Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][OH:16])([O-:3])=[O:2].[H-].[Na+].[CH2:19](Br)[C:20]#[CH:21]>CN(C=O)C.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][O:16][CH2:21][C:20]#[CH:19])([O-:3])=[O:2]
Reactant: C#CCBr
Reactant: O=[N+]([O-])c1ccc(NCCO)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCOCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 15 h
Yield: 64.9 %

Procedure:
2-(2,4-dinitrophenylamino)ethanol (s-1a) (410 mg, 1.80 mmol, 1.0 equiv.) was dissolved in 3 mL of DMF and slowly added to a slurry of NaH (86.4 mg, 3.6 mmol, 2 equiv.) in 5 mL of DMF in a flame dried flask pre-cooled to 0° C. To the resulting slurry, 80% propargyl bromide (0.240 mL, 2.16 mmol, 1.2 equiv.) in toluene, cooled to 0° C., was added slowly. The ice bath was removed and the reaction was allowed to stir at room temperature for an additional 15 hours. The reaction was then re-cooled to 0° C., quenched with saturated NH4Cl, and extracted with diethyl ether (3×150 mL). The organic layers were combined, dried, concentrated under reduced pressure, and chromatographed (silica gel, 1×25 cm, 0% CH3OH in CHCl3, then 2.5% CH3OH in CHCl3) to yield 2,4-dinitro-N-(2-(prop-2-ynyloxy)ethyl)aniline (s-2a) as a dark yellow solid (310 mg, 64.8%). IR (thin film) 3356 (m), 3285 (m), 3105 (w), 2871 (w), 2117 (w), 1616 (s), 1584 (s), 1521 (s), 1499 (m), 1423 (m), 1274 (s), 1089 (s), 920 (m); 1H NMR (400 MHz, CDCl3) δ 9.16 (d, J=2.6 Hz, 1H), 8.76 (bs, 1H), 8.28 (dd, J=9.5, 2.7 Hz, 1H), 6.96 (d, J=9.5 Hz, 1H), 4.25 (d, J=2.4 Hz, 2H), 3.91-3.84 (m, 2H), 3.65 (d, J=5.3 Hz, 1H), 2.50 (t, J=2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 149.5, 136.3, 130.7, 130.4, 124.4, 114.1, 78.9, 75.5, 67.3, 58.7, 43.3. HRMS (ES+) calc'd for C11H11N3O5 (M+H) m/z 266.0732 Found 266.0771.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][NH:11][C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.N1C=CC=CC=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][N:11]([C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])[C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: O=C(Cl)C1CC1
Reactant: Clc1ccc2c(c1)C=Cc1cc(Br)ccc1CN2
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(C1CC1)N1Cc2ccc(Br)cc2C=Cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A solution of 9-Bromo-2-chloro-5,6-dihydro-dibenzo[b,f]azocine (30 mg, 0.09 mmol) (prepared in a manner analogous to that described for Example 1F) in dichloroethane was treated with pyridine (0.02 mL, 0.27 mmol) and cyclopropanecarbonyl chloride (0.011 mL, 0.12 mmol). The reaction mixture was stirred at room temperature for two hours then concentrated, diluted with MeOH and filtered. The crude product was purified by preparative reversed-phase HPLC to afford Example 326A (30 mg, 82%). HPLC Rt=4.05 min. m/z=388 (M+H+)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=1.O>CN(C)C=O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:16]([Cl:21])[CH:15]=1
Reactant: BrC1CCCC1
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(Br)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 98 %

