Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([OH:13])[C:6]([Cl:12])([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]=1[CH3:30])=[O:15].[H-].[Na+].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[Cl-].[NH4+]>C(OCC)C.CN(C=O)C>[CH3:1][C:2]1([CH3:31])[CH:4]([CH:5]([O:13][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=2)(=[O:42])=[O:41])[C:6]([Cl:11])([Cl:12])[C:7]([F:8])([F:10])[F:9])[CH:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:19]=1[CH3:30])=[O:15]
Reactant: Cc1c(COC(=O)C2C(C(O)C(Cl)(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC(C2C(C(=O)OCc3cccc(-c4ccccc4)c3C)C2(C)C)C(Cl)(Cl)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 97 mg (0.20 mmol) of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 3 and dissolved in 0.5 ml of diethyl ether and 0.5 ml of DMF, 12 mg (0.25 mmol) of sodium hydride and 39 mg (0.20 mmol) of p-toluenesulfonyl chloride were added, and the mixture was stirred overnight at room temperature. After an addition of 1 ml of a saturated ammonium chloride aqueous solution, the mixture was extracted with diethyl ether (2 ml×3 times). The extract was dried over anhydrous magnesium sulfate, then filtered and concentrated under reduced pressure to obtain a crude produce. The crude product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/3) to obtain 83 mg of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(1-tosyloxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11]C2C=C(Cl)C=CC=2Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O>C1COCC1>[C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=S(=O)(Nc1cc(Cl)ccc1Cl)c1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccccc1
Reaction time: 12 h
Yield: 52 %

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-chlorophenyl]benzenesulfonamide (1.00 g, 2.97 mmol), triphenylphosphine (1.64 g, 6.24 mmol) and 5S-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pentanol (1.30 g, 5.94 mmol) in THF (12 mL) was added diisopropylazodicarboxylate (1.23 mL, 6.24 mol) dropwise at 0° C. under nitrogen. The resulting mixture was allowed to warm to 22 DC with stirring. Stirring was continued for a period of 12 h followed by the addition of 25 mL of H2O. The mixture was extracted with ether (3×25 mL). The combined organic extracts were washed with 1M NaHCO3 and sat. brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:5 ethyl acetate:hexanes) of the concentrate afforded 830 mg of 4-chloro-N-[5-chloro-2-chlorophenyl]-N-[(R)-1-methyl-4-[(1,1-dimethylethyl)-dimethylsilyl]oxy)butyl]benzenesulfonamide as a yellow oil in 52% yield.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]1([S:17]([C:19]2[CH:20]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][C@@H:39]([C:41]4[CH:52]=[CH:51][C:44]5[O:45][C:46]([CH3:50])([CH3:49])[O:47][CH2:48][C:43]=5[CH:42]=4)[O:38][C:37]3=[O:53])[CH:22]=[CH:23][CH:24]=2)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH:12]1([S:17]([C:19]2[CH:20]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][C@@H:39]([C:41]4[CH:52]=[CH:51][C:44]5[O:45][C:46]([CH3:49])([CH3:50])[O:47][CH2:48][C:43]=5[CH:42]=4)[O:38][C:37]3=[O:53])[CH:22]=[CH:23][CH:24]=2)(=[O:6])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(S(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(S(=O)(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
3-Chloroperoxybenzoic acid (0.088 g) was added to a stirred, cooled (ice-bath) solution of (5R)-3-(6-{4-[3-(cyclopentylsulfinyl)phenyl]butoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.097 g) in DCM (10 ml). The solution was stirred for 0.5 h at room temperature. The solution was diluted with DCM and washed with 2N NaOH solution, water, dried (Na2SO4) and evaporated to give the title compound (0.085 g)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=1)[CH2:2][CH2:3][CH3:4].[CH2:30]([S:34](Cl)(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33].C(N(CC)CC)C.O>O1CCCC1.C(OCC)(=O)C>[CH2:30]([S:34]([O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:7][C:6]=2[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:16][C:17]=1[O:22][CH3:23])(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(O)c(OC)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(OS(=O)(=O)CCCC)c(OC)c1
Yield: 78.7 %

