Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[C:9]([O:13][C:14]([N:16]1[CH2:20][CH:19]2[O:21][CH:18]2[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl-].[Na+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH:19]([O:21][S:25]([CH3:24])(=[O:27])=[O:26])[CH:18]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(OCC(F)(F)F)C(OS(C)(=O)=O)C1
Reaction time: 0.33 h

Procedure:
1.08 g (0.027 mole) of a 60% w/w dispersion of sodium hydride in mineral oil was added, whilst cooling with water, to 15 ml of 2,2,2-trifluoroethanol, and the mixture was stirred for 20 minutes. At the end of this time, 5.0 g (0.027 mole) of 1-t-butoxycarbonyl-3,4-epoxypyrrolidine were added to the mixture, which was then heated under reflux for 3 hours. The reaction mixture was then mixed with a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The concentrate was dissolved in 50 ml of pyridine, and 3.23 g (0.028 mole) of methanesulfonyl chloride were added, whilst ice-cooling, to the resulting solution. The mixture was then stirred at room temperature for 5 hours and then allowed to stand overnight at room temperature. After it had been diluted with 300 ml of water, the reaction mixture was extracted with toluene. The organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 9:1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 7.07 g of 1-t-butoxycarbonyl-3-(2,2,2-trifluoroethoxy)-4-methylsulfonyloxypyrrolidine.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([OH:10])[CH2:8][S:9][C@H:4]12.C(N(CC)CC)C.NC(N)=O.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>CC(C)=O>[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43]([NH:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[O:12])=[C:7]([OH:10])[CH2:8][S:9][C@H:4]12)=[O:44]
Reactant: O=C(Cl)Cc1cccs1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Agent: Cl
Agent: NC(N)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C

Procedure:
To a solution of 1.55 g. of p-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate hydrochloride in 30 ml. of acetone containing 364 mg. (0.5 ml., 3.6 mmole) of triethylamine was added962 mg. of urea. With stirring at room temperature, a solution of 730 mg. (4.4 mmole) of 2-thiophene acetyl chloride in 20 ml. of acetone was added dropwise to the mixture. After 2.5 hours the reaction mixture was filteredand evaporated. The residue was dissolved in ethyl acetate and the solutionwas washed successively with water, a 5% solution of sodium bicarbonate, 5%hydrochloric acid, and a saturated solution of sodium chloride. The washed solution was dried and then was concentrated by evaporation in vacuo to yield 1.2 g. of the reaction product as a crystalline residue. The productwas recrystallized from ethyl acetate to yield pure p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate having the following spectral properties.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25]CC)=[O:24])[CH:16]=[N:15]3)[N:9]=2)=[CH:6][C:5]([C:28]([F:31])([F:30])[F:29])=[CH:4][N:3]=1.[CH3:32][C:33]1[CH:34]=[C:35]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH:36]=[CH:37][C:38]=1[CH2:39][OH:40]>>[CH3:32][C:33]1[CH:34]=[C:35]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:48])([F:49])[F:50])=[CH:43][CH:42]=2)[CH:36]=[CH:37][C:38]=1[CH2:39][O:40][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[C:18]([C:19]([F:22])([F:20])[F:21])=[C:17]([C:23]([OH:25])=[O:24])[CH:16]=[N:15]3)[N:9]=2)=[CH:6][C:5]([C:28]([F:30])([F:31])[F:29])=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C(F)(F)F)cnc3F)n2)c1C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ncc(C(F)(F)F)cc1-c1cccc(-n2ncc(C(=O)O)c2C(F)(F)F)n1

