Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:15]2[C:6](=[CH:7][CH:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[N:10]3)[N:5]([C:16](=[O:18])[CH3:17])[CH:4]([CH3:19])[CH2:3]1.C(N([CH2:25][CH3:26])CC)C.[Cl-:27].[NH4+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Cl:27][C:26]1[CH:25]=[CH:4][C:3]([NH:1][CH:2]2[C:15]3[C:6](=[CH:7][CH:8]=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[N:10]4)[N:5]([C:16](=[O:18])[CH3:17])[CH:4]([CH3:19])[CH2:3]2)=[CH:2][CH:15]=1
Reactant: CC(=O)N1c2ccc3ncccc3c2C(N)CC1C
Reactant: CCN(CC)CC
Reactant: [Cl-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(=O)N1c2ccc3ncccc3c2C(Nc2ccc(Cl)cc2)CC1C
Reaction time: 18 h

Procedure:
[Step 5] 36 mg (0.14 mmol) of the 1-(1-amino-3-methyl-2,3-dihydro-4,7-phenanthrolin-4(1H)-yl)ethanone, 51 mg (0.28 mmol) of copper (II) acetate, 43 mg (0.42 mmol) of triethylamine and 2 ml of a dichloromethane suspension containing 27 mg of molecular sieve (4A) were vigorously stirred for 18 hours. Following completion of the reaction, aqueous ammonium chloride solution was added followed by extraction with chloroform. The extract was washed with water and the organic layer was dehydrated with anhydrous sodium sulfate. The residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (ethyl acetate) and NH silica gel column chromatography (n-hexane:ethyl acetate=2:1) followed by crystallizing with diethyl ether and n-hexane to obtain 7 mg of the target compound in the form of a pale yellow crystalline powder (13%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([OH:13])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].[C:15]([N:19]=[C:20]=[O:21])([CH3:18])([CH3:17])[CH3:16].[N-]=C=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([OH:13])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:6][C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21]
Reactant: COC(=O)[C@H](O)[C@@H](N)c1ccccc1
Reactant: CC(C)(C)N=C=O
Agent: [N-]=C=O
Solvent: C1CCOC1
Product: COC(=O)C(O)C(NC(=O)NC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(2R,3S)-β-phenyl-isoserine methyl ester (4.35 g, 22 mM) is dissolved in 100 mL dry THF and the flask cooled to 0° C. To the solution is added t-butyl isocyanate (2.8 mL, 25 mM). TLC after 15 minutes shows some starting material left so another 0.5 mL of the isocyanate is added. TLC after 1 hour shows no starting material so the solvent is concentrated in vacuo leaving N-(t-butylaminocarbonyl)-β-phenyl isoserine methyl ester (3K).
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[F:9][C:10]1[CH:15]=[C:14](F)[C:13]([Cl:17])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]>CS(C)=O>[F:9][C:10]1[CH:15]=[C:14]([O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[C:13]([Cl:17])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19]
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)c(OCC(F)(F)F)cc1F

Procedure:
22.5 g of 88% potassium hydroxide are suspended in 120 ml of dimethyl sulfoxide. With stirring, 40 g of trifluoroethanol are added dropwise to this suspension. Then, also with stirring, the resultant solution is added dropwise at room temperature to a solution of 96.8 g of 2,4-difluoro-5-chloronitrobenzene in 150 ml of dimethyl sulfoxide. When the addition is complete, the reaction mixture is stirred for a further 2 hours at room temperature. The reaction mixture is then concentrated, the crude product is dissolved in methylene chloride, and the resultant solution is washed with water and dried. Finally, the solvent is distilled off. Purification is effected by chromatography through a column of silica gel with a 10:1 mixture of hexane and ether as eluant. The solvent is distilled off, affording the title compound of the formula ##STR10## in the form of yellow crystals; m.p.: 54°-55° C.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[N:44]=NC(C)=CC=1)[CH2:4][CH2:3]2.ClC1N=[C:55]([S:57][CH3:58])[CH:54]=[CH:53][N:52]=1.C(O)(C(F)(F)F)=O>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:43]1[N:44]=[C:55]([S:57][CH3:58])[CH:54]=[CH:53][N:52]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccc(C)nn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CSc1ccnc(Cl)n1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3nccc(SC)n3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 14 %

