Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15](N)[S:16][C:12]=2[CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[F:21][C:22]1[CH:30]=[C:29]([CH:31]=[O:32])[CH:28]=[CH:27][C:23]=1C(Cl)=O.CCN(C(C)C)C(C)C.Cl[Sn]Cl.[OH-].[Na+]>O.C1COCC1.CCOC(C)=O.CCO.C(O)CO>[CH2:3]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15]([C:23]3[CH:27]=[CH:28][C:29]([CH:31]=[O:32])=[CH:30][C:22]=3[F:21])[S:16][C:12]=2[CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1nc2ccc(Cc3ccccc3)cc2s1
Reactant: O=Cc1ccc(C(=O)Cl)c(F)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(-c2nc3ccc(Cc4ccccc4)cc3s2)c(F)c1
Temperature: 135 °C
Reaction time: 6 h

Procedure:
A solution of 12.3 g KOH in H2O (15 mL) was mixed with ethylene glycol (8 mL). 6-benzylbenzo[d]thiazol-2-amine (3.00 g, 12.5 mmol) was added to the mixture under N2 atmosphere. The mixture was stirred at 135° C. for 6 h, added to a 100 mL volume of ice and acidified to pH 6 using 5M aqueous HCl. The resulting suspension was extracted 2× with DCM. The organic layers were washed 1× with brine, dried over MgSO4, and evaporated to give beige solids (1.81 g, used without further purification). A solution of the crude material (0.695 g, 3.23 mmol) in THF (5 mL) was added to a mixture of 2-fluoro-4-formylbenzoyl chloride (0.55 g) in THF (5 mL) and Hunig's base (0.844 mL, 4.84 mmol) and stirred for 17 h at 24° C. The mixture was diluted with EtOAc, washed 1× with saturated aqueous NaHCO3, 1× with brine, dried over MgSO4 and evaporated to give a red foam (0.916 g, used for the next step). The crude material was treated with EtOH (16 mL), water (2 mL), and concentrated aqueous HCl (8 mL) followed by SnCl2 (1.67 g, 8798 μmol) and heated to reflux for 6 h (heterogeneous). The mixture was cooled to 0° C., basified with 10M aqueous NaOH, and partitioned between water and DCM. The aqueous layer was extracted with DCM (3×) and the combined organic layers were dried over MgSO4 and evaporated. Purification by flash chromatography (hexanes/EtOAc=5:1) gave 4-(6-Benzylbenzo[d]thiazol-2-yl)-3-fluorobenzaldehyde as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.06 (s, 1H), 8.67 (t, J=7.0 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.76-7.73 (m, 2H), 7.43-7.40 (m, 1H), 7.33-7.31 (m, 2H), 7.26-7.23 (m, 3H), 4.16 (s, 2H). MS (ESI) m/z: Calculated: 347.4; Observed: 348.1 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7].O1CCCC1.[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:34]([O:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a solution of 4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (14.4 mg) in a mixture of anhydrous tetrahydrofuran (1 ml) and N,N-dimethylformamide (1 ml) was added sodium hydride (60% oil dispersion, 4.7 mg) in one portion under ice cooling. The mixture was stirred for half an hour at the same temperature and benzylbromide (13.3 mg) was added. After stirred for 2 hours at ambient temperature, the reaction was quenched with water (2 ml) and extracted with diethyl ether (1 ml) three times. The combined organic layers were washed with water, dried, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (diethyl ether/n-hexane=1/1) to give 4-[3-(2-benzyloxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (4.8 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][N:3]=1.[C:18]([NH:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)(=[O:20])[CH3:19].[F-].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CS(C)=O>[CH3:27][C:25]1[N:26]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[S:23][C:24]=1[C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1ccnc(Br)c1)c1ccccc1
Reactant: CC(=O)Nc1nc(C)cs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1nc(C)c(-c2cc(NS(=O)(=O)c3ccccc3)ccn2)s1
Temperature: 150 °C
Yield: 13.4 %

Procedure:
A mixture of N-(2-bromopyridin-4-yl)benzenesulfonamide (700 mg), 2-acetamido-4-methylthiazole (384 mg), palladium(II) acetate (41 mg), caesium fluoride (1.01 g), tri-tert-butylphosphine (0.34M solution in hexane, 1.06 mL) and DMSO (20 mL) was purged with nitrogen. The resultant mixture was heated to 150° C. for 5 hours under an atmosphere of nitrogen. The bulk of the DMSO was evaporated and the residue was treated with water (40 mL). Water was decanted from the resultant gum which was purified by column chromatography on silica using a solvent gradient of 2% to 5% methanol in dichloromethane as eluent. There was thus obtained the title compound as a solid (116 mg); 1H NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 2.44 (s, 3H), 6.93 (d, 1H), 7.32 (s, 1H), 7.60-7.70 (m, 3H), 7.91 (m, 2H), 8.29 (d, 1H), 11.25 (s, 1H), 12.13 (s, 1H); Mass Spectrum: M+H+ 389.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH:17](O)[CH2:16][CH2:15][CH:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:36]=[N+:37]=[N-:38].[Na+]>ClCCl.CS(C)=O.O>[N:36]([CH:17]1[CH2:16][CH2:15][CH:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH:12]1[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1CCC(O)C(NC(=O)OCc2ccccc2)C1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C1CCC(N=[N+]=[N-])C(NC(=O)OCc2ccccc2)C1
Temperature: 30 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a solution of Racemate-ethyl 3-(benzyloxycarbonylamino)-4-hydroxycyclohexanecarboxylate (7.0 g, 22 mmol) and triethylamine (6.7 g, 66 mmol) in dichloromethane (100 mL) was dropwise added methanesulfonyl chloride (5.1 g, 44 mmol) at 0° C., and the mixture was stirred at this temperature for 2 hours. The reaction mixture was washed with water (200 mL×3) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to thereby give crude product (8.0 g, crude) as a yellow oil. A mixture of the above residue (8.0 g, 20 mmol) and sodium azide (7.8 g, 120 mmol) in dimethylsulfoxide (50 mL) was stirred at 100° C. for 18 hours. The reaction mixture was cooled to ˜30° C., dissolved in water (˜300 mL) and extracted with ethyl acetate (200 mL×2). The combined organic layers were washed with brine (˜200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (3.5 g, 46% total yield for two steps) as a colorless oil. MS (ES+) C17H22N4O4 requires: 346, found: 347 [M+H]+, 369 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.[H][H]>C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:4]([F:15])[CH:3]=1
Reactant: [H][H]
Reactant: CC(C)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)Oc1cc(Nc2ccccc2)c(F)cc1Cl
Yield: 69.3 %

Procedure:
A mixture of 4-chloro-2-fluoro-5-isopropoxynitrobenzene (13.5 g) and platinum dioxide (0.4 g) in ethanol (300 ml) was subjected to catalytic reduction with hydrogen at room temperature (ca. 20° C.) under atmospheric pressure, whereby a designed amount of hydrogen was absorbed. The resultant mixture was filtered to remove insoluble materials, and the filtrate was concentrated. The residue was subjected to purification by silica gel chromatography to give 5.6 g of 4-chloro-2-fluoro-5-isopropoxyphenylaniline. nD24.5 1.5360.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CN=C1.N1C=CC=CC=1.[CH:52]([Si:55](Cl)([CH:59]([CH3:61])[CH3:60])[CH:56]([CH3:58])[CH3:57])([CH3:54])[CH3:53]>CN(C)C=O.C(OCC)(=O)C>[CH:52]([Si:55]([CH:59]([CH3:61])[CH3:60])([CH:56]([CH3:58])[CH3:57])[O:38][C@@H:25]1[C@@H:24]([CH2:23][O:22][C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:6]2[CH:39]=[CH:40][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:28][C@@H:27]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:26]1)([CH3:54])[CH3:53]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[Si](C(C)C)(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