Procedure:
The title compound was prepared according to the procedure described in Example 237 Step B, by reaction of the title compound from Example 240 Step A with [3-methyl-4′-(trifluoromethyl)biphenyl-4-yl]methanol (PCT Publication WO2005118542): LCMS m/z 666.8 [M+H]+; 1H NMR (500 MHz, acetone-d6) δ (ppm) 8.78 (d, J=2.3 Hz, 1H), 8.71 (s, 1H), 8.47 (d, J=8.0 Hz, 1H), 8.26 (m, 2H), 8.22 (m, 1H), 7.92 (d, J=8.2 Hz, 2H), 7.88 (m, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.66 (s, 1H), 7.59 (dd, J=7.9, 1.7 Hz, 1H), 5.80 (s, 2H), 2.54 (s, 3H).
Reaction SMILES: C(OC([CH:8]([NH2:44])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:20]([N:22]2[CH2:26][C@@H:25]([CH:27]3[CH2:29][CH2:28]3)[C@H:24]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)[CH2:23]2)=[O:21])[CH:13]=[CH:12]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClC(Cl)C.C1(C)C=CC=CC=1>[NH2:44][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:20]([N:22]2[CH2:26][C@@H:25]([CH:27]3[CH2:29][CH2:28]3)[C@H:24]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)[CH2:23]2)=[O:21])[CH:13]=[CH:12]1
Reactant: CC(C)(C)OC(=O)C(N)CCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a solution of 0.1 g (0.16 mmol) of 1-(N-(3-t-butoxycarbonyl aminopropyl)-7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine in 2 mL of CH2C2 was added 0.3 mL of a 1M solution of TFA in dichloroethane and the reaction mixture was stirred at rt for 24 h. The reaction mixture was then diluted with toluene and concentrated. The residue was purified by chromatography (silica, CHCl3: MeOH: NH3, 90:10:1) to give 0.07 g of the title compound. Mass Spectrum (EI) m/e 503 (M+1).
Reaction SMILES: [CH2:1]([C@H:8]([NH:29][C:30](=[O:70])[C@@H:31]([N:36]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][O:49]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:43]=2)[C:37]1=[O:69])[C@@H:32]([CH3:35])[CH2:33][CH3:34])[C@H:9]([OH:28])[CH2:10][N:11]([S:16]([C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[N:26]/[OH:27])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.Cl>CO>[CH2:1]([C@H:8]([NH:29][C:30](=[O:70])[C@@H:31]([N:36]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][OH:49])[N:43]=2)[C:37]1=[O:69])[C@@H:32]([CH3:35])[CH2:33][CH3:34])[C@H:9]([OH:28])[CH2:10][N:11]([S:16]([C:19]1[CH:20]=[CH:21][C:22](/[CH:25]=[N:26]/[OH:27])=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(CC(C)C)S(=O)(=O)c1ccc(/C=N/O)cc1)N1CCN(Cc2cccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(CC(C)C)S(=O)(=O)c1ccc(/C=N/O)cc1)N1CCN(Cc2cccc(CO)n2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
A solution of the product of Example 286D (0.166 g) in methanol:dichloromethane (2 mL, 3:2) at 0° C. was treated with concentrated HCl (1 mL). The mixture was stirred at 25° C. for 30 min and partitioned into sat NaHCO3 and dichloromethane. The organic layer was separated and dried over NaSO4, filtered, and the solvents were evaporated. The residue was purified using 4% methanol/chloroform to give 69 mg (56%) of the title compound.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[C:7](Cl)(=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[C:10]1([CH:9]=[CH:8][C:7]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)NN
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: CC#N
Product: COC(=O)NNC(=O)C=Cc1ccccc1
Reaction time: 15 h
Yield: 94.8 %

Procedure:
To a solution of 27 g (0.3 moles) of methyl carbazate and 250 ml. of acetonitrile a solution of 50 g. (0.3 moles) of cinnamic chloride and 100 ml. of acetonitrile is added. The reaction mixture is heated to boiling for 15 hours. The mixture is cooled and the precipitated white crystals are filtered off. Thus 62.6 of the desired compound are obtained, yield 94.8%. M.p.: 165° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:24]([F:27])([F:26])[F:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1>>[C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[O:23][CH2:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:24]([F:27])([F:25])[F:26])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C(O)c1ccc(CBr)cc1
Product: O=C(O)c1ccc(COc2cccc(-c3c(-c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [3-(3-Phenyl-8-trifluoromethyl-quinolin-4-yl)-phenol and 4-Bromomethyl-benzoic acid following the procedure of Example 1: mp 108-112° C.; MS m/z 500; HRMS: calcd for C30H20F3NO3+H+, 500.14680; found (ESI, [M+H]+), 500.1461.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH3:12])([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:13]([C:16]([CH3:18])=[O:17])([CH3:15])=O.[OH:19]N1C(=O)C2=CC=CC=C2C1=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[C:16]([C:13]12[CH2:1][C:2]3([CH3:11])[CH2:9][CH:8]([CH2:10][C:4]([CH3:5])([CH2:3]3)[CH2:15]1)[CH2:7]2)(=[O:17])[CH3:18].[C:16]([C:13]12[CH2:10][C:4]3([CH3:12])[CH2:3][C:2]([OH:19])([CH2:11][C:6]([CH3:7])([CH2:5]3)[CH2:15]1)[CH2:1]2)(=[O:17])[CH3:18]
Reactant: CC(=O)C(C)=O
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC12CC3CC(C1)CC(C)(C3)C2
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)C12CC3(C)CC(C)(CC(O)(C3)C1)C2
Product: CC(=O)C12CC3CC(C)(CC(C)(C3)C1)C2
Temperature: 75 °C
Reaction time: 8 h
Yield: 22 %
Yield: 58 %

