Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH3:21])=[O:4].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]=1[CH2:21][Br:22])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(=O)n(CCc2ccccc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(CCc2ccccc2)c1CBr
Yield: 26.1 %

Procedure:
A mixture of 5-bromo-2-methyl-6-oxo-1-phenethyl-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (1 g, 2.86 mmol), N-bromosuccinimide (0.56 g, 3.14 mmol), and benzoyl peroxide (70 mg, 0.286 mmol) in CCl4 (25 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-25% EtOAc/hexanes) to give 320 mg of the title compound as a tan solid. MS: (+) m/z 452.06 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:12]=[CH2:13])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[O:14]([CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH2:12][CH2:13][N:25]2[CH2:26][CH2:27][CH:22]([CH2:21][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:23][CH2:24]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(OCC2CCNCC2)cc1
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Solvent: CCO
Product: CC(C)(C)Oc1cncc(CCN2CCC(COc3ccccc3)CC2)n1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
After dissolving 471 mg of 2-tert-butoxy-6-vinylpyrazine and 505 mg of 4-(phenoxymethyl)piperidine in 10 ml of ethanol, the mixture was stirred for 4 days at 80° C. The reaction solution was concentrated under reduced pressure and the residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain 2-tert-butoxy-6-[2-(4-phenoxymethylpiperidino)ethyl]pyrazine.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)(=O)=O>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CS(=O)(=O)OCCC1CCCCO1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A mixture of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) were heated at 60° C. with stirring for 1 h. 2-(Tetrahydro-2H-pyran-2-yl)ethyl methanesulfonate (142 mg) was added and the reaction was continued for 16 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give crude material (540 mg). The material was purified by normal phase chromatography (ISCO) using 0-20% methanol/EtOAc as eluent to give the title compound as a white solid (88 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C:11](=O)[CH:10]([CH2:16][C:17]([OH:19])=O)[CH2:9]3)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:21][NH2:22]>C(O)C>[N:1]1([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C:11]2=[N:21][NH:22][C:17](=[O:19])[CH2:16][CH:10]2[CH2:9]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: O=C(O)CC1Cc2cc(-n3ccnc3)ccc2C1=O
Solvent: O
Solvent: CCO
Product: O=C1CC2Cc3cc(-n4ccnc4)ccc3C2=NN1
Yield: 48 %

Procedure:
A solution of 1.48 g of 2,3-dihydro-5-(1H-imidazol-1-yl)-1-oxo-1H-indene-2-acetic acid and 0.38 g of 85% hydrazine hydrate in 15 ml of ethanol is heated to reflux for three hours. The reaction mixture is filtered, the residue is washed with ethanol and purified by crystallization from ethanol to give 0.7 g of the product, 2,4,4a,5-tetrahydro-7-(1H-imidazol-1-yl)-3H-indeno[1,2-c]pyridazin-3-one, mp 263°-264° dec.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH2:3][OH:4].Cl[C:9]1[N:14]2[N:15]=[CH:16][N:17]=[C:13]2[N:12]=[CH:11][CH:10]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[N:15]1[N:14]2[C:9]([N:1]3[CH2:7][CH2:6][CH2:5][C@@H:2]3[CH2:3][OH:4])=[CH:10][CH:11]=[N:12][C:13]2=[N:17][CH:16]=1
Reactant: Clc1ccnc2ncnn12
Reactant: OC[C@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OC[C@H]1CCCN1c1ccnc2ncnn12