1.485 g (2.73 mmol) of 5'-O-(4,4'-dimethoxytrityl)thymidine and 0.37 g (5.45 mmol) of imidazole were first dried by azeotropic distillation under reduced pressure with pyridine and then dissolved in 6 ml of dimethylformamide. 875 μl (4.09 mmol) of triisopropylsilyl chloride were added to this solution, and the resulting mixture was stirred overnight at room temperature. At the end of this time, 875 μl of triisopropylsilyl chloride and 0.37 g of imisazole were added to the mixture, which was then stirred for one day. The reaction mixture was then diluted with 100 ml of ethyl acetate and the diluted mixture was washed twice, each time with 100 ml of a 5% w/v aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 100 g of silica gel (70-230 mesh), using methylene chloride containing from 0 to 3% by volume of methanol as the eluent, to give 1.861 g (yield 97%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[NH2:14])[CH:5]=[CH:6][C:7]=1[F:8].C1CCN2C(=NCCC2)CC1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:29]([CH:26]([CH3:28])[CH3:27])(=[O:31])=[O:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC1CCCC1c1ccc(F)c(F)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with (+,−) cis-[2-(3,4-difluoro-phenyl)-cyclopentylamine (1.40 g, 7.10 mmol) from preparation 15, methylene chloride (20.0 mL) and the solution cooled to 0° C. DBU (1.27 mL, 8.52 mmol) and isopropylsulfonyl chloride (0.96 mL, 8.52 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with 1N HCl, brine and the organic layer dried over sodium sulfate. The title compound was purified by radial chromatography eluting with methylene chloride to give 910 mg (42%) of the purified title compound. The nmr was consistent with the assigned structure.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br-].[Na+].C(=O)([O-])O.[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC1(C)N([O])C(C)(C)CCC1.O.C(OCC)(=O)C>[Cl:1][CH2:2][C:3](=[O:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(CCl)COc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCl)COc1ccccc1
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To the mixture consisting of 30 mmol (5.60 g) of 1-chloro-3-phenyloxy-2-propanol, 1.5 mmol (234 mg) of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 33 mmol (3.4 g) of sodium bromide, 90 mmol (7.50 g) of sodium hydrogencarbonate, 75 ml of ethyl acetate and 35 ml of water was added dropwise 47 mmol (32 g) of sodium hypochlorite aqueous solution (1.5 mmol/g) under cooling with ice. Temperature of the reaction system was about 4° C. and pH was about 8.5. After the dropping was completed, stirring was further continued for 30 minute. Thereto was added 20 ml of a 5% sodium thiosulfate aqueous solution and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered off and concentrated under reduced pressure to obtain a crude product. It was purified with silica gel column to obtain 4.51 g of 1-chloro-3-phenyloxy-2-propanon. The yield was 82%.
Reaction SMILES: CN(C)C=O.[Na].[C:7]([O:10][CH2:11][C:12]1[CH2:19][S:18][CH:17]2[N:14]([C:15](=[O:21])[CH:16]2[NH2:20])[C:13]=1[C:22]([OH:24])=[O:23])(=[O:9])[CH3:8].Cl[CH2:26][O:27][C:28](=[O:31])[CH2:29][CH3:30]>C(OCC)(=O)C>[C:28]([O:27][CH2:26][O:23][C:22]([C:13]1[N:14]2[CH:17]([S:18][CH2:19][C:12]=1[CH2:11][O:10][C:7](=[O:9])[CH3:8])[CH:16]([NH2:20])[C:15]2=[O:21])=[O:24])(=[O:31])[CH2:29][CH3:30]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CCC(=O)OCCl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)OCOC(=O)C1=C(COC(C)=O)CSC2C(N)C(=O)N12
Reaction time: 3 h

Procedure:
To 35 ml of dimethyl formamide is added 7.5 g of the sodium salt of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, and the solution is stirred at room temperature for about 30 minutes after which 8 ml of chloromethylpropionate is added. Stirring is continued at room temperature for about 3 hours. The mixture is diluted with ethyl acetate and washed with water. The organic layer is separated and evaporated to dryness. The residue is recrystallized from ethyl acetate to give 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid propionyloxymethyl ester.
