Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.COP([CH2:19][C:20]1[N:21]([CH3:36])[C:22]2[C:27]([N:28]=1)=[C:26]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[N:25]=[C:24]([Cl:35])[N:23]=2)(=O)OC.[C:37]([O:41][C:42]([N:44]1[CH2:47][C:46](=O)[CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:47][C:46](=[CH:19][C:20]2[N:21]([CH3:36])[C:22]3[C:27]([N:28]=2)=[C:26]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[N:25]=[C:24]([Cl:35])[N:23]=3)[CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: COP(=O)(Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)OC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1c(C=C2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
To a solution of diisopropylamine (1.4 mL, 9.8 mmol) in THF (3 mL) at −78° C. was added n-BuLi (3.9 mL, 9.8 mmol, 2.5 M in hexanes) and the resulting mixture allowed to stir for 20 min. The resulting solution was added to a pale green solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)phosphonic acid dimethyl ester (3.36 g, 8.9 mmol) in THF (80 mL) at −78° C. The resulting mixture was warmed to r.t. before a solution of 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (1.76 g, 10.2 mmol) in THF (10 mL) was added. The resulting pink mixture was stirred for 16 h then quenched with H2O. The mixture was concentrated in vacuo and the residue was partitioned between DCM and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-70%) affording the title compound as a green powder (3.46 g, 92%). 1H NMR (CDCl3, 400 MHz): δ 6.33-6.32 (1 H, m), 4.91-4.90 (2 H, m), 4.71-4.70 (2 H, m), 4.28 (4 H, brd s), 3.81 (4 H, t, J=4.74 Hz), 3.71 (3 H, s), 1.48 (9 H, s).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCCCCCCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: BrCCCCCCCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
12-Bromododecan-1-ol (1.83 g) was dissolved in 7 ml of dried THF, and sodium hydride (331.2 mg) was added to this solution. The reaction mixture was stirred at room temperature for 30 minutes, then benzyl bromide (0.99 ml) was added using a syringe, and the reaction mixture was refluxed for 24 hours while stirring. Saturated ammonium chloride solution was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with saline solution, dried over magnesium sulfate, and filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (hexane:dichloromethane=8:2) gave 1-((12-bromododecanoxy)methyl)benzene as a colorless oil at a 73% yield.
Reaction SMILES: [Na+].[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(OC)(C)(C)C.Cl>O>[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)O)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of p-toluenesulfinic acid sodium salt (30 g) in H2O (100 mL) was added methyl t-butyl ether (50 mL) followed by dropwise addition of conc HCl (15 mL). After stirring 5 min, the organic phase was removed and the aqueous phase was extracted with methyl t-butyl ether. The organic phase was dried (Na2SO4) and concentrated to near dryness. Hexane was added and the resulting precipitate collected to afford p-toluenesulfinic acid; yield 22 g.
Reaction SMILES: CS(Cl)(=O)=O.C(C1SC2C(C(=O)N2C(=C(OS(C)(=O)=O)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N=1)C1C=CC=CC=1.N1CCOCC1.[CH2:51]([C:58]1[S:64][CH:63]2[CH:60]([C:61](=[O:90])[N:62]2[C:65](=[C:82]([N:84]2[CH2:89][CH2:88][O:87][CH2:86][CH2:85]2)[CH3:83])[C:66]([O:68][CH:69]([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[O:67])[N:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.[Br:91]Br>O1CCCC1.N1C=CC=CC=1.C(N(CC)CC)C>[CH2:51]([C:58]1[S:64][CH:63]2[CH:60]([C:61](=[O:90])[N:62]2[C:65](=[C:82]([N:84]2[CH2:85][CH2:86][O:87][CH2:88][CH2:89]2)[CH2:83][Br:91])[C:66]([O:68][CH:69]([C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)[C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[O:67])[N:59]=1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Reactant: BrBr
Agent: CC(OS(C)(=O)=O)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: C1COCCN1
Product: O=C(OC(c1ccccc1)c1ccccc1)C(=C(CBr)N1CCOCC1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reaction time: 3.5 h
Yield: 70 %