Procedure:
A solution of 400 mg (1 mmol) of methyl 3-{3-butoxy-4-[3-(4-hydroxy-3-methoxyphenyl)propyl]phenyl}propanoate, 170 μl (1.3 mmol) of butanesulfonyl chloride and 250 μl of triethylamine in 10 ml of tetrahydrofuran is stirred for 12 hours at room temperature. After addition of water and extraction with ethyl acetate, the organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residual oil is purified by chromatography on a column of silica eluted with an 8/2 heptane/ethyl acetate mixture. 410 mg of methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-3-butoxyphenyl)propanoate are obtained in the form of a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O.CC[N+]1C=CC(C2C=C[N+](CC)=CC=2)=CC=1.[Br-].[Br-].S(S([O-])=O)([O-])=O.[Na+].[Na+]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)CCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: CC[n+]1ccc(-c2cc[n+](CC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCCCNc1c(N)cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A solution of ethyl 5-(3-nitroquinolin-4-ylamino)pentanoate (151 g, 476 mmol) in dichloromethane (1 L) was added to a solution of sodium hydrosulfite (248.5 g, 1.427 mol), potassium carbonate (259.3 g, 1.876 mol), and ethyl viologen dibromide (1.78 g, 4.75 mmol) in water (1 L), and the reaction was stirred overnight at ambient temperature. An analysis by TLC indicated the presence of starting material; additional sodium hydrosulfite (5.0 g, 29 mmol) was added to the reaction, which was stirred for one additional hour. The organic layer was separated, washed with water (3×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 131.51 g of ethyl 5-(3-aminoquinolin-4-ylamino)pentanoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19]Cl)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCN2CCOCC2)CC1
Yield: 89 %

Procedure:
4-(3-Chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.64 g), morpholine (1.6 mL, 1.3 eq.), potassium carbonate (2.17 g, 1.1 eq.), potassium iodide (1.11 g, 0.47 eq.) were refluxed together in dry MeCN (100 mL) overnight. Concentration in vacuo, then aqueous work-up followed by flash chromatography gave 4-(3-morpholin-4-yl-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (89%). Treatment with 2M HCl in ether gave product (4.46 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)[CH:3]=1)=[O:6]
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)C1CCN(c2cc(C=O)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a solution of 3-fluoro-4-nitrobenzaldehyde 63 (0.793 g, 5 mmol) in DMSO (5 mL) was added methyl piperidine-4-carboxylate (0.7 mL, 5 mmol) and cesium carbonate (1.76 g, 5 mmol). The reaction mixture was stirred at room temperature for 30 min, heated to 70° C. for 2 h, and diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 30% to 60% EtOAc in hexanes) gave methyl 1-(5-formyl-2-nitrophenyl)piperidine-4-carboxylate 64 (0.931 g, 68% yield) as a yellow oil. Mass spectrum: calculated for C14H16N2O5 292.1. found 293.1 (M++1).
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:26]=[N:25][C:24](Cl)=[CH:23][N:22]=1.N12CCCN=C1CCCCC2>CN1C(=O)CCC1.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:24]3[CH:23]=[N:22][C:21]([Cl:20])=[CH:26][N:25]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Clc1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnc(Cl)cn3)CC2)CC1
Temperature: 110 °C

Procedure:
The tert-butyl 4,4′-bipiperidine-1-carboxylate (1.27 g, 4.7 mmol) and 2,5-dichloropyrazine (670 mg, 4.5 mmol) were dissolved in NMP (5 ml) at room temperature, and 1,8-diazabicyclo[5.4.0]-undec-7-ene (1 mL, 6.8 mmol) added drop-wise. The mixture was heated at 110° C. for 1 h, allowed to cool to r.t. and diluted with 50 mL of ethyl acetate. The solution was washed with water (10 mL ×1), brine (10 mL ×1), dried over magnesium sulfate, filtered, and concentrated in vac. The residue was purified by chromatography on silica gel with 10% acetone:hexanes to yield the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[N:16]=[N:15][C:14]=1[O:25]C)=[CH:7]2)([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[C:14](=[O:25])[NH:15][N:16]=[C:17]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[CH:18]=1)=[CH:7]2)([CH3:3])[CH3:2]
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2cc(C(C)C)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1ccc2[nH]c(-c3cc(-c4ccncc4)n[nH]c3=O)cc2c1
Temperature: 150 °C
Yield: 10.5 %

Procedure:
To a solution of 139 mg (crude material) 5-isopropyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-1H-indole in 2.5 ml EtOH is added 2.5 ml aq. NaOH (1 M). The mixture is heated for 10 min at 150° C. using microwave. After cooling to room temperature the mixture is filtered and purified by HPLC to give 14 mg (11%) of the desired product as yellow solid.
Reaction SMILES: [O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>CN(C=O)C>[N:62]1([C:26]([C:25]2[CH:24]=[CH:23][C:22]([C:19]3[N:18]=[C:17]([C@H:12]4[CH2:13][CH2:14][CH2:15][CH2:16][N:11]4[C:9](=[O:10])[CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[O:21][N:20]=3)=[CH:30][CH:29]=2)=[O:27])[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.07 mmol of (R)-4-{5-[1-(2-Phenoxy-acetyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzoic acid were treated with 1 eq. of TBTU/DIPEA in 1 ml DMF for 10 min and 2 eq. of Morpholine added. Ther reaction is stirred overnight at room temperature and the product isolated via preperative HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:5].Br[C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:33][C:27]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[CH3:1])=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: Cc1ccccc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccccc3C)cc2)cc1
Yield: 20 %

