Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:29]([OH:32])[CH2:30][OH:31].[C:33]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:27][C:4]1[N:3]2[O:32][CH2:29][CH2:30][O:31][C:2]2=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([CH3:33])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:5]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: OCCO
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(C)N2OCCOC2=C(C(=O)OCC)C1(C)c1ccccc1[N+](=O)[O-]

Procedure:
A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (388.37 mg), ethylene glycol (186.21 mg) and p-toluenesulfonic acid (catalytic amount) in absolute benzene. (5 ml) was refluxed for 45 minutes under azeotropic dehydration. The reaction mixture was allowed to stand and washed twice with an aqueous solution of sodium bicarbonate. After removal of the solvent, the residue immediately turned into crystals. Thus obtained crystals were recrystallized from a mixture of ethanol and diisopropyl ether to give yellow pure crystals (0.32 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-ethylenedioxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p 152° to 153.5° C. (7) A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.9518 g) and triphenylphosphine (1.4425 g) in carbon tetrachloride (20 ml) was refluxed for 5 hours. After removal of the solvent, the residue was added to water and extracted with ethyl acetate. The extract was washed with water and dried. Removal of the solvent gave an orange-yellow oil (3.63 g). This oil was subjected to column chromatography on silica gel with an eluent (benzene:ethyl acetate=5:2) to give an oil (517 mg) of diethyl 2-methyl-4-(2-nitrophenyl)-6-chloromethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: C(Cl)(Cl)Cl.[NH4+:5].[OH-].O.[C:8]([C:16]([C:31]([OH:33])=[O:32])([OH:30])[C:17]([C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:21])[C:18]([OH:20])=[O:19])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[C:22]([C:17]([C:18]([OH:20])=[O:19])([OH:21])[C:16]([C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:30])[C:31]([OH:33])=[O:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:23]1([CH2:22][C:17]([NH2:5])([C:16]2[CH:8]=[CH:9][CH:14]=[CH:13][CH:31]=2)[CH3:18])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [NH4+]
Agent: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC(N)(Cc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
The filtrate residue which was saved in Illustration 4, was treated with 1 L CHCl3 and 0.9 L 5% NH4OH, shaken vigorously, the layers separated and the organic phase washed with 4×800 ml 5% NH4OH and 2×500 ml H2O, then dried over MgSO4 and evaporated to an oil 32.3 g, which is enriched in (+)-1,2-diphenyl-2-propylamine. This oil (32.3 g, 0.153 mol) was dissolved in 200 ml hot 95% ethanol and added to a stirred solution of (+)-dibenzoyl tartaric acid monohydrate (57.55 g, 0.153 mol) in 600 ml of refluxing 95% ethanol. A white solid crystallized immediately, which was stirred at reflux for 5 minutes, then allowed to cool to ambient temperature. The solid was collected by filtration and vacuum dried at 80° C. for 8 hours to give 71.6 g of (+)-1,2-diphenyl-2-propylamine (+)-dibenzoyltartrate, mp 197°-198° C., [α]D =+95.8° (C=0.5, CH3OH). 5.0 g of this salt was dissolved in 250 ml CHCl3 and 200 ml 5% NH4OH, shaken vigorously, the layers separated and the organic phase washed with 3×200 ml 5% NH4OH and 2×200 ml H2O and dried over MgSO4. The solvent was evaporated to give 1.75 g of (+)-1,2-diphenyl-2-propylamine as an oil. The maleate salt was prepared by dissolving this oil in 25 ml ethyl acetate and adding the solution to a hot solution of maleic acid (1.02 g, 8.78 mmole) in 50 ml 3/1 ethyl acetate/isopropanol. Upon cooling a white solid crystallized, which was collected by filtration and vacuum dried to give 2.06 g of (+)-1,2-diphenyl-2-propylamine maleate, mp 177°-178° C., [α]D =+27.3° (C=1, CH3OH).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]N(C)C)[C:12]=2[S:21][CH3:22])[CH:3]=1.C1(C)C=CC=CC=1.[Cl:30]C(OCC)=O.O>C(OCC)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][Cl:30])[C:12]=2[S:21][CH3:22])[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: CSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CSc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 0 °C
Reaction time: 17 h
Yield: 80.6 %

