Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccccc1
Yield: 73.3 %

Procedure:
In a 250 mL round bottom flask was dissolved 10.0 g (55 mmol) of trans-4-hydroxyproline methyl ester hydrochloride 14 (Bachem) in 100 mL anhydrous pyridine at 0° C. with stirring to give a cloudy white mixture. To this was added 7.9 mL (62 mmol, 1.1 equiv.) of benzenesulfonyl chloride in four portions over 15 minutes to give a bright yellow mixture. This reaction mixture was stirred under a CaCl2 drying tube at 4° C. (cold room) overnight, then concentrated in vacuo, and the residue dissolved in ethyl acetate (˜200 mL.) The solution was washed with 1 N HCl (three times), with H2O, 1 N NaOH (three times), then brine, and the organic solution was dried (MgSO4), filtered, and concentrated to give a yellow oil. This was dissolved in ethyl acetate, loaded onto silica, and eluted with 3:2 ethyl acetate/hexanes to give 11.5 g (40.3 mmol, 73%) of compound 15 as a white crystalline solid. 1H-NMR (400 MHz, CDCl3, δ ppm) 7.85 (dt, J=2 Hz, 7 Hz, 2H), 7.57 (tt, J=1 Hz, 8 Hz, 1H), 7.49 (td, J=2 Hz, 7 Hz, 2H), 4.41 (br s, 1H), 4.37 (t, J=8 Hz, 1H), 3.70 (s, 3H), 3.57 (dd, J=4 Hz, 11 Hz, 1H), 3.37 (dt, J=2 Hz, 11 Hz, 1H), 2.17 (m, 2H), 2.06 (m, 1H); 13C-NMR (400 MHz, CDCl3, δ ppm) 173.01, 138.05, 133.43, 129.42, 128.05, 70.37, 59.85, 56.83, 52.99, 39.81; m/z: 286 (M+1)+. See, for example, DiCesare, P., et al.; J. Med. Chem.; 35(22), pp. 4205–4213 (1992), which is incorporated by reference in its entirety.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)[CH2:8][O:7][CH2:6][C:5]=12.C([Sn](=O)CCCC)CCC.C[Si]([N:32]=[N+:33]=[N-:34])(C)C>C1(C)C=CC=CC=1>[NH:32]1[C:14]([C:13]2[CH:16]=[CH:17][C:10]([CH:9]3[CH2:8][O:7][CH2:6][C:5]4=[CH:1][N:2]=[CH:3][N:4]34)=[CH:11][CH:12]=2)=[N:15][N:34]=[N:33]1
Reactant: N#Cc1ccc(C2COCc3cncn32)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: c1cc(C2COCc3cncn32)ccc1-c1nnn[nH]1
Temperature: 125 °C

Procedure:
A solution of 0.17 mmol of 4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)benzonitrile (Example 1) and 0.017 nimbi of dibutyltin oxide in 4.6 ml of toluene is mixed with 3.34 mmol of trimethylsilyl azide. The reaction mixture is heated at 125° C. overnight. It is cooled to room temperature and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15](OC)=[O:16])[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][OH:16])[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=CCO)C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
Into a cooled (−78° C.) solution of 4-methoxycarbonylmethylene-3,3-dimethylpiperidine-1-carboxylic acid t-butyl ester (1.8 g, 6.4 mmol) in tetrahydrofuran (50 mL) obtained in the above 1) was slowly dropped, under an atmosphere of argon, 1 M diisobutylaluminum hydride in toluene (15.9 mL, 15.9 mmol). After dropping, the reaction mixture was stirred for 2 hours at the same temperature. After the reaction was completed, ethanol (10 mL) was added at 0° C. and allowed to warm to room temperature gradually. The reaction mixture was then concentrated under a reduced pressure, treated with an aqueous solution of 20% sodium potassium tartrate (50 mL), and stirred for 30 minutes. After stirring, the reaction mixture was extracted with ether, and dried over anhydrous sodium sulfate. After drying, the extract was filtered and filtrate was concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, hexane:ethyl acetate=2: 1) to obtain 0.95 g (yield 58.6%) of 4-(2-hydroxyethylidene)-3,3-dimethylpiperidine-1-carboxylic acid t-butyl ester. Its physical property is shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[H][H]>O1CCCC1.CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[NH2:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N)cc1-c1cccc(Cl)c1
Yield: 89.5 %