Procedure:
One dissolves diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hdyroxyethylidene)acetate (4.84 g) in tetrahydrofuran (60 ml), cools to -20° C., adds triethylamine (2.84 ml) with stirring, adds dropwise methanesulfonyl chloride (0.82 ml) to the yellow solution, and lets react for 30 minutes. To the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, one adds morpholine (0.96 ml) at -40° C., stirrs for 3.5 hours, adds pyridine (0.77 ml) to the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -40° C., adds bromine (0.49 ml), and stirs for 30 minutes to give diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α -(2-bromo-1-morpholinoethylidene)acetate. To this solution, one adds dropwise for 3 hours at room temperature 5% hydrochloric acid (72 ml) and methanol (60 ml), stirs, and keeps in a refrigerator overnight. The reaction mixture is evaporated to give residue which is dissolved in methylene chloride, washed with water, dried over sodium sulfate, and evaporated. Purification of the obtained residue (5.83 g) by chromatography over silica gel containing 10% water (150 g) gives from the fraction eluted with a mixture of benzene and ethyl acetate (4:1) diphenylmethyl 7-phenylacetamido-3hyroxy-3-cephem-4-carboxylate (3.51 g) by recrystallization from n-hexane. m.p. 93°-96° C. Yield: 70%. IR: νmaxCHCl3 3410, 1782, 1674, 1610 cm-1. NMR: δCDCl3 3.20s2H, 3.64s2H, 4.97d(4Hz)1H, 5.66dd(9:4Hz)1H, 6.77d (9Hz)1H, 6.90s1H, 7.35m15H.
Reaction SMILES: C(C1SC2C(C(=O)N2C(=C(O)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N=1)C1C=CC=CC=1.CS(Cl)(=O)=O.C(C1SC2C(C(=O)N2C(=C(OS(C)(=O)=O)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N=1)C1C=CC=CC=1.N1CCOCC1.[CH2:86]([C:93]1[S:99][CH:98]2[CH:95]([C:96](=[O:125])[N:97]2[C:100](=[C:117]([N:119]2[CH2:124][CH2:123][O:122][CH2:121][CH2:120]2)[CH3:118])[C:101]([O:103][CH:104]([C:111]2[CH:116]=[CH:115][CH:114]=[CH:113][CH:112]=2)[C:105]2[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=2)=[O:102])[N:94]=1)[C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1.[Br:126]Br>O1CCCC1.N1C=CC=CC=1.C(N(CC)CC)C>[CH2:86]([C:93]1[S:99][CH:98]2[CH:95]([C:96](=[O:125])[N:97]2[C:100](=[C:117]([N:119]2[CH2:120][CH2:121][O:122][CH2:123][CH2:124]2)[CH2:118][Br:126])[C:101]([O:103][CH:104]([C:111]2[CH:112]=[CH:113][CH:114]=[CH:115][CH:116]=2)[C:105]2[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=2)=[O:102])[N:94]=1)[C:87]1[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=1
Reactant: BrBr
Reactant: CC(=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Agent: CC(O)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: CC(OS(C)(=O)=O)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(OC(c1ccccc1)c1ccccc1)C(=C(CBr)N1CCOCC1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reaction time: 3.5 h
Yield: 70 %