Procedure:
A mixture of 3 mmol of 1,3-dimethyladamantane, 18 mmol of biacetyl, 0.3 mmol of N-hydroxyphthalimide, 0.015 mmol of cobalt (II) acetate, and 3 ml of acetic acid was stirred at 75° C. under an oxygen atmosphere (1 atm) for 8 hours. Products in the reaction mixture were found, by gas chromatographic analysis, to be 1-acetyl-3,5-dimethyladamantane (yield 58%), and 1-acetyl-3,5-dimethyl-7-adamantanol (yield 22%) at a conversion rate of 1,3-dimethyladamantane of 94%.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.C([O:18][NH:19][CH2:20][C@@H:21]1[C@@H:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][N:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35]CC2C=CC=CC=2)[C:22]1=[O:43])C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:26]([C@H:25]1[CH2:24][N:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[C:22](=[O:43])[C@@H:21]1[CH2:20][N:19]([OH:18])[CH:1]=[O:3])[CH2:27][CH2:28][CH3:29]
Reactant: O=CO
Reactant: CCCC[C@H]1CN(CCCCCOCc2ccccc2)C(=O)[C@@H]1CNOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCCC[C@H]1CN(CCCCCO)C(=O)[C@@H]1CN(O)C=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A mixture of formic acid (0.011 mL, 0.29 mmol) and acetic anhydride (0.026 mL, 0.28 mmol) was heated to 50° C. for 1 h. To this mixture at room temperature was added a mixture of [(3S,4R)-3-(benzyloxyaminomethyl)-1-(5-benzyloxypentyl)-4-butyl-pyrrolidin-2-one (65 mg, 0.14 mmol) and triethylamine (0.02 mL, 0.18 mmol) in methylene chloride (3 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was diluted with methylene chloride (5 mL) and quenched with water (5 mL). The organic phase was washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated. The residue was dissolved in methanol (3 mL) and stirred under a hydrogen balloon in the presence of palladium on activated carbon (40 mg) for 4 h. The reaction mixture was filtered, concentrated, and the residue was purified by HPLC to afford 25 mg (58%) of N-[(3S,4R)-4-butyl-1-(5-hydroxypentyl)-2-oxopyrrolidin-3-yl-methyl]-N-hydroxyformamide as a colorless glass: 1H NMR (CD3OD) δ 8.33 (s, 0.5 H), 7.98 (s, 0.5 H), 3.80 (m, 1 H), 3.57 (m, 3 H), 3.33 (m, 3 H), 3.07 (t, 1H), 2.55 (m, 1 H), 2.12-2.26 (m, 1H), 1.33-1.71 (m, 12 H), 0.94 (t, 3 H). MS(ES) m/e 301 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:20])[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][CH:12]=1.CO.[NH2:24][O:25][K].C(O)(=O)C>C(OCC)(=O)C>[CH2:13]([N:8]1[CH2:9][CH2:10][CH2:11][CH:12]=[C:6]([CH2:5][CH2:4][C:3]([NH:24][OH:25])=[O:2])[C:7]1=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NO[K]
Reactant: COC(=O)CCC1=CCCCN(Cc2ccccc2)C1=O
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CCC1=CCCCN(Cc2ccccc2)C1=O)NO
Temperature: 0 °C
Reaction time: 3 h
Yield: 42.4 %