Procedure:
Potassium carbonate (2.0 g) and bromocyclopentane (0.775 mL) were added to a solution of 4-bromo-2-chlorophenol (1.0 g) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for four days. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated ammonium chloride solution and water, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 4-bromo-2-chloro-1-(cyclopentyloxy)benzene as a colorless oil (1.31 g, 98%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=O)C.Cl.[NH2:48][C@@H:49]([CH2:53][CH2:54][CH2:55][CH2:56][NH:57]C(OCC1C=CC=CC=1)=O)[C:50]([NH2:52])=[O:51].C(N1CCNCC1)C1C=CC=CC=1>>[NH2:57][CH2:56][CH2:55][CH2:54][CH2:53][C@H:49]([NH:48][C:40]([CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:44]([CH3:46])[CH3:45])=[C:32]([CH3:43])[CH:33]=1)=[O:41])[C:50](=[O:51])[NH2:52]
Reactant: NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: c1ccc(CN2CCNCC2)cc1
Product: Cc1cc(OCCC(=O)N[C@@H](CCCCN)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methyl-phenyl]methyl}-5-isopropyl-1H-pyrazole and (S)-2-amino-6-(benzyloxycarbonylamino)hexanamide hydrochloride instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzyl-piperazine, respectively.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.Cl>CCO.O1CCOCC1>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[S:3][C:4]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Clc1ccc2nc(Nc3ccc(Br)cc3)sc2c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a suspension of 2,6-dichlorobenzothiazole (2.52 g, 12.3 mmol) and 4-bromoaniline (2.12 g, 12.2 mmol) in EtOH (15 mL) was added 4 N HCl in dioxane (0.2 mL, 0.8 mmol). The reaction mixture was stirred at 140° C. in a microwave reactor for 1 h. After cooling to room temperature, the resulting suspension was filtered. The collected solid was washed with MeOH (10 mL), and dried in a 50° C. vacuum oven for 16 h to afford 3.28 g (80%) of the title compound as a white solid. HPLC/MS (method C): retention time=4.24 min, [M+H]+=339.0.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([CH2:16][OH:17])[C:13]([C:18]#[N:19])=[CH:12]2)=[CH:7][CH:6]=1)C.[CH2:21](N(CC)CC)[CH3:22].CS(Cl)(=O)=O>O1CCCC1>[C:18]([C:13]1[C:14]([CH2:16][O:17][CH2:21][CH3:22])=[CH:15][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:20])=[CH:10][CH:9]=2)[CH:12]=1)#[N:19]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(CO)c2)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCOCc1cn(-c2ccc(C(=O)O)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a solution of 4-(3-cyano-4-hydroxymethylpyrrole-1-yl)benzoic acid ethyl ester (0.022 g) in tetrahydrofuran (1 mL) were added triethylamine (0.0082 g) and methane sulfonylchloride (0.0093 g) under ice-cooling. After warming to ambient temperature, this mixture was stirred for 30 minutes. The insoluble material of this reaction mixture was removed by filtration, and this filtrate was added to a mixture of ethanol (1.125 g) and sodium hydride (60%, 0.13 g), and this mixture was stirred for 5 hours. To this reaction mixture was added water, and this mixture was stirred at room temperature for 1 hours. To this reaction mixture was added 2 mol/L hydrochloric acid (3 mL), this mixture was extracted with ethyl acetate. This organic layer was washed with brine, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=88/12−81/19) to give the title compound (0.010 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13]CC)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(c1ccccc1)N1CCN(C(C)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCN(C(C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Ethyl 2-(4-acetylpiperazin-1-yl)-2-phenylacetate (285 mg, 0.98 mmol) was dissolved in a mixture EtOH (6.5 ml) and water (3.3 ml). LiOH (23.5 mg, 0.98 mmol) was added and the reaction was stirred at room temperature overnight. LiOH (23.5 mg, 0.982 mmol) was added again and the mixture was stirred for additional 24 hours. EtOH was evaporated and 1N HCl was added dropwise to the aqueous solution till pH 6-7 before evaporating to dryness. The crude was purified by flash chromatography (DCM/MeOH=75/25) to obtain 2-(4-acetylpiperazin-1-yl)-2-phenylacetic acid (246 mg, 96% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15](=[O:17])[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15](=[O:17])[NH2:16])[CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NCC(N)=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N(CC(N)=O)Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(carbamoylmethyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g, 2.03 mmol) in dichloroethane (5.0 mL) was added 4-chlorobenzaldehyde 0.34 g, 2.44 mmol), sodium triacetoxy borohydride (0.86 g, 4.06 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using ethyl acetate. 1H-NMR (CDCl3) δ: 1.50 (9H, s), 1.60–1.80 (2H, m), 2.10 (1H, m), 3.10–3.60 (8H, m), 5.65 (1H, br, s), 6.90 (1H, br, s) 7.20–7.40 (4H, m). ESI-MS m/z: 367(M+1), UV retention time: 1.94 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:13]2[CH:22]=[CH:21][N:20](S(C3C=CC(C)=CC=3)(=O)=O)[C:14]=2[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1.[CH:33]1([OH:37])[CH2:36][CH2:35][CH2:34]1.[H-].[Na+]>O1CCCC1>[CH:33]1([O:37][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:4][C:3]=2[C:12]2[C:13]3[CH:22]=[CH:21][NH:20][C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: OC1CCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(S(C)(=O)=O)ccc4F)cn(C)c(=O)c32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OC2CCC2)c2cc[nH]c2c1=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A 4 mL vial was charged with a stir bar, a solution of Example 138a (30 mg, 0.063 mmol) in tetrahydrofuran (1 mL), a solution of cyclobutanol (32 mg, 7 equivalents, 0.46 mmol) in tetrahydrofuran (1 mL) and neat sodium hydride (19 mg, 7 equivalents, 0.46 mmol). The reaction mixture was stirred at 60° C. for 16 hours. The crude material was filtered, concentrated, and purified by reverse phase HPLC (C18, 10-100% CH3CN/water (0.1% TFA)) to afford the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ ppm 7.98-7.75 (m, 2H), 7.33 (d, J=1.4 Hz, 2H), 7.16 (d, J=8.7 Hz, 1H), 6.15 (d, J=2.8 Hz, 1H), 4.82 (p, J=7.2 Hz, 1H), 3.59 (s, 3H), 3.19 (d, J=8.5 Hz, 3H), 2.47-2.38 (m, 2H), 1.96 (p, J=9.6 Hz, 2H), 1.81-1.72 (m, 1H), 1.72-1.57 (m, 1H). MS (ESI+) m/z 373 (M+H)+.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[C:18]([OH:20])=[O:19])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[CH2:36]([N:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:42](Cl)=[O:43])[CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:42](=[O:43])[N:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:14][C@H:13]2[C:18]([OH:20])=[O:19])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCN(CCCCC)C(=O)Cl
Reactant: O=C(O)[C@@H]1CNCCN1C(=O)N(c1ccccc1)c1cccc(Cl)c1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.1 %