Reaction SMILES: [Cl-].C[Al+]C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.C[O:13][C:14]([C:16]1[CH:17]=[C:18]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:19]=[C:20]2[O:24][CH:23]([CH3:25])[CH2:22][C:21]=12)=O>>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:14]([C:16]1[CH:17]=[C:18]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=2)[CH:19]=[C:20]2[O:24][CH:23]([CH3:25])[CH2:22][C:21]=12)=[O:13]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Reactant: Nc1ccccn1
Agent: C[Al+]C
Agent: [Cl-]
Product: CC1Cc2c(cc(Oc3ccc(S(C)(=O)=O)cc3)cc2C(=O)Nc2ccccn2)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
Dimethylaluminum chloride (1.0 M solution in hexanes, 3 mL, 3.0 mmol) was added to a solution of 2-aminopyridine (282 mg, 3.0 mmol) in 1,2-dichloromethane at 0° C. The mixture was stirred at room temperature for 15 min and then 6-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (1f) (108 mg, 0.30 mmol) in 1,2-dichloromethane (3 mL) was added. The mixture was stirred at room temperature overnight, and carefully quenched with 20% aqueous potassium sodium tartrate tetrahydrate (5 mL), diluted with H2O (30 mL), extracted with CH2Cl2 (2×50 mL) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 50% EtOAc in hexane to give a white solid (67 mg, 53% yield). 1H NMR (400 MHz, CDCl3) δ 8.39 (br. s., 1 H) 8.21-8.34 (m, 2 H) 7.87-7.96 (m, 2 H) 7.70-7.81 (m, 1 H) 7.04-7.17 (m, 3 H) 6.94 (d, J=2.02 Hz, 1 H) 6.67 (d, J=1.77 Hz, 1 H) 4.97-5.18 (m, 1 H) 3.71 (dd, J=16.67, 8.84 Hz, 1 H) 3.19 (dd, J=16.67, 7.58 Hz, 1 H) 3.07 (s, 3 H) 1.53 (d, J=6.32 Hz, 3 H); LCMS for C22H20N2O5S m/z 425.10 (M+H)+; Anal. Calcd. for C22H20N2O5S.0.2H2O: C, 61.73; H, 4.80; N, 6.54. Found: C, 61.71; H, 4.81; N, 6.41.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>CCO>[N:15](=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[OH:16]
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(=NO)c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of 4-oxo-4-phenylbutyric acid (1.0 g, 5.3 mmol) in 50 mL of EtOH was added hydroxylamine hydrochloride (742 mg, 11 mmol) and sodium acetate (1.8 g, 21 mmol). The reaction flask was heated at 80° C. for 4 h and was then cooled to room temperature. Addition of water and filtration of the resultant precipitate afforded, after recrystallization (10:1 chloroform:hexane), 620 mg (60%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-]>ClC(Cl)C.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)COC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 7 h
Yield: 47.3 %

Procedure:
To a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 25 mmol) and rhodium(II)acetate (180 mg) in 500 ml dichloroethane at 80° C. was added (over 90 min) ethyl diazoacetate (4.2 ml, 50 mmol) in 220 ml dichloroethane. The mixture was stirred for 7 h and quenched with aqueous sodium bicarbonate (2×100 ml). The organic phase was isolated and washed with brine (2×100 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (80g) in petroleum ether:ethyl acetate (4:1) to give 3.4 g of 4-(ethoxycarbonylmethoxy)piperidine-1-carboxylic acid tert-butylester. The product was taken up in 40 ml of a 1 M lithium hydroxide solution in water:methanol (1:3) and stirred for 60 min. The mixture was concentrated in vacuo and dissolved in 20 ml of water, acidified to pH 4 with 1M aqueous hydrogen chloride and extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate and concentrated in vacuo to give 1.79 g of 4-(carboxymethoxy)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C(N(CC)CC)C.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:18]([NH2:25])[C@H:17]1[OH:26]>CCCCO>[Cl:8][C:4]1[N:3]=[C:2]([NH:25][C@@H:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][C@@H:17]2[OH:26])[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: O[C@H]1Cc2ccccc2[C@H]1Nc1cncc(Cl)n1
Temperature: 115 °C
Yield: 54.5 %

Procedure:
To a solution of 2,6-dichloropyrazine (5.0 g, 34 mmol) in n-BuOH (30 mL) was added triethylamine (6.8 g, 9.4 mL, 67 mmol) and (1R,2S)-(+)-cis-1-amino-2-indanol (5.0 g, 34 mmol). The mixture was heated at 115° C. overnight. The solution was cooled to rt and concentrated. Dissolve material in EtOAc (200 mL) and remove insoluble material by vacuum filtration. Wash filtrate sequentially with 4 N NaOH and sat. aq. NaCl. Dry organic extract over MgSO4, filter and concentrate. Purify by biotage MPLC (90 g column, 10% ethyl acetate/hexanes) to afford 4.85 g (57%) of (1R,2S)-1-[(6-chloropyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol as a solid: 1H NMR (CDCl3) δ 2.83-2.87, 3.08-3.13, 3.32, 4.54, 5.11, 5.28-5.31, 7.18-7.28, 7.73, 8.12; MS (ESI+) for C13H12ClN3O m/z 262 (M+H)+.