Procedure:
One dissolves diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (4.84 g) in tetrahydrofuran (60 ml), cools to -20° C., adds triethylamine (2.84 ml) with stirring, adds dropwise methanesulfonyl chloride (0.82 ml) to the yellow solution, and lets react for 30 minutes. To the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, one adds morpholine (0.96 ml) at -40° C., stirs for 3.5 hours, adds pyridine (0.77 ml) to the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -40° C., adds bromine (0.49 ml), and stirs for 30 minutes, to give diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl] -α-(2-bromo-1-morpholinoethylidene)acetate. To this solution, one adds dropwise 5% hydrochloric acid (72 ml) and methanol (60 ml), stirs for 3 hours at room temperature, and keeps in a refrigerator overnight. The reaction mixture is evaporated to give residue which is dissolved in methylene chloride, washed with water, dried over sodium sulfate, and evaporated. Purification of the obtained residue (5.83 g) by chromatography over silica gel containing 10% water (150 g) gives from the fraction eluted with a mixture of benzene and ethyl acetate (4:1) diphenylmethyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (3.51 g) by recrystallization from n-hexane. m.p. 93°-96° C. Yield: 70%. IR: νmaxCHCl3 3410, 1782, 1674, 1610 cm-1. NMR: δCDCl3 3.20s2H, 3.64s2H, 4.97d(4 Hz)1H, 5.66dd(9:4)1H, 6.77d(9 Hz)1H, 6.90s1H, 7.35 ml5H.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:18](=[O:20])[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:12](=[O:22])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]([O:33][CH2:34][CH2:35][O:36]N)([CH3:32])([CH3:31])[CH3:30]>CC(N(C)C)=O>[C:29]([O:33][CH2:34][CH2:35][O:36][N:17]1[C:18](=[O:20])[C:19]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:11][C:12](=[O:22])[N:13]([CH3:21])[C:14]=2[N:15]=[CH:16]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OCCON
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(OCCOC(C)(C)C)cnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
Compound 5F (250 mg, 0.61 mmol), potassium carbonate (209 mg, 1.51 mmol) and 1-chloro-2,4-dinitronbenzene (307 mg, 1.51 mmol) were stirred in DMA at 80° C. for 1.5 h. O-(2-tert-Butoxy-ethyl)-hydroxylamine was added at r.t and the reaction was stirred for 1 h at 80° C. Purification by prep-HPLC gave 43 mg (12%) of the title compound as an off-white solid. MS (ES) [m+H] calc'd for C20H22FIN4O4, 529; found 529.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH2:6])[CH3:2].[Cl:8][CH2:9][C:10](Cl)=[O:11]>>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH:6][C:10](=[O:11])[CH2:9][Cl:8])[CH3:2]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)CCl
Product: CCOC(=O)CNC(=O)CCl

Procedure:
The ester prepared in step 1 is reacted with chloroacetylchloride at a temperature of from about -10° to +10° C. in a suitable solvent in the presence of a suitable base to produce chloroacetylglycine ethyl ester. Solvents useful in this reaction include water, dichloromethane, and dichloroethane. Suitable bases include sodium bicarbonate, sodium carbonate, potassium carbonate, and sodium hydroxide. If the aminoacid is used in the form of its hydrochloride, a two-fold excess of base must be used.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C([O:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)C1C=CC=CC=1.CN(C)C1C=CC=CC=1.Cl>ClCCl>[Br:20][C:15]1[CH:14]=[C:13]([OH:12])[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Oc1cc(F)cc(Br)c1
Reaction time: 0.17 h
Yield: 66.6 %

Procedure:
Add aluminum chloride (13.51 g, 101.38 mmol) to 1-benzyloxy-3-bromo-5-fluoro-benzene (9.50 g, 33.79 mmol, prepared according to WO 03/101956) and dimethylaniline (40.96 g, 337.92 mmol) in dichloromethane (84 mL) at −0° C. under nitrogen and stir 10 minutes. Remove ice-bath and stir 2 hours. Add 60 mL 2N hydrochloric acid dropwise. Separate layers and wash the organic layer with 2N hydrochloric acid (4×50 mL). Extract the organic layer with 3N potassium hydroxide (4×50 mL). Acidify with 5N hydrochloric acid and extract with dichloromethane (3×50 mL). Dry the dichloromethane layer (sodium sulfate) and concentrate to give 4.3 g (66.6%) of the desired compound as an oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.N1C=CC=CC=1.[C:64](OC(=O)C)(=[O:66])[CH3:65]>ClCCl>[C:64]([O:50][CH:45]1[CH2:44][CH2:43][CH:42]([CH:41]=[C:40]([CH:24]2[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28](=[O:29])[CH:30]([CH2:35][CH:36]=[CH2:37])[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]3[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]3[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]3[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:21](=[O:22])[O:23]2)[CH3:51])[CH2:47][CH:46]1[O:48][CH3:49])(=[O:66])[CH3:65]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: CC(=O)OC(C)=O
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(C)=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 5 h