Procedure:
To a suspension of 1.05 g (2.3 mmole) of (S)-1-[N-(3-chlorophenyl)-N-phenylcarbamoyl]piperazine-2carboxylic acid hydrobromide (from Step C) in 20 ml of methylene chloride was added 1.23 g (9.5 mmole) of N,N-diisopropylethylamine followed by the dropwise addition of a solution of 523 mg (2.38 mmole) of dipentylcarbamoyl chloride (from Example 1, Step C-2) in 5 ml of methylene chloride. After stirring 24 hours at 25° C., the solution was extracted with 2N HCl, then H2O and dried over MgSO4. The dried methylene chloride solution was concentrated in vacuo and the residue was dissolved in isopropyl ether and was diluted with petroleum ether (bp. 30°-60° C.) until cloudy. The oil which precipitated was then decanted, redissolved in isopropanol and concentrated in vacuo to yield 464 mg (36%) of (S)-1-[N-(3-chlorophenyl)-N-phenylcarbamoyl]-4-(dipentylcarbamoyl)piperazine-2-carboxylic acid as a glassy solid; TLC showed a single spot, Rf 0.75 (Analtech SGF plates developed with isoamyl alcohol:acetone:water [5:2:1]).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])[NH2:5].[CH3:13][O:14][C:15]1([C:18](OC)=[O:19])[CH2:17][CH2:16]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:4]([NH:5][C:18]([C:15]2([O:14][CH3:13])[CH2:17][CH2:16]2)=[O:19])=[CH:3][C:2]=1[Cl:1])([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ccc(N)cc1Cl
Reactant: COC(=O)C1(OC)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC1(C(=O)Nc2ccc(OC(C)C)c(Cl)c2)CC1
Yield: 21.2 %