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-(6-methylpyridazin-3-ylamino)ethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-chloro-4-(methylthio)pyrimidine (0.016 g, 0.100 mmol) was used in place of 3-bromo-6-methylpyridazine. Iterative purification of the crude mixture by reverse phase preparative HPLC first using Prep HPLC Method 9 and then repurification by Prep HPLC Method 10 gave the title compound as a white glassy solid (12.0 mg, 14% yield) bis TFA salt. LCMS: m/e 697.5 (M+H)+, 2.30 min (method 11). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 7.99-7.85 (m, 3H), 7.17 (d, J=8.2 Hz, 2H), 6.75-6.63 (m, 1H), 5.26 (d, J=4.6 Hz, 1H), 4.82 (s, 1H), 4.70 (br. s., 1H), 3.96 (s, 1H), 3.85 (br. s., 2H), 3.43-3.34 (m, 1H), 3.25 (br. s., 1H), 2.72 (br. s., 1H), 2.55 (s, 3H), 2.10 (dd, J=17.1, 6.4 Hz, 1H), 2.04 (d, J=15.3 Hz, 1H), 2.01-1.89 (m, 3H), 1.89-1.77 (m, 2H), 1.70 (s, 4H), 1.68-1.49 (m, 5H), 1.46 (d, J=7.3 Hz, 3H), 1.42-1.18 (m, 7H), 1.18-1.06 (m, 2H), 1.03 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H), 0.91 (br. s., 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=4)=[CH:21][CH:20]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH:33]1C=CC2N(O)N=NC=2C=1.CO[C@@H](C)C(O)=O.C(N(C(C)C)CC)(C)C.C(Cl)CCl>C(Cl)Cl>[CH3:1][O:2][C@@H:3]([CH3:33])[C:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=4)=[CH:21][CH:20]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1)=[O:5]
Reactant: On1nnc2ccccc21
Reactant: COCC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Agent: CO[C@@H](C)C(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H](C)C(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-methyl-N-(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine (3.58 mL, 0.394 mmol) (See step 3, Example 282), HOBT (0.015 g, 0.099 mmol), (S)-2-methoxypropanoic acid (0.049 g, 0.473 mmol), diisopropylethylamine (0.364 mL, 2.090 mmol), and EDC (0.091 g, 0.473 mmol) in DCM (5 mL) was stirred at RT overnight. The reaction mixture was concentrated, then taken up in H2O. The solid was collected by filtration, air-dried and purified by ISCO column (75% EtOAc/Hexanes) to give the title compound. MS (ESI, pos. ion) m/z: 448.2 (M+1). IC50 (uM) 0.000335.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:16][CH2:15][C:14](=[O:17])[NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:16][CH2:15][C:14](=[O:17])[N:13]([CH3:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CNC(=O)CO2)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2CN(C)C(=O)CO2)cc1OC
Temperature: 25 °C
Yield: 96.9 %

Procedure:
2-(3,4-dimethoxyphenyl)morpholin-5-one (0.10 g, 0.42 mM) produced in Example 1, sodium hydride (60%) (0.02 g, 0.46 mM), and methyl iodide (0.07 g, 0.51 mM) were dissolved in dry N,N-dimethylformamide (2 ml) and the mixture was stirred at room temperature for one night. Water was added to the reaction solution, the solution was extracted with methylene chloride, the extract was dried over anhydrous sodium sulfate, then the solvent was removed in vacuo to obtain a crude product as a yellow oil. The crude product was purified by flash chromatography (SiO2: eluted by 3% methanol/methylene chloride) to obtain the above-described compound (yield 96.9%) as a colorless solid.
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21]C)=O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:41]([CH:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][NH2:52])[CH2:46][CH2:45]1)([CH3:43])[CH3:42]>>[NH3:9].[C:1]1([CH:7]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:52][CH2:51][CH2:50][N:47]3[CH2:48][CH2:49][CH:44]([CH:41]([CH3:43])[CH3:42])[CH2:45][CH2:46]3)=[O:21])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)C1CCN(CCN)CC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN4CCC(C(C)C)CC4)nc32)[C@H](O)[C@@H]1O
Product: N
Temperature: 25 °C
Yield: 123.3 %