Procedure:
To a solution of the FR-900506 substance (10.4 mg) in dichloromethane (0.2 ml) were added pyridine (0.1 ml) and acetic anhydride (0. C5 ml) at room temperature, and the mixture was stirred for 5 hours. The solvent was removed from the reaction mixture under reduced pressure. The residue was subjected to silica gel thin layer chromatography (developing solvent: diethyl ether and dichloromethane, 1:2 v/v) to give 12-[2-(4-acetoxy-3-methoxycyclohexyl)-1-methylvinyl]-17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (6.0 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[CH:18]=[O:19]>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][C:10]=1[CH:18]=[O:19]
Reactant: Brc1ccccn1
Reactant: O=Cc1cc(B(O)O)ccc1F
Product: O=Cc1cc(-c2ccccn2)ccc1F
Yield: 64 %

Procedure:
General Procedure G using 2-bromopyridin and 4-fluoro-3-formylbenzeneboronic acid gave the title compound as colourless crystals in 64% yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O)(=[O:4])=[O:3]>CO.OS(O)(=O)=O.[Pd]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CS(=O)(=O)c1ccccc1N
Temperature: 5 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
2-Methylsulfonylnitrobenzene (13.0 g , 0.065 mol) was suspended in MeOH (140 mL) and 2N H2SO4 (60 mL). 6% Pd/C catalyst (50% wet; 3 g) was added to the suspension and it was hydrogenated at 40 psi in a Parr shaker for 4 hours. The solution was filtered, the catalyst washed twice with 10 mL of MeOH and concentrated on the rotary evaporator to a volume of 80 mL. The suspension was cooled to 5° C. with stirring and 15 mL of aqueous 10 N sodium hydroxide was added and stirred for 30 minutes at 5° C. The solid was filtered, washed with water and dried at 40° C. in vacuum (30 in. Hg) to give 10.5 g (95% yield) of 2-methylsulfonylaniline.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]2C(=O)C3=CC=CC=C3C2=O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>COC(C)(C)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCN)C1c1cccc([N+](=O)[O-])c1
Yield: 78.2 %

Procedure:
Prepared by a method analogous to that of Example 1(b) from 6.75 g (11.5 mmol) of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(8-phthalimidooctyloxy)carbonyl-pyridine and 1.7 ml (34.5 mmol) of hydrazine hydrate. 4.13 g (78%) of yellow crystals melting at 129°-131° C. obtained with tert.-butyl methyl ether.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl>[CH2:20]([O:18][C:15]1[CH:16]=[CH:17][C:8]([OH:7])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OCc2ccccc2)ccc1O
Yield: 69 %

Procedure:
To a refluxed suspension of K2CO3 (32.8 g, 238 mmol) in methanol (180 mL) and CHCl3 (350 mL) was then added a mixture of methyl 2,5-dihydroxybenzoate (10.0 g, 59.5 mmol) and bromomethylbenzene (7.10 mL, 59.5 mmol) in methanol/CHCl3 (50 mL/25 mL) drop wise over 30 minutes. The resulting mixture was stirred at reflux for another 4 hours. After cooling down and filtration, the filter cake was washed with CHCl3 (20 mL). The combined filtrate was concentrated under reduced pressure. The residue was redissolved in CHCl3 (200 mL), washed with HCl (1N) (100 mL×2). The organic was then washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (8:1) to give methyl 5-(benzyloxy)-2-hydroxybenzoate (10.6 g, 69.0%) as a white solid.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:41])[CH2:20][C@H:21]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:16][OH:17])=O)C1C=CC=CC=1.C(O)C.CCO.[H][H]>C(N(CC)CC)C.CCN(CC)CC.[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:41])[CH2:20][C@H:21]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:16][OH:17]
Reactant: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)CCCNC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)CCCN)OCc1ccccc1
Reaction time: 2 h