Procedure:
Under a nitrogen atmosphere, 4-chloro-2-(3-dimethylaminomethyl-2-methysulfanyl-phenoxy)-benzonitrile (1.02 g, 3.06 mmol) was dissolved in anhydrous-toluene (10 mL). The solution was cooled to 0° C. and ethyl chloroformate (900 μL, 9.2 mmol) was slowly added. The reaction mixture was stirred for 17 h, allowing it to reach room temperature. Water (5 mL) and diethyl ether (5 mL) were added and the organic layer was separated and dried with MgSO4. After filtration, the solution was absorbed onto silica gel (1.5 g) and the solvent was removed in vacuo. This material was chromatographed on an ISCO CombiFlash Chromatography System to yield 4-chloro-2-(3-chloromethyl-2-methysulfanyl-phenoxy)-benzonitrile as a clear oil (800 mg, 81%).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CN(OC)[C:17](=[O:19])[CH3:18]>O1CCCC1>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:17](=[O:19])[CH3:18]
Reactant: c1cc2sccc2cn1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cc2cnccc2s1
Temperature: -45 °C
Reaction time: 0.75 h

Procedure:
A solution of thieno[3,2-c]pyridine (5.0 g) in 75 mL THF (tetrahydrofuran) was cooled to −45° C. in a CH3CN/dry ice bath. n-Butyllithium (1.6M in hexanes) (35.0 ml) was added dropwise maintaining the internal temperature at or below −40° C. The addition took about 45 minutes. The reaction was stirred for 1 hour at −45° C. N-methyl-N-methoxyacetamide in 5 mL THF was added and as a result the reaction warmed to −30° C. The reaction was stirred at −45° C. for 1.5 hours. The reaction was quenched with saturated NH4Cl. The aqueous layer had a pH of about 8. The aqueous layer was extracted three times into EtOAc. The combined organic extracts were washed with brine and dried over MgSO4. The material was filtered, concentrated on a rotary evaporator and subjected to column chromatography (Biotage Horizon system, 120 g Analogix column, equilibrate with hexanes, elute with 50% EtOAc/hexanes). The most pure fractions were concentrated on a rotary evaporator and then triturated with Et2O to remove some color and collect a pale orange solid by filtration (2.667 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[CH:29]([NH2:32])([CH3:31])[CH3:30]>C1COCC1>[OH:16][C@@H:15]([CH2:17][NH:32][CH:29]([CH3:31])[CH3:30])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@@H]1CO1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@@H](O)CNC(C)C
Temperature: 75 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
A mixture of (2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (250 mg, 0.66 m.mol), (prepared as described for the starting material in Example 304), and isopropylamine (1.5 ml) in THF (10 ml) was stirred at 75° C. for 18 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography using gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2S)-7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (210 mg, 73%).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.[C:23]([CH2:31][CH2:32][C:33](O)=[O:34])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCOCC1>[O:30]=[C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:31][CH2:32][C:33]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=[O:34]
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: Cc1ccc(N)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)CCC(=O)c2ccccc2)cc1
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
EDC (347 mg, 1.81 mmol) and HOBT (254 mg, 1.88 mmol) were added to mixture of p-toluidine (129 mg, 1.20 mmol) and 3-benzoylpropionic acid 27 (218 mg, 1.21 mmol) in 1,4-dioxane (3 mL) at room temperature. It was stirred for 20 minutes and then added triethylamine (0.5 mL, 3.59 mmol). The reaction mixture was stirred for 20 h at room temperature and the solvent was evaporated under vacuum. The residue was purified by flash silica gel column chromatography (hexane:ethyl acetate=3:1 to 2:1) yielded the compound 28 (252 mg, 78%). 1H-NMR (CDCl3, 300 MHz) δ 2.30 (s, 3H), 2.80 (t, J=6.3 Hz, 2H), 3.45 (t, J=6.3 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.47 (m, 2H), 7.58 (m, 1H), 7.99 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:23][C:24]2[NH:28][C:27]3[CH:29]=[CH:30][C:31]([C:33]#[N:34])=[CH:32][C:26]=3[N:25]=2)=[C:4]2[C:8](=[C:9]([CH:11]=[CH2:12])[CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[CH:5]2.[OH-].[K+].C(N)CC(C)C>CCO>[CH3:1][C:2]1[C:3]([CH2:23][C:24]2[NH:28][C:27]3[CH:29]=[CH:30][C:31]([C:33]#[N:34])=[CH:32][C:26]=3[N:25]=2)=[C:4]2[C:8](=[C:9]([CH:11]=[CH2:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: C=Cc1cc(C)c(Cc2nc3cc(C#N)ccc3[nH]2)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Agent: CC(C)CCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=Cc1cc(C)c(Cc2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-((5-Methyl-1-tosyl-7-vinyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (23 mg, 0.049 mmol) was dissolved in EtOH (1 mL) and KOH (27.7 mg, 0.493 mmol) and isoamylamine (0.11 mL, 0.986 mmol) were added and the mixture was stirred at 100° C. in the microwave for 30 minutes. The mixture was then stirred at 100° C. in the microwave for another 15 minutes. The reaction was purified directly by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 313.1 (M+H).
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)(=[O:9])[CH:7]=[CH2:8].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)([C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1)[OH:38].[NH4+].[Cl-]>C1COCC1.C(N(CC)CC)C>[OH:38][C:37]([C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=1)([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)[C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:22]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6](=[O:9])[CH:7]=[CH2:8])=[CH:26][CH:25]=1)=[O:24]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: OC(c1ccc2ccccc2c1)(c1ccc2ccccc2c1)[C@@H]1CCCN1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)N2CCC[C@H]2C(O)(c2ccc3ccccc3c2)c2ccc3ccccc3c2)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of mesyl chloride (0.1 ml) in 1 ml of dry THF is added dropwise under argon over a period of 15 minutes to a cooled (−20° C.) solution of 4-(6-acryloyloxyhexyloxy)benzoic acid (0.38 g) and triethylamine (0.52 ml) in 10 ml of dry THF. The obtained reaction mixture is stirred for 60 min at −20° C. then treated with a solution of (S)-dinaphthalen-2-ylpyrrolidin-2-ylmethanol (0.46 g) in 5 ml of dry THF and further stirred at −20° C. for 2 h. The reaction mixture is then allowed to warm to room temperature, and stirring is continued overnight. The reaction mixture is then poured into 40 ml of saturated NH4Cl solution and extracted with 4×40 ml of diethyl ether and 20 ml of dichloromethane. The combined organic extracts are washed with saturated NaCl solution (2×80 ml), dried over MgSO4, filtered and evaporated to give a brownish residue. This was purified by chromatography over a short silica column (CH2Cl2 / Et2O : 19 / 1 ) to give acrylic acid (S)-6-[4-[2-(hydroxydinaphthalen-2-ylmethyl)pyrrolidine-1-carbonyl]phenoxy]hexyl ester as a white crystalline material. Yield 0.51 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[OH:18])[C:5]([NH:7][CH:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[O:6].[CH2:19]([O:21][C:22](OCC)(OCC)OCC)[CH3:20]>>[CH2:9]([CH:8]([NH:7][C:5]([C:4]1[CH:15]=[CH:16][C:17]2[O:18][C:22]([O:21][CH2:19][CH3:20])=[N:1][C:2]=2[CH:3]=1)=[O:6])[CH2:12][CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: CCOC(OCC)(OCC)OCC
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(N)c1
Product: CCCC(CCC)NC(=O)c1ccc2oc(OCC)nc2c1