Procedure:
Methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino) carbonyl]-3,4-dihydroxytetra-hydro-2-furanyl}-9H-purine-2-carboxylate (Preparation 11) (100 mg, 0.18 mmol) and 2-(4-isopropyl-1-piperidinyl)ethylamine (Preparation 17) (300 mg, 1.76 mmol) were heated at 120° C. under a nitrogen atmosphere for three hours. The reaction mixture was allowed to cool to room temperature and purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (90:10:1 by volume) to afford the title compound as a white solid (76 mg, 62%).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].Cl.[CH3:21]O>>[ClH:1].[NH2:2][CH:3]([CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:6][CH3:21])=[O:5]
Reactant: CO
Reactant: NC(C(=O)O)C(c1ccccc1)c1ccccc1
Agent: Cl
Product: COC(=O)C(N)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Through a solution of 2-amino-3,3-diphenylpropanoic acid hydrochloride (35.0 g, 126 mmol) in methanol (500 ml) was bubbled hydrogen chloride for 3 h. The solution was stirred at room temperature for 120 h and the solvent removed in vacuo. Addition of diethyl ether gave methyl 2-amino-3,3-diphenylpropanoate hydrochloride, m.p.=213°-215° C.(dec.). 1H NMR (360 MHz, DMSO-d6) δ8.70 (3H, vbs), 7.20-7.57 (10H, m), 4.94 (1H, d, J=11 Hz), 4.36 (1H, d, J=11 Hz), 3.39 (3H, s). m/z (CI+) 256(MH).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][NH:6]3.[CH2:22]=[O:23]>C(O)(=O)C>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][OH:23]
Reactant: C=O
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2
Solvent: CC(=O)O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2CO

Procedure:
100 mg of the compound (5) obtained in Example 1 was dissolved in 3 ml of acetic acid, and while stirring, 1.5 ml of formalin was added to the solution. The solution was stirred for 30 minutes, and the deposited solid matter was filtered off and washed with ether to obtain 64 mg of the subject compound (177).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:8][CH:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11](I)=[CH:10]2)[CH2:6]1)[CH3:3].[C:20]1([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][C:30](B4OC(C)(C)C(C)(C)O4)=[CH:31][CH:32]=3)[N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:8][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:30]3[CH:29]=[C:28]4[C:33]([CH:34]=[CH:35][C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:27]4)=[CH:32][CH:31]=3)=[CH:10]2)[CH2:6]1)[CH3:3]
Reactant: CN(C)CC1CC(n2cc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C[C@H]1C[C@@H](n2cc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)ncnc32)C1
Temperature: 80 °C