Procedure:
In a three-neck flask, the catalyst (150 mg of 20% palladium/carbon) was added to the solution of (2R)-5-(benzyloxycarbonylamino)-2-[(R)-3-benzyloxytetradecanoylamino]pentan-1-ol (3.0 g; 5.27 mmol) in a mixture of triethylamine Et3N (6 ml)/HPLC-grade ethanol EtOH (300 ml). Air was discharged under vacuum then the flask was loaded with hydrogen. The reaction mixture was hydrogenated at room temperature for 2 hours then the catalyst was filtered off and the filtrate was concentrated to provide the desired product as a homogenous white solid. Rf=0.2, 5/1 0/0.5 CH2Cl2-MeOH-Et3N, m.p.=47-48° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][C:12]([F:11])([F:21])[F:22])=[CH:15][CH:16]=1)=[O:9]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cncc(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 59.1 using 5-bromonicotinic acid and 4-(trifluoromethoxy)aniline to afford white crystals. UPLC-MS (Condition 2) tR=1.11 min, 361.1/363 [M+H]+.
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]([O-:13])[C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])O)[OH:8])[OH:6].[K+].Cl>C(O)(C)C>[C:4]1(=[O:3])[O:13][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C1O[C@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 7.6 %

Procedure:
To a three necked flask (2 L , equipped with an ice/water bath, mechanical stirrer and vented to a trap containing an aqueous solution of potassium hydroxide, was added potassium (D)-lyxonate (177.18 g, 0.87 mol) and isopropanol (1.2 L). To this cooled vigorously stirred slurry was introduced gaseous HCl, via a sparge tube, at such a rate that the temperature did not exceed 40° C. HCl sparging was continued for 40 min at which time HCl fumes were detected at the caustic trap and the internal temperature began to fall. Sparging was discontinued and the mixture slowly heated to reflux (Caution: HCl fumes were vigorously expelled when the mixture approached the reflux temperature). After refluxing for 10 min, the mixture was cooled and concentrated under reduced pressure to a volume of about 250 mL. The residue was heated to attain solution and allowed to slowly cool to room temperature, during which time crystallization occurred. This highly crystalline product was filtered, washed with cold isopropanol (75 mL), air dried for 1 h and then vacuum dried overnight to provide 90.9 g of desired 2. The mother liquor and washings were reduced in volume to 75 mL, crystallized, filtered and dried as described above to give an additional 9.74 g of 2. The first and second crops were combined to provide 100.64 g of D-lyxono-1,4lactone 2 (77.6): DISC mp 112.51° C. [lit. (1), (2) mp 110-112 and 114° C.]; Analysis calculated for C5H8O5 : C, 40.54; H, 5.44. Found: C, 40.38; H, 5.51%
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].NC(NC1SC(C2C=CC=CC=2C=O)=CC=1C(N)=O)=O>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: BrCC1CC1
Reactant: Oc1ccccc1Br
Agent: NC(=O)Nc1sc(-c2ccccc2C=O)cc1C(N)=O
Product: Brc1ccccc1OCC1CC1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
Prepared from cyclopropylmethyl bromide and 2-bromophenol by the method of Example 42 (b) except that the reaction mixture was stirred at 75° C. for 4 h. This gave the product as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-nitropyridine (500 mg, 2.46 mmol) and 1-methylpiperazine (1 mL) is heated at 80° C. for 2 hour. Then water is added. The aqueous layer is extracted with EtOAc, and the organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, MeOH:CH2Cl2=0.7:99.3 to 6:93) to give 520 mg of the title compound as yellow solid.