Procedure:
Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N-(1-propylbutyl)benzamide (example 41a) and tetraethoxymethane: mp 128-129° C.; MS (M+H, 305.1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c[nH]c23)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A154) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].Cl.[C:18](OC(=O)CN)([CH3:21])([CH3:20])[CH3:19].C[N:28]1[CH2:33][CH2:32][O:31]CC1.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:28][C@H:33]([C:32]([CH:4]([CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)[C:2](=[O:1])[OH:3])=[O:31])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H](N)C(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a solution of biotin (0.83 g, 3.4 mmol) in 60 mL of DMF was added glycine t-butyl ester hydrochloride (0.57 g, 3.4 mmol), N-methylmorpholine (0.92 mL, 8.36 mmol), 1-hydroxybenzotriazole (0.61 g, 3.99 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbo-diimde hydrochloride (0.65 g, 3.4 mmol). The reaction mixture was stirred at room temperature for 7 days. The DMF was concentrated, ethyl acetate was added, and the organic layer was washed with water, 0.5 N HCl, saturated sodium bicarbonate, and brine. The ethyl acetate layer was dried (MgSO4) and concentrated to yield tert-butylglycylbiotin as a white solid which was primarily one spot on TLC (0.611 g, 1.71 mmol, 50%). Mass spec [M+H]+ at m/z 358.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH2:34][OH:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][CH2:34][OH:35])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCO)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 130 mg, 0.3 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. prior to the addition of 2-aminoethanol (27.6 mg, 0.452 mmol), 4-methylmorpholine (0.133 mL, 1.206 mmol), and HATU (149 mg, 0.392 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention=33.8 min) to give (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (34 mg, 0.065 mmol, 21.3% yield): LCMS [M+H]+=475.1; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, dd, J=8.35, 4.39 Hz), 7.64-7.77 (4 H, m), 7.47-7.64 (3 H, m), 5.10-5.21 (1 H, m), 4.46 (2 H, t, J=5.49 Hz), 3.55-3.69 (2 H, m), 3.37 (1 H, m). HPLC Peak RT=8.6 min (Analytical Method A).
Reaction SMILES: [CH2:1]([NH:8][NH:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][N:13]1[S:37]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=1)(=[O:39])=[O:38])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:59][O:60][C:61]1[CH:66]=[CH:65][C:64]([S:67](Cl)(=[O:69])=[O:68])=[CH:63][CH:62]=1>C(Cl)Cl>[CH2:1]([N:8]([S:67]([C:64]1[CH:63]=[CH:62][C:61]([O:60][CH3:59])=[CH:66][CH:65]=1)(=[O:69])=[O:68])[NH:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17][C:18]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:14][N:13]1[S:37]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=1)(=[O:39])=[O:38])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NNCc1ccccc1)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)NC(=O)[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2S(=O)(=O)c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.3 %