Procedure:
To a mixture of 2-(3-chlorophenyl)-4-nitroanisole (0.5 g, 1.9 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added platinum (IV) oxide (1 mg). The reaction was stirred at room temperature under one atmosphere of hydrogen for 4.5 hours. The slurry was filtered through Celite and concentrated under reduced pressure to afford 3-(3-chlorophenyl)-4-methoxyaniline as a light yellow oil (405 mg, 1.7 mmol).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[Br:13][C:14]1[C:15](/[CH:20]=[N:21]/[S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:16][CH:17]=[CH:18][CH:19]=1>C1COCC1>[Br:13][C:14]1[C:15]([CH:20]([NH:21][S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1Br
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)NC(c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Reaction time: 4 h

Procedure:
To a stirred suspension of magnesium (2.143 g, 88 mmol) in THF (50 mL), was added 4-bromobenzotrifluoride (5.06 mL, 36.2 mmol). Stirring was continued for 4 h (caution: slightly exothermic, cooled with a water bath if needed). The resulting mixture was added to a stirred solution of (S,E)-N-((3-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (5.1 g, 17.64 mmol) in THF (100 mL) at −78° C. in a dropwise fashion. The mixture was stirred for another hour after addition and the reaction was then quenched with saturated aqueous NH4Cl, extracted with Et2O (3×20 mL), dried over Na2SO4, concentrated, and purified by column chromatography using silica (100-200 mesh) with 5% EtOAc in hexane as eluent to give the title compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].[N:21]([C:24]([CH3:30])([CH3:29])[C:25](OC)=[O:26])=[C:22]=[O:23].O>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:25](=[O:26])[C:24]([CH3:30])([CH3:29])[NH:21][C:22]1=[O:23]
Reactant: COC(=O)C(C)(C)N=C=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N)C1
Solvent: ClCCl
Solvent: O
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2C(=O)NC(C)(C)C2=O)C1
Product: Cl
Reaction time: 8 h

Procedure:
(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (50 mg, enantiomer B, preparation as described in WO2004085404) was dissolved in absolute dichloromethane (5 ml), and methyl 2-isocyanato-2-methylpropionate was added dropwise with stirring. After being stirred for 3 h and left to stand overnight, the mixture was admixed with water, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The fractions comprising product were purified, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was dissolved in acetonitrile (1 ml) and admixed with 10% hydrochloric acid. After stirring for 2 h, the mixture was diluted with water (3 ml) and freeze-dried. 68 mg of the title compound were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][S:9][CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:31][O:32][C:33](=[O:62])[C@H:34]([CH2:58][CH2:59][S:60][CH3:61])[NH:35][C:36](=[O:57])[CH2:37][N:38]([CH2:50][C@@H:51]([NH2:56])[CH:52]([CH3:55])[CH2:53][CH3:54])[CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1.CCN(CC)CC>CN(C=O)C>[CH3:31][O:32][C:33](=[O:62])[C@H:34]([CH2:58][CH2:59][S:60][CH3:61])[NH:35][C:36](=[O:57])[CH2:37][N:38]([CH2:50][C@@H:51]([NH:56][C:11](=[O:13])[CH2:10][S:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[C@@H:52]([CH3:55])[CH2:53][CH3:54])[CH2:39][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1
Reactant: CCC(C)[C@H](N)CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12
Reactant: O=C(O)CSCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cccc2ccccc12)NC(=O)CSCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(4-Nitrobenzylthio)acetic acid (68 mg, 300 μmol), dissolved in DMF (4 mL), was treated with HOBT (51 rag, 300 μmol), EDC (65 mg, 300 μmol), and N-[2(S)-amino-3-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (133 mg, 250 μmol). The pH was adjusted to 7.5 with Et3N (110 μL, 250 μmol) and the mixture was stirred at ambient temperature for 16 h. The mixture was concentrated and the residue was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with H2O (2×50 mL), dried (MgSO4), filtered, and concentrated to give a crude product which was purified by chromatography (silica gel, eluting with 1:1 to 1:2 hexane: EtOAc) to provide the title compound. 1H NMR (CDCl3); δ0.89 (t, 3H, J=7.5 Hz), 0.91 (d, 3H, J=6.9 Hz), 1.02-1.19 (m, 1H), 1.37-1.6 (m, 2H), 1.67-1.79 (m, 1H), 1.85-1.98 (m, 1H), 1.95 (s, 3H), 2.0-2.1 (m, 3H), 2.74 (dd, 1H, J=3, 12 Hz), 2.86-3.01 (m, 3H), 3.21 (d, 1H, J=14 Hz), 3.29 (d, 1H, 14 Hz), 3.69 (s, 3H), 3.74 (d, 1H, J=12 Hz), 3.8 (d, 1H, J=12 Hz), 3.83-3.94 (m, 1H), 4.05 (d, 1H, J=9 Hz), 4.18 (d, 1H, J=9 Hz), 4.41-4.49 (m, 1H), 6.7 (d, 1H, J=8 Hz), 7.39-7.53 (m, 7H), 7.8-7.9 (m, 2H), 8.14-8.22 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([C:23]#[C:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:7][CH2:6][C:5]2[C:8]([CH3:22])=[C:9]([O:14]CC3C=CC=CC=3)[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1>[Ni].C(O)C.C(OCC)(=O)C>[CH3:13][C:10]1[C:11]([CH3:12])=[C:4]2[C:5]([CH2:6][CH2:7][C@:2]([CH2:23][CH2:24][CH2:25][C@@H:26]([CH2:27][CH2:28][CH2:29][C@@H:30]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:37])[CH3:38])([CH3:1])[O:3]2)=[C:8]([CH3:22])[C:9]=1[OH:14]
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(C#CCC(C)CCCC(C)CCCC(C)C)O2
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 6 h
Yield: 101.2 %