Procedure:
A mixture consisting of 5.6 g of 3-chloro-4-isopropoxyaniline, 3.9 g of methyl 1-methoxycyclopropanecarboxylate and 1.8 g of sodium methoxide in 50 ml of benzene was refluxed for 3 hours. The reaction mixture was concentrated to a volume of 25 ml, poured over ice water, acidified with hydrochloric acid and extracted with ether. The extract was dried, filtered and concentrated. Purification by silica chromatography gave 1.8 g of product as a white crystalline solid; m.p. 86°-87° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[S:13]([O-:16])([O-:15])=[O:14].[Na+:17].[Na+].C(O)C.BrCCS([O-])(=O)=O.[Na+]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:13]([O-:16])(=[O:15])=[O:14].[Na+:17]
Reactant: BrCCCCCCCCCCBr
Reactant: O=S([O-])[O-]
Agent: O=S(=O)([O-])CCBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCCCCCCBr

Procedure:
1,10-Dibromodecane (7.5 g, 25 mmol), sodium sulfite (1.4 g, 11 mmol), ethanol (25 mL) and water (20 mL) were reacted and worked up analogously to sodium 2-bromoethane sulfonate. Yield: 1.8 g (23%) colorless solid, melting point 342° C., IR (ATR): {tilde over (ν)}=3541 (s), 3481 (s), 2916 (s), 2874 (m), 2853 (s), 2095 (w), 1627 (m), 1472 (m), 1307 (w), 1281 (w), 1250 (w), 1230 (m), 1197 (m), 1178 (s), 1055 (m), 1044 (m), 968 (w), 796 (m), 721 (w), 640 (w), 608 cm−1 (m). HRMS (ESI) (C10H21BrNaO3S+): calculated 323.0287. found 323.0602, Δ=31.5 mmu.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.O[NH:11][C:12](=[NH:24])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:9][N:24]=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=3)[N:11]=2)[N:4]=[CH:3]1
Reactant: N=C(NO)c1ccc(OC(F)(F)F)cc1
Reactant: Cn1cnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cn1cnc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
To a solution of 1-methyl-1H-imidazole-4-carboxylic acid (1.5 g, 11.9 mmol) in DMF (30 mL), N-hydroxy-4-(trifluoromethoxy)benzimidamide (3.1 g, 14.3 mmol), HOBT (2.2 g, 14.3 mmol) and EDCI (2.7 g, 14.3 mmol) were added in sequence. The mixture was stirred at 140° C. overnight, then cooled to RT, quenched by water (100 mL), and extracted with EtOAc (2×50 mL). The combined organic phases were washed by water (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by silica gel column chromatography (EtOAc:Petroleum ether=1:5) to give 5-(1-methyl-1H-imidazol-4-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (1.8 g, 40.0%). MS (ES+) C13H9F3N4O2 requires: 310, found: 311 [M+H]+.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10](O)([CH3:13])([CH3:12])[CH3:11].ClCCl.[OH:18][C:19]1([C:22]([OH:24])=[O:23])[CH2:21][CH2:20]1>[Cu]Cl.C(O)(=O)C>[OH:18][C:19]1([C:22]([O:24][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:23])[CH2:21][CH2:20]1
Reactant: CC(C)(C)O
Reactant: O=C(O)C1(O)CC1
Agent: Cl[Cu]
Agent: CC(C)N=C=NC(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(O)CC1
Reaction time: 96 h

Procedure:
At room temperature under shielded light, to N,N′-diisopropylcarbodiimide (99.75 g) was added copper(I) chloride (1.57 g), and then tert-butanol (83 ml) was added dropwise over 20 minutes, followed by stirring for 4 days. The supernatant (48 ml) was added dropwise to a dichloromethane suspension (120 ml) of 1-hydroxycyclopropanecarboxylic acid (17.12 g) using an ice bath over 15 minutes. The temperature was brought back to room temperature, followed by stirring for 40 hours, and then acetic acid (11.5 ml) was added and stirred for 1 hour. The reaction suspension was filtered, and ice water and sodium hydrogen carbonate were added to the filtrate for neutralization. After the precipitate was filtered off, the organic layer separated from the filtrate was washed with saturated sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After pentane was added to the residue, insolubles were filtered off, and the filtrate was concentrated under reduced pressure to afford tert-butyl 1-hydroxycyclopropanecarboxylate (11.65 g).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH3:11])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C@H:14]1[CH2:18][CH2:17][NH:16][C@H:15]1[CH3:19].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([CH2:10][CH3:11])=[C:8]([N:16]2[CH2:17][CH2:18][C@H:14]([OH:13])[C@@H:15]2[CH3:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCc1c(F)ccc(C#N)c1Cl
Reactant: C[C@@H]1NCC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCc1c(N2CC[C@H](O)[C@@H]2C)ccc(C#N)c1Cl