Procedure:
108 mg of compound (d) prepared by the above Step 3 was dissolved in methanol solution (0.376 mmol) and then 1.7 M methanolic suspension solution containing NH2OK (1.315 ml, 2.63 mmol) was added thereto at 0° C. and the resulting mixture was stirred for 3 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10 ml of ethyl acetate solution, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with methanol/chloroform (1:10) solvent mixture as an eluant to give 46 mg of the title compound (e1) (yield: 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([CH:18]([CH3:40])[C:19](=[O:39])[NH:20][CH2:21][C:22]2[C:23]([C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:6][CH2:5][C:4]1[CH:14]=[CH:15][C:16]([CH:18]([CH3:40])[C:19]([NH:20][CH2:21][C:22]2[C:23]([C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)=[N:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)=[O:39])=[CH:17][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)ccc1CNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)ccc1CN
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.8 %

Procedure:
To a stirred solution of tert-butyl 2-methoxy-4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzylcarbamate (161 mg, 0.29 mmol) in dichloromethane (4 mL), cooled to 0° C., were added trifluoroacetic acid (2 mL). The resulting reaction mixture was stirred for 2 h at 0° C. and 2 h at room temperature, then basified to pH 8-9 with aq. NaHCO3. The mixture was filtered using celite pad. The filtrate dissolved in dichloromethane and extracted with NaHCO3. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-(Aminomethyl)-3-methoxyphenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (151 mg) was obtained as 99% yield.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:20][C:21]([C@@H:23](/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]2([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])OCC[O:46]2)[C@@:24]([OH:36])([CH2:32][CH2:33][O:34][CH3:35])[C:25]([O:27]C(C)(C)C)=[O:26])=[O:22])[C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].O.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:20][C:21]([C@@H:23](/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](=[O:46])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C@@:24]([OH:36])([CH2:32][CH2:33][O:34][CH3:35])[C:25]([OH:27])=[O:26])=[O:22])[C:14](=[O:15])[NH:16][CH2:17][CH2:18][OH:19])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)NCCO)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)O)C(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
(2S,3S,E)-tert-Butyl 3-((S)-3-(4-(but-2-ynyloxy)phenyl)-1-(2-hydroxyethylamino)-1-oxopropan-2-ylcarbamoyl)-11-(2-heptyl-1,3-dioxolan-2-yl)-2-hydroxy-2-(2-methoxyethyl)undec-4-enoate (11.3 mg, 0.014 mmol) was dissolved in dichloromethane (0.5 mL), and water (50 μL) was added. Trifluoroacetic acid (1.5 mL) was further added. The reaction mixture was stirred at room temperature for 5 hours, and then concentrated. The resulting residue was dissolved in methanol (1.0 mL). To the solution was added an aqueous solution (50 μL) of 28% ammonia and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the resulting residue was then diluted in ethyl acetate, and washed with an aqueous solution of 0.5 M citric acid. The separated organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, then filtered, and concentrated. The resulting residue was purified by diol silica gel thin layer chromatography (dichloromethane/methanol) to obtain the target compound as colorless oil at a yield of 80%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=S.[S].CC(O)C>[Hg]=O.C(#N)C>[N:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9]2[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)=[CH:14][CH:15]=1
Reactant: Oc1ccccc1NC(=S)NCc1ccncc1
Agent: O=[Hg]
Agent: [S]
Solvent: CC#N
Solvent: CC(C)O
Product: c1ccc2oc(NCc3ccncc3)nc2c1
Yield: 56 %

Procedure:
A mixture of 14 parts of N-(2-hydroxyphenyl)-N'-(4-pyridinylmethyl)thiourea, 20 parts of mercury(II) oxide, 1 part of sulfur, 160 parts of 2-propanol and 160 parts of acetonitrile was stirred and refluxed for 14 hours. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The oily residue was crystallized from acetonitrile, yielding 6.8 parts (56%) of N-(4-pyridinylmethyl)-2-benzoxazolamine; mp. 147.9° C. (intermediate 74).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[F:21][C:22]([F:43])([F:42])[C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH:35]([CH3:39])[C:36](Cl)=[O:37])=[CH:32][CH:31]=2)=[N:27][CH:28]=1>C1(C)C=CC=CC=1>[F:42][C:22]([F:21])([F:43])[C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH:35]([CH3:39])[C:36]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:37])=[CH:32][CH:31]=2)=[N:27][CH:28]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Reactant: CCCCCCCCCCCCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 10 °C