Procedure:
(step 12) To 200 mg (0.3 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid N′-benzyl-hydrazide in 3 ml CH2Cl2 were added 60 μl (0.35 mmol, 1.2 eq) N,N-diisopropylethylamine, 72.5 mg (0.35 mmol, 1.2 eq) 4-methoxybenzene sulfonylchloride and 22.5 mg (0.12 eq) DMAP-poly at 0° C. The suspension was shaken at RT for 3 days, additional 25 μl (0.15 mmol, 0.5 eq) N,N-diisopropylethylamine, 31 mg (0.15 mmol, 0.5 eq) 4-methoxybenzene sulfonylchloride and 22.5 mg (0.12 eq) DMAP-poly were added and the reaction was continued for a day. After filtration and washing of the resin with CH2Cl2, the organic phase was concentrated and the crude material purified by flash chromatography yielding 152 mg (61%) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid N′-benzyl-N′-(4-methoxy-benzenesulfonyl)-hydrazide which was directly subjected to the following reaction.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([NH:9][C:10]2=O)[CH2:7]3)=[CH:4][C:3]=1[F:15].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:12]=[C:11]2[C:5]([CH:6]3[CH2:14][CH:8]([N:9]=[C:10]2[Cl:17])[CH2:7]3)=[CH:4][C:3]=1[F:15]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1NC2CC(C2)c2cc(F)c(Br)cc21
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1cc2c(cc1Br)C(Cl)=NC1CC2C1
Temperature: 25 °C
Yield: 82 %

Procedure:
Into a 20000-mL 4-necked round-bottom flask was placed a solution of 5-bromo-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6-trien-8-one (800 g, 2.96 mol, 1.00 equiv) in toluene (10000 mL), followed by the addition of PCl5 (1540 g, 7.40 mol, 2.50 equiv) in several batches at 25° C. over 1 hour. The resulting solution was heated to reflux for 5 hr, cooled to room temperature and diluted with 5000 mL of ether. The solids were collected by filtration and dissolved in 10000 mL of ether. The resulting mixture was washed with 5000 mL of ammonia (10%), dried over anhydrous sodium sulfate and concentrated under vacuum to afford 700 g (82%) of 5-bromo-8-chloro-4-fluoro-9-azatricyclo[8.1.1.0[2,7]]dodeca-2,4,6,8-tetraene as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[N:12]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)[C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(=O)[nH]1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nc2ccccc2c(=O)n1CCOc1ccc([N+](=O)[O-])cc1
Yield: 64.4 %

Procedure:
The title compound (1.246 g, 64%) was prepared from 2-ethyl-4-oxo-3,4-dihydroquinazoline (1.0 g, 5.7 mmol) and 4-[2-bromoethoxy]nitrobenzene (1.696 g, 6.8 mmol) and K2CO3 (1.58 g, mmol) as a base by a similar procedure to that described in preparation 1.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][CH2:21]N(C(OCC3C=CC=CC=3)=O)[CH2:19]2)[CH2:14]1)=[O:11])=[O:7].[S:38]1CCC(=O)C1.O=C1CCN(C(OCC2C=CC=CC=2)=O)C1>>[O:11]=[C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][CH2:21][S:38][CH2:19]2)[CH2:14]1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:33]=[CH:34][CH:35]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:4]=1
Reactant: O=C1CCSC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3)C2)C1
Agent: O=C1CCN(C(=O)OCc2ccccc2)C1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCSC2)C1

Procedure:
The title compound was synthesized in similar fashion to benzyl (3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidine-1′-carboxylate, whereby dihydrothiophen-3(2H)-one was substituted for benzyl 3-oxopyrrolidine-1-carboxylate, and was isolated, as a mixture of diastereomers, as a white solid. 1H-NMR (CDCl3) δ: 1.55-1.66 (m, 1H), 1.71-1.81 (m, 1H), 2.03-2.14 (m, 1H), 2.15-2.26 (m, 1H), 2.33-2.39 (m, 1H), 2.52-2.58 (m, 1H), 2.63-2.73 (m, 3H), 2.74-2.81 (m, 4H), 4.07 (d, J=4.8 Hz, 2H), 4.36-4.38 (m, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.81 (t, J=4.9 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.03 (s, 1H). MS m/z: 402 (M+1)