Procedure:
A mixture of [2S-(4R*,8R*,)]-3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-1-tridecynyl)-6-(phenylmethoxy)-2H-1-benzopyran, (200 mg, 0.39 mmol) and 40 mg of Raney Nickel in 5 mL of ethanol and 5 mL of ethyl acetate was hydrogenated at 25° C. and atmospheric pressure for 6 h. Workup in the usual manner and purification of the crude product by chromatography on silica gel (eluent 1:5 ether-hexanes) gave 170 mg of (2R,4'R,8'R)-α-tocopherol as a pale yellow oil, identical in all aspects with a known sample.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].C(O[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(C)(C)C>CCO.[Pd]>[CH2:14]([O:13][C:11]([C@H:10]1[C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][N:8]([C:28]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:34])[CH2:9]1)=[O:12])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OCC

Procedure:
A mixture of (3S*,4S*)-1-benzyl-pyrrolidine-3,4-dicarboxylic acid diethyl ester (82.8 g, 271.14 mmol), di-tert-butylcarbonate (88.76 g, 406.71 mmol) and Pd/C 10% (8 g) in EtOH (1.5 L) is stirred under hydrogen atmosphere. The crude material is filtered over a pad of Celite and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/acetone 100:0 to 95:5). TLC, Rf (CH2Cl2/acetone 95:5)=0.51. MS (LC-MS): 216.2 [M+H-Boc]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([CH2:27][C:28]#[N:29])(=[O:26])=[O:25]>>[C:1]([C:5]1[CH:6]=[C:7](/[CH:8]=[C:27](/[S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)(=[O:26])=[O:25])\[C:28]#[N:29])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCS(=O)(=O)c1ccccn1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccccn2)cc(C(C)(C)C)c1O

Procedure:
M34 was prepared with 3,5-di-t-butyl-4-hydroxybenzaldehyde and (pyrid-2-yl)sulfonyl acetonitrile under similar conditions as described for M26.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][NH:14][CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][N:14]([CH3:15])[CH3:13]
Reactant: CNC
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Yield: 81.2 %