Procedure:
Nitrogen was bubbled into a mixture of 7-(3-dimethylaminomethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (891.5 mg, 2.401 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-quinoline (795 mg, 2.40 mmol), Na2CO3 (634 mg, 5.98 mmol), and Pd(PPh3)4 (171 mg, 0.148 mmol; 6 mol %) in DMF (40 mL)/water (8 mL) for 5 min at ambient temperature, then the mixture was heated to 80° C. (bath temp.) for 4.5 h. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (4×30 mL), and the combined extracts were washed with brine and dried over MgSO4. The crude material (yellow oil) was chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (1-28)→5% MeOH in CH2Cl2 (29-56)->10% MeOH in CH2Cl2 (57-80)→10% MeOH in CH2Cl2 with 0.07M NH3 (81-130)]. Mixed fractions were chromatographed again [5 g/25 mL cartridge, eluting with CH2Cl2 (1-5)→5% MeOH in CH2Cl2 (6-24)→10% MeOH in CH2Cl2 with 0.07M NH3 (25-40)]. One obtained the target compound as beige solid. 1H NMR (CDCl3, 400 MHz): δ=2.10-2.23 (mc, 2H), 2.27 (s, 6H), 2.35-2.46 (mc, 1H), 2.49 (d, J=6.8 Hz, 2H), 2.77-2.86 (mc, 2H), 5.17 (brs, 2H), 5.20-5.30 (mc, 1H), 7.31 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.6, 8.4 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.94 (d, J=8.1 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.5 Hz, 1H), 8.30 (brs, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=27.13 (+), 36.50 (2C, −), 45.26 (+), 45.73 (2C, +), 66.10 (−), 101.20 (Cquart), 116.07 (Cquart), 119.00 (+), 120.74 (+), 125.98 (Cquart), 127.38 (+), 127.55 (2C, +), 128.28 (+), 128.47 (+), 128.86 (2C, +), 129.52 (+), 136.45 (Cquart), 136.55 (+), 139.41 (Cquart), 148.51 (Cquart), 150.92 (Cquart), 152.04 (+), 156.99 (Cquart), 158.13 (Cquart). MS (ES+): m/z 449.2 (23) [MH+], 404.1 (4) [MH+—HN(CH3)2], 338.2 (4) [MH+—C4H5CH2N(CH3)2]. HPLC: tR=2.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CCCCCCCC.C(Cl)(=O)CCCCCCC.C(Cl)(=O)CCCCCCCCCCCCCCC>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: CCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1

Procedure:
This compound was prepared using the procedure for palmitoyl-2′-deoxyguanosine, substituting the appropriate amount of octanoyl chloride for palmitoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:37]([O:40][CH2:41][C:42](O)=[O:43])(=[O:39])[CH3:38].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:42](=[O:43])[CH2:41][O:40][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCC(=O)O
Reactant: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(=O)COC(C)=O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Yield: 60.6 %

Procedure:
To (1S,2R,4aS,5R,8R,8aR)-2,8a-dihydroxy-3,8-dimethyl-5-(1-methylethenyl)-1, 2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 139, 210 mg, 0.4 mmol) and 4-dimethylaminopyridine (65 mg, 0.53 mmol) in dichloromethane (10 ml) was added (acetyloxy)acetic acid (60 mg, 0.51 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.58 mmol). The resultant mixture was stirred at room temperature and upon completion was concentrated in vacuo. The crude product was purified by chromatography on a Biotage® 12M column eluting with hexane:ethyl acetate (2:1). The pure fractions were combined and the solvent removed in vacuo to give the title product (150 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:29])[CH2:9][C:10]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12].[OH-].[Na+].C(O)C>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:29])[CH2:9][CH:10]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(CCc1ccccc1)(CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A mixture of diethyl 2-[2-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]-2-(2-phenylethyl)malonate (4.87 g, 9.41 mmol), 1 N aqueous sodium hydroxide (10.4 mL, 10.40 mmol), ethanol (10 mL), and acetone (10 mL) was stirred at 50° C. overnight. The mixture was concentrated and the residue was dissolved in dimethoxyethane (20 mL), and stirred at 80° C. overnight. The mixture was concentrated, and the residue was dissolved in ethyl acetate (30 mL). The solution was washed with water (2×5 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The material obtained was purified by flash chromatography (10:90 ethyl acetate/hexane) to give ethyl 4-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate as a light yellow oil (3.53 g, 99% yield). LC-MS ret. time 4.18 min, m/z 446.0 (MH+); 1H NMR (CDCl3) δ: 1.33 (t, 3H), 1.83-2.17 (m, 2H), 2.58 (s, 3H), 2.67-2.78 (m, 2H), 3.00 (dd, 1H), 3.14 (m, 1H), 3.49 (dd, 1H), 4.09 (q, 2H), 7.14-7.36 (m, 5H), 7.47-7.55 (m, 2H), 7.72-7.83 (m, 3H), 8.33 (d, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[CH:2]=[CH2:3].CCC(OO)=[O:16]>C1C=CC=CC=1>[O:16]1[CH2:3][CH:2]1[CH2:1][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1
Reactant: C=CCc1ccc2c(c1)OCO2
Reactant: CCC(=O)OO
Solvent: c1ccccc1
Product: c1cc2c(cc1CC1CO1)OCO2