Procedure:
Using 2-chloro-4-fluoro-3-ethylbenzonitrile (1.01 g), (2S,3S)-3-hydroxy-2-methylpyrrolidine (8.25 mmol) and lithium carbonate (813 mg), the title compound was obtained as a colorless solid (yield: 147 mg) by an operation similar to that in Example 3.
Reaction SMILES: [Na].[CH:2]1([OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8].Cl[CH:11]([CH3:15])[C:12](O)=[O:13].S(=O)(=O)(O)O>C(O)C.O>[CH3:15][CH:11]1[O:9][CH:2]2[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7]2)[O:8][C:12]1=[O:13]
Reactant: OC1CCCCC1O
Reactant: CC(Cl)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC1OC2CCCCC2OC1=O
Reaction time: 5 h

Procedure:
25.3 gm (1.1 mol) of sodium were dissolved in 500 ml of ethanol under dry nitrogen. 116 gm (1 mol) of 1,2-cyclohexane-diol were added to the solution at room temperature. Then, the ethanol was completely removed under vacuum. 163 gm (1.2 mol) of the ethyl ester of 2-chloropropionic acid were added to the mono-sodium salt of 1,2-cyclohexane-diol so obtained, at 50° C., and the mixture was allowed to stand for 5 hours at 80° C. to react further. Then, the reaction mixture was decomposed with water and acidified with sulfuric acid. The organic phase was separated and the aqueous phase was extracted twice with ether. After combining the organic phases, these were washed neutral with water and sodium bicarbonate solution, dried over sodium sulfate and reduced under vacuum. The crude product obtained was distilled under high vacuum. 76 gm of 4-methyl-2,5-dioxabicyclo-[4,4,0]-decan-3-one were obtained with the following analytical data:
Reaction SMILES: CC([N:5]([CH:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH2:10]1)[C:6](=[O:8])[O-:7])(C)C.C(O)(=O)C.[CH3:26][C:27](N(C1CCNCC1)C(=O)[O-])([CH3:29])[CH3:28]>[Pd].C(O)C>[NH:12]1[CH2:11][CH2:10][CH:9]([NH:5][C:6](=[O:8])[O:7][C:27]([CH3:29])([CH3:28])[CH3:26])[CH2:14][CH2:13]1
Reactant: CC(C)(C)N(C(=O)[O-])C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)N(C(=O)[O-])C1CCNCC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCNCC1

Procedure:
A mixture of 1,1-dimethylethyl[1-(phenylmethyl)-4-piperidinyl]carbamate (0.355 mole), 10% palladium-on-carbon (10.0 g.) in 43 ml. of acetic acid and 90 ml. of ethanol was hydrogenated under low pressure at room temperature for a 96 hr. period. The reaction mixture was filtered and concentrated in vacuo. Residual oil was taken up in chloroform, washed with 20% aqueous sodium carbonate solution and the aqueous phase extracted with additional chloroform. The combined chloroform extracts were dried (MgSO4) and evaporated in vacuo to afford 64.2 g. (90%) of 1,1-dimethylethyl4-piperidinylcarbamate, m.p. 153°-157°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[CH:41]=[C:40]([CH3:42])[N+:39]([O-:43])=[C:38]([CH3:44])[CH:37]=1>>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:15]=[CH:16][C:17]([C:36]3[CH:41]=[C:40]([CH3:42])[N+:39]([O-:43])=[C:38]([CH3:44])[CH:37]=3)=[CH:18][CH:19]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.086, m/z=461.1; 1H NMR (CDCl3) 1.34 (m, 1H), 1.50 (d, 3H), 1.61-1.72 (m, 2H), 1.88-2.00 (m, 2H), 2.18 (m, 1H), 2.22-2.34 (m, 2H), 2.62 (s, 6H), 2.88 (m, 1H), 3.51 (t, 2H), 5.65 (m, 1H), 6.93 (d, 2H), 7.21 (m, 1H), 7.26 (m, 4H), 7.29-7.38 (m, 4H).