Procedure:
Ethyl 2-Methyl-2-{4-[2-(2-methyl-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(2-methyl-benzamido)-ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 1. Yield: 20% of theory; m.p. <20° C
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][N:8](C)[CH2:9][CH:10]1[CH:16]=[CH:15][C:14]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1>C1C=CC=CC=1>[CH3:7][N:8]([CH2:9][CH:10]1[CH:16]=[CH:15][C:14]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)[C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CN(C)CC1C=Cc2cc([N+](=O)[O-])ccc2CC1
Solvent: c1ccccc1
Product: CCOC(=O)N(C)CC1C=Cc2cc([N+](=O)[O-])ccc2CC1

Procedure:
50 ml of ethyl chloroformate were added dropwise over 5 minutes at 20° C. under nitrogen to a mixture of 7.9 g of N,N-dimethyl-2-nitro-6,7-dihydro [5H] benzocycloheptene-7-methanamine in 50 ml of benzene and the mixture was refluxed for 2 hours and then evaporated to dryness. The residue was extracted with ether and the ether phase was washed with N hydrochloric acid solution and then with water, was dried and distilled to dryness under reduced pressure to obtain 9 g of ethyl methyl-[(2-nitro-6,7-dihydro [5H] benzocycloheptene-7-yl) methyl]-carbamate in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 2-aminobenzonitrile (2.36 g (20.0 mmol in pyridine (10.0 ml), p-toluenesulfonyl chloride (4.20 g (22.0 mmol) was added with stirring at room temperature. After 15 hours' stirring at room temperature, water (100 ml) was added to the reaction mixture and stirring was continued for another 30 minutes. The crystals separated were filtered, washed with water and re-dissolved in chloroform. The soluble part in 1% aqueous sodium hydroxide solution was extracted from the chloroform solution. The extract was made acidic with hydrochloric acid and re-extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a product which then crystallized. The crystals were washed with diisopropyl ether and filtered to give 4.83 g (89%) of 2′-cyano-p-toluenesulfonanilide as white crystals.
Reaction SMILES: [C:1](OC(=O)N([C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3NC(CC)CC)C=C1)C(=O)CC)(C)(C)[CH3:2].COC1C=C[C:39]([CH:42]([NH:51][C:52]2[N:60]=[C:59]([Cl:61])[N:58]=[C:57]3[C:53]=2[N:54]=[CH:55][N:56]3[C@@H:62]2[CH2:66][C@H:65]([N:67]([C:75](OC(C)(C)C)=[O:76])[C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@@H:64]([OH:82])[C@H:63]2[OH:83])[C:43]2[CH:48]=CC(OC)=CC=2)=[CH:38]C=1>>[C:71]([O:70][C:68](=[O:69])[N:67]([C@H:65]1[CH2:66][C@@H:62]([N:56]2[CH:55]=[N:54][C:53]3[C:57]2=[N:58][C:59]([Cl:61])=[N:60][C:52]=3[NH:51][CH:42]([CH2:43][CH3:48])[CH2:39][CH3:38])[C@H:63]([OH:83])[C@@H:64]1[OH:82])[C:75](=[O:76])[CH2:1][CH3:2])([CH3:72])([CH3:74])[CH3:73]
Reactant: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@@H]2C[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H](O)[C@H]2O)c2ccc(OC)cc2)cc1
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)C1
Product: CCC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared from {(1S,4R)-4-[2-chloro-6-(1-ethyl-propylamino)-purin-9-yl]-cyclopent-2-enyl}-propionyl-carbamic acid tert-butyl ester using a procedure analogous to that of (1R,2S,3R,5S)-3-(6-{[bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-5-(di-Boc-amino)-cyclopentane-1,2-diol (see Example 1). Purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). 1H nmr (MeOD, 400 MHz); 8.10(s, 1H), 4.80(m, 1H), 4.65(m, 1H), 4.35(m, 1H), 4.20(m, 1H), 2.85(m, 2H), 2.60(m, 1H), 2.35(m, 1H), 1.70(m, 2H), 1.65(s, 9H), 1.60(m, 2H), 1.15(t, 3H), 0.95(t, 6H).
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:9]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(N)C(=O)O
Agent: C[C@H](NC(=O)c1ccccc1)C(=O)O
Solvent: O
Product: CC(C)[C@H](N)C(=O)O
Temperature: 95 °C

