=[O:27]
Reactant: O=c1c(CO)coc2ccc(Br)cc12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1coc2ccc(Br)cc2c1=O
Temperature: 40 °C

Procedure:
A warm (40° C.) solution of 29.8 g. (0.1 mole) of sodium dichromate dihydrate in 80 ml of glacial acetic acid is added over a 5-minute period to a stirred, warm (60° C.) solution of 25.5 g. (0.1 mole) of 6-bromo-3-(hydroxymethyl)chromone in 300 ml of glacial acetic acid. The temperature rises to 72° C. After one-half hour, water (1400 ml) is added and the mixture is heated at 80° C. for a few minutes. The mixture is cooled and filtered to give 13.6 g. (54%) of good quality aldehyde. Recrystallization from ethyl acetate gives pure 6-bromo-3-formylchromone having mp 186°-188° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[CH:9]=O)=[CH:4][CH:3]=1.[C:20](=[O:23])(O)[O-:21].[K+].[C:25](NCC(O)=O)(=[O:27])C.C(OC(=O)C)(=O)C.Cl>O.C(O)(=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[CH2:9][C:25](=[O:27])[C:20]([OH:21])=[O:23])=[CH:4][CH:3]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Oc1ccc(F)cc1
Reactant: CC(=O)NCC(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)C(=O)Cc1cc([N+](=O)[O-])ccc1Oc1ccc(F)cc1

Procedure:
183.4 G. of 2-(4-fluoro-phenoxy)-5-nitro-benzaldehyde are stirred at reflux for 20 minutes together with 71 g. of potassium bicarbonate and 82 g. of acetylglycine in 395 ml. of acetic anhydride. Then, there are added successively 1.62 liters of glacial acetic acid, 870 ml. of water and 675 ml. of concentrated hydrochloric acid, and the mixture is stirred for 5 hours at reflux. The resulting mixture is cooled and 1.2 liters of water are added. The mixture is extracted with 3.1 liters of methylene chloride in 3 portions. The methylene chloride solutions are washed twice with 2 liters of water each time and subsequently extracted with a solution of 250 g. of sodium carbonate in 4.5 liters of water. The obtained bicarbonate solutions are acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solutions are dried over sodium sulfate and evaporated in vacuo. The crystalline residue is boiled out with 400 ml. of benzene. The crystals are removed by filtration and there is obtained 2-(4-fluoro-phenoxy)-5-nitro-phenylpyruvic acid having a melting point of 142°-143° C. By concentration of the filtrate, there is obtained an additional amount of this compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]=1[CH3:12])=[O:3].C1(=O)OC(=[O:17])C=C1.[H][H]>>[CH3:1][C:2]([C:4]12[O:17][C:5]1([CH3:12])[CH2:6][CH2:7][CH2:8][C:9]2([CH3:11])[CH3:10])=[O:3]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(=O)C1=C(C)CCCC1(C)C
Reactant: [H][H]
Product: CC(=O)C12OC1(C)CCCC2(C)C
Yield: 95 %

Procedure:
8.3 g (0.05 M) of 2,6,6-trimethyl-cyclohex-1-enyl methyl ketone have been treated with maleic anhydride and hydrogen peroxyde according to Example 1, to give, after extraction and purification as described above, 8.5 g (yield 95%) of the desired product, b.p. 85°/6 Torr:
Reaction SMILES: O[CH2:2][C:3]#[C:4][CH2:5][C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].N1C=CC=CC=1.P(Br)(Br)[Br:23]>C(OCC)C>[Br:23][CH2:2][C:3]#[C:4][CH2:5][C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: BrP(Br)Br
Reactant: CCCCCC#CCC#CCC#CCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC#CCC#CCC#CCBr

Procedure:
6 g of 1-hydroxy-2,5,8-tetradecatriyne prepared above, dissolved in 30 cm3 of ethyl ether, are introduced into a round-bottomed flask equipped with an argon inlet. 0.05 cm3 of pyridine is added and 1 cm3 of phosphorus tribromide is added dropwise, and the mixture is then brought to reflux for 3 hours.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[CH3:35][N:36]([C:38](ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:37].F[P-](F)(F)(F)(F)F.[C:59]([N:66]1[CH2:71][CH2:70][CH:69]([NH2:72])[CH2:68][CH2:67]1)([O:61]C(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:72][CH:69]5[CH2:68][CH2:67][N:66]([C:59](=[O:61])[CH2:35][N:36]([CH3:38])[CH3:37])[CH2:71][CH2:70]5)=[O:30])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:6][CH2:5][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C=C[C@@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)CN(C)C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-Boc-4-aminopiperidine. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml). The resulting product was further acylated using N,N-dimethylacetyl chloride. The title product using preparative HPLC and neutralized with bicarbonate. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-2.05 (m, 12 H) 2.19 (s, 6 H) 2.92-3.21 (m, 4 H) 3.28 (s, 3 H) 3.72-3.87 (m, 2 H) 3.94 (s, 3 H) 3.99-4.20 (m, 2 H) 4.36 (d, J=15.41 Hz, 1 H) 4.89 (d, J=8.34 Hz, 1 H) 5.31-5.45 (m, 2 H) 6.01 (ddd, J=17.49, 12.69, 10.74 Hz, 1 H) 7.47 (d, J=1.77 Hz, 2 H) 7.83 (s, 1 H) 8.15 (d, J=7.83 Hz, 2 H) 8.31 (d, J=8.08 Hz, 1 H). [M+H] calc'd for C32H43FN8O4, 623; found 623.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N:19]=[N+]=[N-])[C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10])[NH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13]2
Reactant: COC(=O)C(=Cc1cc(OC)c(OC)c(OC)c1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2cc(OC)c(OC)c(OC)c2[nH]1