Procedure:
n-Dodecanol(2.5 grams; 0.134mol), toluene (80 ml) and triethylamine (5 ml) were placed into a 300 ml, 3-necked glass reaction flask equipped with stirrer, thermometer, reflux condenser, and nitrogen line. 2-[4-(5-trifluoromethyl-2-pyridinyloxy)phenoxy]propanoic acid chloride (4.45 grams; 0.0125 mol) in toluene (30 ml) was added dropwise to the reaction mixture with stirring at a temperature of about 10° C. The temperature of the reaction mixture was allowed to rise to room temperature and stirred overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:28]=[CH:27][C:16]4=[N:17][O:18][C:19]([C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([I:26])[CH:21]=5)=[C:15]4[CH:14]=3)OCC[O:9]2)=[CH:4][CH:3]=1>O1CCCC1.C(Cl)Cl.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:17][CH:16]1[CH:15]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([I:26])[CH:21]=2)=[O:18])[CH:14]=[C:13]([C:8](=[O:9])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:28]=[CH:27]1
Reactant: Clc1ccc(C2(c3ccc4noc(-c5cccc(I)c5)c4c3)OCCO2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC1C=CC(C(=O)c2ccc(Cl)cc2)=CC1C(=O)c1cccc(I)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
5-[2-(4-Chloro-phenyl)-[1,3]dioxolan-2-yl]-3-(3-iodo-phenyl)-benzo[c]isoxazole (65.4 g, 130 mMol) was dissolved in a solution of tetrahydrofuran (THF) (500 mL) and DCM (100 mL). To this solution, was added 500 mL of titanium(III) chloride (10 wt. % solution in 20-30 wt. % hydrochloric acid (HCl)) and the reaction mixture was stirred for 1 hour. An additional 100 mL of titanium(III) chloride (10 wt. % solution in 20-30 wt. % HCl) was added to the reaction mixture and the reaction mixture was stirred for 2.5 hours. The reaction mixture was then poured into ice water and the resulting heterogeneous solution was extracted with DCM. The DCM layer was successively washed with aqueous saturated NaHCO3 and brine. The DCM layer was dried over MgSO4, filtered and concentrated under vacuum to give titled compound as an orange oil (60 g). The oil was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH:27]([NH2:30])([CH3:29])[CH3:28]>C(Cl)Cl.O>[CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:7]
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: CC(C)N
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(C)C)c1[N+](=O)[O-]
Yield: 80.2 %

Procedure:
A solution of 3-methyl-2-nitrobenzoic acid (2.00 g, 11.0 mmol) and triethylamine (1.22 g, 12.1 mmol) in 25 mL of methylene chloride was cooled to 10° C. Ethyl chloroformate was carefully added and a solid precipitate formed. After stirring for 30 minutes isopropylamine (0.94 g, 16.0 mmol) was added and a homogeneous solution resulted. The reaction was stirred for an additional hour, poured into water and extracted with ethyl acetate. The organic extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure to afford 1.96 g of the desired intermediate as a white solid melting at 126-128° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.CC(C)([O-])C.[K+].I[C:17]1[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1.O>O1CCCC1>[Br:23][C:20]1[CH:19]=[N:18][C:17]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[N:22][CH:21]=1
Reactant: Brc1cnc(I)nc1
Reactant: OC1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cnc(OC2CN3CCC2CC3)nc1
Reaction time: 0.5 h

Procedure:
3-Quinuclidinol (Aldrich, 254 mg, 2 mmol) in tetrahydrofuran (Aldrich, anhydrous, 10 mL) was treated with potassium tert-butoxide (224 mg, 2 mmol) at ambient temperature for 1 hour. 2-Iodo-5-bromo-pyrimidine (Aldrich, 568 mg, 2 mmol) was then added. After stirring for 30 minutes, the mixture was treated with water (5 mL) and extracted with CHCl3:isopropyl alcohol (10:1, 3×10 mL). The extracts were combined and concentrated under reduced pressure. The title compound was purified by flash chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.15) as a solid (287 mg, yield, 50%). 1H NMR (300 MHz, MeOH-d4) δ 1.52-1.65 (m, 1H), 1.66-1.93 (m, 2H), 2.00-2.15 (m, 1H), 2.22-2.31 (m, 1H), 2.79-3.09 (m, 5H), 3.38-3.49 (m, 1H), 5.06-5.15 (m, 1H), 8.64 (s, 2H) ppm. MS (DCl/NH3) m/z 284 (M+H)+ 286 (M+H)+.