Procedure:
Twenty four grams of DL-valine and 19.3 g of N-benzoyl-L-alanine were suspended in 200 mL of deionized water. The suspension was heated to 95° C. to form a clear solution, which was cooled slowly. When the solution was cooled to room temperature after 2 hours, the precipitated crystals were separated by filtration, washed with 50 mL of deionized water, and dried to obtain 26.8 g of crystalline L-valine N-benzoyl-L-alanine complex (L-valine to N-benzoyl-L-alanine molar ratio of 1:1).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23](Cl)=[O:24])[CH:19]=[CH:20][CH:21]=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][CH3:14].[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][OH:31].N1C=CC=CC=1>O1CCCC1>[OH:31][CH2:30][C:29]1[CH:28]=[C:27]([NH:26][C:23](=[O:24])[CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cccc(CO)c1
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2cccc(CO)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 10.5 g of 3-(tetradecyloxy)benzeneacetyl chloride in 110 ml of tetrahydrofuran is added a solution of m-aminobenzyl alcohol in 110 ml of tetrahydrofuran containing 9.05 g of pyridine followed by stirring at ambient temperature for 4 hours and storing in a refrigerator over the weekend. The solvent is evaporated and the residue is poured into water and extracted with tetrahydrofuran:ether. The organic layer is washed with dilute hydrochloric acid, dried and filtered through a pad of magnesium silicate. The filtrate is evaporated and the residue purified by high pressure liquid chromatography using 2:1 hexane:ethyl acetate to give 3.6 g of the desired product as a white powder, m.p. 108°-110° C. and 5.B g of a white powder, m.p. 86°-90° C. found to be 3-(tetradecyloxy)-[3-[[[3-(tetradecyloxy)phenyl]acetyl]amino]phenyl]benzeneacetic acid methyl ester.
Reaction SMILES: [C:1]([NH:22][CH2:23][CH2:24][O:25][P:26](=[O:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18]CC.C(O)(=O)CCCCCCC/C=C\CC=CCC=CCC>>[C:1]([NH:22][CH2:23][CH2:24][O:25][P:26](=[O:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)NCCOP(=O)=O
Agent: CCC=CCC=CC/C=C\CCCCCCCC(=O)O
Product: CCC=CCC=CC/C=C\CCCCCCCC(=O)NCCOP(=O)=O

Procedure:
This compound was prepared as described above for (5), using 0.5 mmol (139 mg) of cis-9,12,15-octadecatrienoic acid; yield 80 mg, (40%); Rf 0.10-0.15 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 8H, ω-CH3); 1.3(s, 8H, 4CH2); 1.4-1.5(br, s, 2H, CH2CH2CO); 2.0-2.2 (m, 6H, CH2CO and 2CH2CH═CH); 2.7-2.9 (br s, 4H, 2HC═CH—CH2—CH═CH); 3.1-3.2 (br s, 2H, CH2NH); 3.7-3.8 (br s, 2H, CH2OP); 5.2-5.4 (br s, 6H, 3HC═CH); 8.2-8.4 (m, 3H, NH and 2POH).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.CC(O)=O>CN(C=O)C.CC(O)(C)C>[O:5]1[CH2:6][CH2:7][CH:2]([O:1][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:3][CH2:4]1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: N#Cc1ccc(OC2CCOCC2)cc1
Temperature: 60 °C

Procedure:
Step-1: To a stirred solution of 4-hydroxytetrahydropyran (3.80 g, 0.0373 mol) in dry DMF (50 mL) was added 95% NaH solid (1.12 g, 0.0466 mol) in small portions over 5-10 min. After the evolution of gas had subsided, 4-chlorobenzonitrile (5.18 g, 0.038 mol) was added in one portion, and the mixture heated to 60° C. overnite. The mixture was diluted with tBuOH (about 5 mL) and neutralized to pH 7 using glacial AcOH. The DMF was concentrated in vacuo, and the crude product chromatographed over a 120 g Isco column using 30% DCM/hexanes to DCM as an eluent to get step-1 product, 4-(tetrahydropyran-4-yloxy)benzonitrile), as a white solid. (5.7 g, 76%): LC Rt=2.72; 1H NMR (300 MHz, (CD3)2CO-d6) δ 1.63-1.75 (m, 2H), 2.02-2.10 (m, 2H), 3.55 (ddd, J=11.8, 9.1, 3.3 Hz, 2H), 3.90 (dt, J=12.0, 4.5 Hz, 2H), 4.76 (septet, J=4.5 Hz, 1H), 7.16 (d, J=9 Hz, 2H), 7.69 (d, J=9 Hz, 2H).