Reaction SMILES: [C:1]([C:3]([C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])#[N:2].[Li]C.[BH4-].[Na+].Cl.[OH-].[Na+].[CH3:23]C#N>CO.O.C1COCC1>[NH2:13][CH:12]([C:11]1[CH:10]=[CH:9][C:8]([C:3]([CH2:4][CH3:5])([CH2:6][CH3:7])[C:1]#[N:2])=[CH:15][CH:14]=1)[CH3:23]
Reactant: CCC(C#N)(CC)c1ccc(C#N)cc1
Reactant: CC#N
Agent: Cl
Agent: [BH4-]
Agent: [Li]C
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(C#N)(CC)c1ccc(C(C)N)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4-(1-Cyano-1-ethylpropyl)benzonitrile (936 mg, 5.51 mmol) is added to THF (20.0 mL), and the resulting solution is cooled to −78° C. MeLi (3.44 mL, 5.51 mmol) is added, and the solution is stirred for 20 minutes. NaBH4 (208 mg, 5.51 mmol) is mixed in MeOH (20.0 mL) and added to the first solution. The resulting solution is warmed to room temperature and stirred for 1 hour. 1N HCl (50.0 mL) is added followed by 1N NaOH (60.0 mL). The aqueous phase is extracted with EtOAc (4 times 50.0 mL) and the combined organic phases are dried with MgSO4, filtered and concentrated on the rotovaporator. The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5u) 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (528 mg, 2.44 mmol, 44%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.77 (t, J=7.32 Hz, 6H) 1.22 (d, J=6.45 Hz, 3H) 1.82-2.07 (m, 4H) 3.97 (q, J=6.64 Hz, 1H) 7.32 (d, J=8.40 Hz, 2H) 7.40 (d, J=8.20 Hz, 2H).
Reaction SMILES: [CH2:1]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12](Cl)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:27][C:28]1[CH:29]=[C:30]([C:38]([O:40][CH3:41])=[O:39])[CH:31]=[C:32]([CH:37]=1)[C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C.O>O1CCCC1>[CH2:1]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12]([NH:27][C:28]1[CH:37]=[C:32]([C:33]([O:35][CH3:36])=[O:34])[CH:31]=[C:30]([CH:29]=1)[C:38]([O:40][CH3:41])=[O:39])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Cl
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Nc1cc(C(=O)OC)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 2-decyltetradecanoyl chloride from Step 1 in dry tetrahydrofuran (80 mL) was added dropwise slowly to a suspension of dimethyl 5-aminoisophthalate (Sigma-Aldrich, 4.40 g, 21.0 mmol), triethyl amine (4.4 mL, 31.5 mmol), and dry tetrahydrofuran (100 mL) under an inert atmosphere at 0° C. The reaction was allowed to warm slowly to room temperature and was stirred overnight. Deionized water (10 mL) was added and the tetrahydrofuran was removed by rotary evaporation. The crude residue was then dissolved in 250 mL of ethyl acetate and washed with 3 successive 100 mL portions of deionized water. The ethyl acetate was then removed from the organic phase by rotary evaporation and the product was dried in vacuo to give crude dimethyl 5-(2′-decyltetradecanamido)isophthalate (12.56 g) as a pale yellow solid.