Procedure:
1 g of commercially available (D)-prolinol, 1.5 g of 7-chloro-[1,2,4]triazolo-[1,5-a]pyrimidine and 2.6 g of N-ethyldiisopropylamine are heated at 130° C. in a microwave for 3 h in 60 ml of 1-butanol. The butanol is subsequently removed in vacuo, the residue is taken up in ethyl acetate, mixed with water, adjusted to pH 12 using 1 N NaOH solution, phases are separated, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel, giving 1.7 g of ((R)-1-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylpyrrolidin-2-yl)methanol as beige crystals;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=[O:4].[H-].[Na+].[CH3:25]I>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:25])[C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)c1cncn1C1c2ccccc2C(=O)NC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)N(C)C1(C)C
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester (55 mg, 0.184 mmol) in DMF (3.7 mL) at −10° C. is added sodium hydride (60% dispersion in oil 10 mg, 0.25 mmol). The reaction is stirred for 5 min at −10° C. and then placed at room temperature for 10 min. The resulting red solution is re-cooled to −10° C. and methyl iodide (0.025 mL, 0.40 mmol) is added dropwise. The reaction is placed at room temperature. After 10 min the yellow reaction mixture is quenched by the addition of saturated aqueous NH4Cl (ca. 1 mL). The resulting mixture is diluted with ethyl acetate and saturated aqueous NaHCO3. The layers are separated and the aqueous layer is extracted twice with ethyl acetate (ca. 10 mL). The organic layers are combined, dried with Na2SO4, filtered and concentrated in vacuo to afford 3-(2,3,3-trimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester as a yellow foam requiring no further purification prior to the next transformation; HRMS (ES) m/z 300.1354 [(M+H)+; calculated for C16H18N3O3: 340.1348]; 1H NMR (400 MHz, MeOD) δ ppm 1.30 (s, 3H), 1.41 (s, 3 H), 3.10 (s, 3 H), 4.04 (br. s., 3 H), 6.85 (br. s., 1 H), 7.50 (br. s., 1 H), 7.61-7.73 (m, 2 H), 8.09-8.27 (m, 3 H).
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].N(C(OC(C)(C)C)=O)[C@H:29](C(OC)=O)CCCCNC(OCC1C=CC=CC=1)=O>>[CH2:21]([O:20][C:18]([NH:1][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:15]([O:17][CH3:29])=[O:16])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1

Procedure:
The title compound was prepared from Z-L-Lys(Boc)OH by following the procedure described for example 4, intermediate 31. Intermediate 49 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 7.47 (m, 5H), 6.76 (t, 1H), 5.09 (s, 2H), 4.51 (m, 1H), 3.68 (s, 3H), 3.18 (m, 2H), 1.90 (m, 2H), 1.55 (m, 2H), 1.38 (s, 9H), 1.25 (m, 2H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C=C.[C:23]1(OC2C=CC=CC=2)[CH:28]=CC=C[CH:24]=1>CCOCC>[CH2:28]([C:10]1[CH:9]=[C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)[CH:7]=[CH:6][C:5]=1[OH:4])[CH:23]=[CH2:24]
Reactant: C=CCOc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: C=CCc1cc(N2CCN(c3ccncc3)CC2)ccc1O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
The product from step (i) (5 g) was heated under argon in gently refluxing diphenyl ether (15 g) for 21/2 hours. The mixture was cooled to room temperature and ether (70 ml) was added. The solid material was filtered and purified by flash chromatography on silica gel, eluting with methanol/dichloromethane (1/4 v/v) to give 2-allyl-4-[4-(4-pyridyl)piperazin-1-yl]phenol (0.88 g) as a solid, m.p. 180°-182° C.; NMR (d6 -DMSO) δ8.88(1H,s), 8.19(2H,dd), 6.87(2H,dd), 6.7(3H,m), 5.88-6.03(1H,m), 5.0(2H,m), 3.44(4H,t), 3.28(2H,d), 3.05(4H,t); m/e 296 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.[C:17](Cl)(=[O:28])[O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CCOC(C)=O>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[CH:9]=[CH:10][N:5]4[N:4]=[CH:3][C:2]([Br:1])=[C:6]4[N:7]=3)[CH2:12][CH2:13]2)=[O:28])=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To 2.00 g (7.09 mmol) of 3-bromo-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine dissolved in 40 mL of EtOAc at 0° C., was added 1.71 g (8.51 mmol) of 4-nitrophenyl carbonochloridate, followed by 1.97 mL (14.18 mmol) of TEA. After 5 minutes stirring at 0° C., the ice bath was removed, and stirring continued at RT for about 2 hr. It was diluted with 50 mL of 50% EtOAc/hex. The desired product was filtered out, and dried to obtain 3.17 g (100% yield) of an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH2:24])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2CCCN(C(=O)OCc3ccccc3)C2)cc1N
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.2 %