Procedure:
Xylene (15 mL) was placed in a three-necked flask and stirred under reflux, and a xylene solution (30 mL) of methyl 3-(3,4,5-trimethoxyphenyl)-2-azidopropenoate (1.2 g) was added dropwise over 3 hours. The reaction mixture was refluxed for 1 hour and concentrated under reduced pressure. Water was added to the residue to conduct extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane 1:3) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[C:9](=[O:14])[NH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][C:5]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][C:3]=1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=1.N1C=CC=C[CH:33]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:15]([C:5]1[CH:6]=[C:7]([C:8]2[C:9]([O:14][CH3:33])=[N:10][CH:11]=[CH:12][CH:13]=2)[C:2]([NH:1][C:38](=[O:40])[CH3:39])=[C:3]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)[CH:4]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: c1ccncc1
Reactant: CC(C)(C)c1cc(CCc2ccc(NS(C)(=O)=O)cc2)c(N)c(-c2ccc[nH]c2=O)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(CCc2ccc(NS(C)(=O)=O)cc2)c1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
step 6—To solution of 88 (0.087 g, 0.19 mmol) in DCM (5 mL) at 0° C. was added pyridine (23 □L) and followed by acetic anhydride (0.02 mL, 0.23 mmol). The reaction was allowed to warm to RT and stirred overnight then diluted with DCM and saturated aqueous NaHCO3. The aqueous layer was separated and extracted with DCM. The combined extract was washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified on a preparative SiO2 TLC plate developed with 40% EtOAc/hexanes to afford 0.045 g (46%) of N-[4-tert-butyl-2-[2-(4-methanesulfonylamino-phenyl)-ethyl]-6-(2-methoxy-pyridin-3-yl)-phenyl]-acetamide (90) as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:26]=[CH:27][C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[N:29]=3)=[N:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:13][CH:12]=1.CO.[OH-].[K+]>C1COCC1.O>[CH3:34][C:32]1[CH:31]=[C:30]([CH3:35])[N:29]=[C:28]([CH:27]=[CH:26][C:15]2[C:14]3[C:18](=[CH:19][C:11]([NH:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:36])=[O:2])=[CH:12][CH:13]=3)[N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:16]=2)[CH:33]=1
Reactant: COC(=O)c1ccccc1Nc1ccc2c(C=Cc3cc(C)cc(C)n3)nn(C3CCCCO3)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)nc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Temperature: 70 °C

Procedure:
To a stirred solution of 2-[3-[2-(4,6-Dimethyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid methyl ester (1.98 g, 4.11 mmol) in THF:MeOH (12 ml, 3:1) was added Potassium hydroxide (1.15 g, 20.5 mmol) dissolved in H2O (3 ml). The reaction was heated at 70° C. for 2 hr, cooled, concentrated under reduced pressure to about 5 ml and diluted with more water. The solution was neutralized with 2N HCl and the precipitate was collected by filtration and washed with water to give 2.00 g (quantitative) of a bright yellow solid. 1H NMR (DSMO-d6) δ 513.12 (1H, broad s), 9.82 (1H, s), 8.13 (1H, d, J=8.7 Hz), 7.95 (1H, dd, J=1.5, 8.0 Hz), 7.89 (1H, d, J=16.4 Hz), 7.60 (1H, s), 7.50 (1H, d, J=16.4 Hz), 7.46 (1H, d, J=6.9 Hz), 7.37 (1H, d, J=7.7 Hz), 7.20 (1H, d, J=8.7 Hz), 7.06 (1 H, s), 6.86 (1H, t, J=6.9 Hz), 5.85 (1H, d, J=7.3 Hz), 3.82 (2H, m), 2.50 (3H, s, obscured by dmso), 2.48 (2H, m), 2.34 (3H, s), 2.03 (2H, m), 1.76 (1H, m), 1.59 (2H, m). Anal. Calcd for C28H28N4O3.0.5 KOH: C, 67.72; H, 5.79; N, 11.28.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH2:3][CH2:2]1.[Cl:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>C(OCC)(=O)C>[Cl-:25].[O:1]1[CH2:6][CH2:5][N:4]([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:15][CH2:14][N+:13]([CH2:26][C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([CH2:18][CH2:17]3)[CH2:12]2)=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCOCC1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccccc1)N1CCOCC1)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.1 %

Procedure:
(R)-Quinuclidin-3-yl 2-morpholino-2-phenylacetate (43 mg, 0.13 mmol) was dissolved in ethyl acetate (1.3 ml) and 2-chloro-1-phenylethanone (22.1 mg, 0.14 mmol) was added. The solution was stirred at room temperature for two days. The solvent was evaporated and the residue was triturated with Et2O to obtain (3R)-3-(2-morpholino-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (53 mg, 84% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][C:52](=[O:54])[CH3:53])=[C:46]([CH:50]=2)[C:47](O)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]>C(Cl)Cl>[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][C:52](=[O:54])[CH3:53])=[C:46]([CH:50]=2)[C:47]([NH:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(OC)c(OC)c(OC)c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.8 %

Procedure:
3,4,5-Trimethoxyaniline (0.216 g, 1.18 mmol), triethylamine (0.119 g, 1.18 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.199 g, 1.18 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.109 g, 0.202 mmol, 38%).