Procedure:
305 g of 5-(2-propenyl)-1,3-benzodioxole were reacted with 105 g of a 21.52% strength solution of perpropionic aicd in benzene at 32° C. as described in Example 1. After a reaction time of 2.5 hours, the peracid conversion was 98%. 5-(Oxiranylmethyl)-1,3-benzodioxole was formed with a selectivity of 85%. For working up, the reaction mixture was introduced into a distillation unit operating with a thin film evaporator and was separated into a top product, which contained benzene, propionic acid and unreacted 5-(2-propenyl)-1,3-benzodioxole, and into a bottom product, which consisted essentially of 5-(oxiranylmethyl)-1,3-benzodioxole. After redistillation of this bottom product, 37.0 g of 5-(oxiranylmethyl)-1,3-benzodioxole were obtained in a purity of 99.9%.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C@H:6]([CH3:11])[C:7]([F:10])([F:9])[F:8])[CH2:4][OH:5].CN1CCOCC1.[Si](Cl)(C)(C)C.[Cl:24][C:25]1[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=1>CN1CCNCC1.C(Cl)Cl>[Cl:24][C:25]1[S:29][C:28]([S:30]([NH:2][C@H:3]([CH2:4][OH:5])[C@H:6]([CH3:11])[C:7]([F:10])([F:9])[F:8])(=[O:32])=[O:31])=[CH:27][CH:26]=1
Reactant: C[C@@H]([C@H](N)CO)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: CN1CCNCC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@H]([C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
(2S,3S)-2-Amino-4,4,4-trifluoro-3-methyl-butan-1-ol HCl (10) (385.5 g, 1.99 moles) was stirred with 3.8 L CH2Cl2 and 1007 g (9.96 mole, equivalents) 1-methylmorpholine was added with a wash of 200 mL CH2Cl2. At 20-30° C., Me3SiCl (443 g, 4.08 mole, 2.05 equivalents) was over 15-30 minutes. The solution was stirred for 1 h at 20-30° C., then cooled to 15-20° C. 454 g (2.09 moles, 1.05 equivalents) of 5-chloro-thiophene-2-sulfonyl chloride was added over 10-15 minutes at 18 to 24° C. and washed with 190 mL CH2Cl2. The temperature rose to 31.5° C. over 30 minutes with the reactor in a bath at 30° C. The mixture was stirred for 16 hours and tested by HPLC to assure that excess (1-10%) 5-chloro-thiophene-2-sulfonyl chloride remains. 22 mL 1-methylpiperazine (0.199 mole, 0.1 equivalents) was added. The solvent was removed by distillation under vacuum at 90 mm Hg in a bath at 20-30° C. 3.65 L isopropyl acetate and 2 N H2SO4 (2 L) were added, the mixture was stirred for 20 minutes and the layers separated. The aqueous layer was back extracted with 0.5 L isopropyl acetate. 2 L 2 N H2SO4, 2 L ½ saturated NaHCO3 and 2 L water were used as a wash. The layers were clarified by filtration through 0.2 μM filter. The isopropyl acetate was removed under vacuum (40 to <10 mm Hg) to dryness giving 675 g of crude 5-Chloro-N-[(1S,2S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-methylpropyl]thiophene-2-sulfonamide. The product was recrystallized from 10 volumes of 1:4 EtOAc/Heptanes giving 499 g after drying at 55° C. for 16 hours. A second crop of 49 g may be obtained from the mother liquors for a total yield of 548 g, 81%.