Procedure:
3-(3-Amino-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester (Example 13; 230 mg, 0.71 mmol) was dissolved in 5 mL dimethylformamide. Cesium carbonate (462 mg, 1.42 mol) and ethyl bromoacetate (86 μL, 0.78 mmol) were added and the mixture stirred at ambient temperature under a nitrogen atmosphere for 72 h. An additional 86 μL of ethyl bromoacetate were added and the reaction stirred an additional 24 h. The mixture was diluted with 100 mL water and extracted with diethyl ether (2×50 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 20% ethyl acetate/hexanes to yield 152 mg (52%) of 3-[3-(ethoxycarbonylmethyl-amino)-4-methyl-phenyl]-piperidine-1-carboxylic acid benzyl ester as a clear oil.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7](O)=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH2:26]([O:33][C:34](=[O:46])[C@H:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:36][C:37](=[O:41])[C@H:38]([CH3:40])[NH2:39])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([O:33][C:34](=[O:46])[C@H:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:36][C:37](=[O:41])[C@H:38]([CH3:40])[NH:39][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)N)C(=O)OCc1ccccc1
Reactant: CC(=O)N[C@@H](C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of acetylalanine (0.03 mole) and N-methylmorpholine (0.03 mole) in dry tetrahydrofuran (200 ml) at -20° to -25° is added isobutyl chloroformate (0.03 mole). After 10 minutes, a suspension of the crude alanylleucine benzyl ester hydrochloride (0.03+ mole) and N-methylmorpholine (0.04 mole) in tetrahydrofuran (25 ml) is added in portions over 1/2 hour. The mixture is allowed to warm to room temperature over a period of 2 hours and stirred overnight. The reaction mixture is evaporated to dryness and the residue is purified by chromatography on silica gel (200 gm) and elution with 10% methanol in chloroform to give acetylalanylalanylleucine benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2cc(F)cc(Cl)c2)CCNC1
Reaction time: 1.5 h
Yield: 64.4 %

Procedure:
To a solution of tert-butyl 3-(3-chloro-5-fluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (2.43 g, 7.7 mmol) in dichloromethane (80 mL), was added trifluoroacetic acid (5 mL). The mixture was stirred for 1.5 h after which the mixture was basified with aqueous sodium carbonate (10%, 50 mL) and evaporated. Ethyl acetate (100 mL) was added, the mixture was washed with brine and the organic phase was dried (MgSO4) and evaporated. Purification on a Biotage (solute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1), and by HPLC on Waters OBD 018, 5 μm (MeOH/33 mM NH3, 20:80 to 0:100), gave the title compound (1.07 g). MS m/z (rel. intensity, 70 eV) 215 (M+, bp), 157 (47), 129 (65), 109 (61), 95 (43).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]([C@@H:10]([CH2:17][CH2:18][CH3:19])[CH2:11][N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:25][CH3:26].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@@H:10]([CH2:17][CH2:18][CH3:19])[CH2:11][N:12]2[CH2:15][CH:14]([O:16][CH2:25][CH3:26])[CH2:13]2)[CH3:9])=[O:7])=[CH:20][CH:21]=1
Reactant: CCC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Cl)cc1
Reactant: CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC[C@@H](CN1CC(OCC)C1)N(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To (S)-4-chloro-N-(1-(3-hydroxyazetidin-1-yl)pentan-2-yl)-N-methylbenzamide (Example 8.2 A) (85 mg, 0.27 mmol) in dry THF (3 mL) was NaH (60% in mineral oil) (16.41 mg, 0.41 mmol) added carefully. The mixture was stirred at rt for 30 minutes then iodoethane (0.023 mL, 0.29 mmol) was added in one portion. The mixture was left standing at rt on. NaHCO3 and DCM were added and the two layers were separated using a phase separator. The organic phase was concentrated and the residue was purified by preparative HPLC to give the title compound (36 mg, 39%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.71, 0.86, 0.93-1.08, 1.08-1.32, 1.33-1.49, 2.36, 2.49-2.53, 2.54-2.61, 2.66, 2.70, 2.72-2.80, 3.19-3.32, 3.48, 3.96, 7.32, 7.38, 7.47. HRMS (M+H)+: calculated 339.1839. found 339.1840.
Reaction SMILES: [CH2:1]([PH:9](=[O:11])[OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(O)C>[CH2:1]([P:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:10])[OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCCCCCC
Reactant: CCCCCCCC[PH](=O)O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCCCCCCCP(=O)(O)CCCCCCCC
Yield: 32.8 %

Procedure:
To a stirred mixture of 46.5 g (0.261 mol) of n-octylphosphinic acid in 250 mL 95% ethanol, 1-octene (58.6 g, 0.5218 mol) was added followed by 9.042 g (0.026 mol) of 70% benzoyl peroxide. The resulting mixture was refluxed for 8 hs, and then another 6.758 g (0.0196 mol) of benzoyl peroxide was added and the reaction continued to reflux for an extra 8 hs. A third 4.244 g of benzoyl peroxide was added (0.01305 mol) and refluxing continued for an extra 8 hs. The resulting mixture was cooled in the refrigerator, filtered, and 11.8 g of di-n-octylphosphinic acid was recovered using a rotary evaporator. The solid was washed with 100 mL of cooled 95% ethanol and the filtrate was concentrated on the rotary vacuum and replaced in the refrigerator. Another 24.9 g di-n-octylphosphinic acid was obtained on cooling to attain a total of 36.7 g (48.4% yield).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH:15]1([O:14][CH2:13][CH2:12][NH:11][C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([C:32]4[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:25](=[O:26])[O:24][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:30][CH:31]=4)=[CH:3][N:4]=3)[N:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: Brc1cnc2ccc(NCCOC3CCCC3)nn12
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cnc3ccc(NCCOC4CCCC4)nn23)cc1
Yield: 70 %

Procedure:
The 3-bromo-N-(2-(cyclopentyloxy)ethyl)imidazo[1,2-b]pyridazin-6-amine was coupled with (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid under the Suzuki coupling conditions as described in example 5.6.76, Part B to obtain 70% product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:23])[CH3:22]
Reactant: COc1ccc(O)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(OC)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
4-Methoxyphenol (3.29 g, 26.5 mmol), K2CO3 (7.32 g, 53 mmol), and ethyl 2-bromopropionate (4.8 g, 26.5 mmol) were combined in anhydrous DMF (50 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce a golden oil (4.8 g, 81%) 1H NMR (250 MHz, CDCl3): δ 6.76 (d, 2H, J=7.9), 6.73 (d, 2H, J=7.9), 4.58 (q, 1H, J=6.1), 4.14 (q, 2H, J=7.2), 3.69 (s, 3H), 1.52 (d, 3H, J=6.1), 1.19 (t, 3H, J=7.2). MS [EI+] 225 (M+H)+, [EI−] 223 (M−H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:33][CH2:32][C:20]2([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]2)[CH2:19][CH2:18]1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[C:39]([O:42][CH3:43])[C:40]=1[OH:41]>>[Cl:34][C:35]1[CH:36]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:33][CH2:32][C:20]3([CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]3)[CH2:19][CH2:18]2)[CH:38]=[C:39]([O:42][CH3:43])[C:40]=1[OH:41]
Reactant: COc1cc(B(O)O)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC5(CCN(C(=O)OC(C)(C)C)C5)CC4)c3c2)cc(Cl)c1O
Yield: 191.5 %

Procedure:
Following general procedure F, tert-butyl 8-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl]-2,8-diazaspiro[4,5]decane-2-carboxylate (50 mg, 0.097 mmol) was reacted with 3-chloro-4-hydroxy-5-methoxyphenylboronic acid (41 mg, 0.161 mmol) to afford the crude product (110 mg) as a brown oil: ESI MS m/z 593 [C33H38ClN3O5+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[N:15]1([CH2:20][C:21](O)=[O:22])[CH:19]=[N:18][CH:17]=[N:16]1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.CN(C=O)C>[N:15]1([CH2:20][C:21]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[S:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH:3]=2)=[O:22])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: Nc1ccc2sc3ccccc3c2c1
Reactant: O=C(O)Cn1cncn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1cncn1)Nc1ccc2sc3ccccc3c2c1
Yield: 84.3 %

Procedure:
2-Aminodibenzthiophene (Bull. Soc. Chim. Fr. (1996), 133 (6), 597-610; 500 mg, 2.5 mmol) was dissolved DMF (10 ml) and 2-(1,2,4-triazol-1-yl)acetic acid (318 mg, 2.5 mmol) was added in one portion followed by 1-hydroxybenztriazole hydrate (383 mg, 5.0 mmol) and EDAC (960 mg, 5.0 mmol). The resultant mixture was stirred for 16 hours at ambient temperature then poured on to water (100 ml). A fine white solid was collected which was washed extensively with water, methanol (25 ml) and ether (25 ml) to leave a colourless solid (650 mg). NMR: 10.62 (brs, 1H), 8.18 (m, 2H), 8.16 (m, 1H), 7.99 (m, 3H), 7.62 (dd, 1H), 7.50 (m, 2H), 5.20 (s, 2H); m/z 309.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:7]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:6][C@H:5]([S:12][C:13](=[O:15])[CH3:14])[CH2:4]1.C(O[C@H:20]1[O:37][C@@H:36]([CH3:38])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]1[O:22][C:23](=[O:25])[CH3:24])(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:28]([O:27][C@@H:26]1[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:36]([CH3:38])[O:37][C@H:20]([O:1][CH2:2][C@@H:3]2[CH2:4][C@@H:5]([S:12][C:13](=[O:15])[CH3:14])[CH2:6][N:7]2[S:8]([CH3:11])(=[O:10])=[O:9])[C@@H:21]1[O:22][C:23](=[O:25])[CH3:24])(=[O:30])[CH3:29]
Reactant: CC(=O)S[C@@H]1C[C@@H](CO)N(S(C)(=O)=O)C1
Reactant: CC(=O)O[C@H]1O[C@@H](C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@H](OC[C@@H]2C[C@@H](SC(C)=O)CN2S(C)(=O)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of thioacetic acid (3R,5S)-S-(5-hydroxymethyl-1-methanesulfonyl-pyrrolidin-3-yl) ester (0.070 g) and 1,2,3,4-tetra-O-acetyl-6-deoxy-beta-L-mannopyranose [G. Hodosi and P. Kovàc, Carbohydr. Res., 303, 239-243 (1997)] (0.138 g) in dichloromethane (10.0 ml) was treated with trimethylsilyl trifluoromethanesulphonate (0.075 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, poured into a sodium bicarbonate solution, and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:1 as eluent to obtain acetic acid (2S,3R,4R,5S,6S)-4,5-diacetoxy-2-[(2S,4R)-4-acetylsulfanyl-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-6-methyl-tetrahydro-pyran-3-yl ester (0.105 g) as a syrup, MS: 543 (M+NH4+). Acetic acid (2S,3R,4R,5S,6S)-4,5-diacetoxy-2-[(2S,4R)-4-acetylsulfanyl-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-6-methyl-tetrahydro-pyran-3-yl ester (0.080 g) was reacted as described for the S-Acetyl deprotection (see below) to obtain (2S,3R,4R,5R,6S)-2-[(2S,4R)-4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-6-methyl-tetrahydro-pyran-3,4,5-triol (0.035 g) as a colourless foam, MS: 358 (MH+).