Procedure:
2-chloro-5-nitrobenzaldehyde (1 g, 5.39 mmol) was dissolved in THF (10 mL), and added with dimethylamine (2 M THF solution, 2.7 mL, 5.39 mmol). The reaction solution was cooled to 0° C., and NaBH(OAc)3 (1.6 g, 7.55 mmol) was slowly added thereto, followed by stirring for 12 hours or more at room temperature. The reaction mixture was added with water, and subjected to extraction with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (940 mg, 81%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[CH3:28][N:29]([CH2:31][C:32](O)=[O:33])[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])[CH2:2][CH2:3]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(C(=O)CN(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a solution of [(S)-1-(1-piperidin-4-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine 113 (97 mg, 0.268 mmol), dimethylaminoacetic acid (30 mg, 0.294 mmol) and DIPEA (230 μL, 1.34 mmol) in DMF (5 mL) was added HATU (153 mg, 0.401 mmol) and the mixture was stirred at RT for 1 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined, then concentrated in vacuo, purified by column chromatography (Si—PCC, gradient 0-20% 2M NH3/MeOH in DCM) and triturated with diethyl ether. The product thus obtained was further purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-60% 0.1% NH4OH in acetonitrile/water) and loaded into an Isolute® SCX-2. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The basic fractions were then combined and concentrated in vacuo affording 125 as a white solid (40 mg, 33%). LCMS: RT 1.67 min [M+H]+ 448.1. 1H NMR (CDCl3 plus MeOD, 400 MHz): δ 8.45 (1H, s), 7.94 (1H, s), 7.77 (1H, d, J=7.62 Hz), 7.41 (1H, d, J=7.73 Hz), 7.26-7.17 (3H, m), 6.10 (1H, s), 4.99-4.81 (1.5H, m), 4.64-4.53 (0.5H, m), 4.38-4.27 (0.5H, m), 4.21-4.08 (0.5H, m), 3.32-3.01 (2H, m), 2.87-2.16 (10H, m), 2.05-1.27 (6H, m). Signals split due to presence of rotamers
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([C:15](O)=[O:16])=[CH:5][C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)(=O)C(Cl)=O.[CH2:30]([C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=1)[CH3:31].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH2:30]([C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[C:36]=1[C:15]([C:6]1[CH:7]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]([O:2][CH3:1])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1)=[O:16])[CH3:31]
Reactant: COc1c(-c2ccccc2)cc(C(=O)O)cc1-c1ccccc1
Reactant: CCc1cc2ccccc2o1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(OC)c(-c2ccccc2)c1
Yield: 73 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 2'-methoxy-[1,1';3',1"]terphenyl-5'-carboxylic acid (1.031 g, 3.388 mmol), oxalyl chloride (0.325 mL, 3.727 mmol), commercial 2-ethylbenzofuran (0.4953 g, 3.388 mmol) and tin (IV) chloride (0.436 mL, 3.727 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 1.070 g, (73%) of the title compound. 1H NMR (DMSO-d6) δ 1.24 (t, 3 H), 2.90 (quartet, 2 H), 3.21 (s, 3 H), 7.30-7.67 (m, 14 H), 7.75 (s, 2 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[C:23]([O:25][CH3:26])=[O:24])[CH:16]=[N:15]1>C(Cl)Cl>[O:11]=[CH:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[C:23]([O:25][CH3:26])=[O:24])[CH:16]=[N:15]1
Reactant: COC(=O)c1cccc2cnn(CCO)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)c1cccc2cnn(CC=O)c12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (1.3 mL, 15.5 mmol) was added dropwise to a mixture of dimethyl sulfoxide (1.8 mL, 25.8 mmol) and methylene chloride (4 mL) at −78° C. After addition was complete, the mixture was stirred at −78° C. for 30 min. A solution of methyl 1-(2-hydroxyethyl)-1H-indazole-7-carboxylate (2.8 g, 12.9 mmol) from Step D above in methylene chloride (40 mL) and added dropwise while maintaining the temperature at −78° C. The reaction was then stirred at −78° C. for 1-2 h. The reaction was quenched with N,N-diisopropylethylamine, cooled to 0° C., and sat. NaHCO3 was added. The aqueous phase was extracted several times with methylene chloride and the combined organic layers were dried (Na2SO4), filtered and concentrated to give methyl 1-(2-oxoethyl)-1H-indazole-7-carboxylate as a yellow oil (3.8 g, crude): 1H NMR (300 MHz, CDCl3) δ 9.79 (s, 1H), 8.16 (s, 1H), 8.14-8.08 (m, 2H), 7.98 (d, J=7.5 Hz, 1H), 5.61 (s, 2H), 3.99 (s, 3H); MS (ESI+) m/z 219 (M+H).
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.C([O:15][P:16]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)([O:18]CC)=[O:17])C>CN(C=O)C>[P:16]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12])([OH:18])([OH:17])=[O:15]
Reactant: CCOP(=O)(COCCCCBr)OCC
Reactant: Nc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CCCCOCP(=O)(O)O
Reaction time: 2 h

Procedure:
To a slurry of 0.962 g (22.8 mmol) of 57% NaH in 150 ml of distilled DMF was added in one portion 3.363 gm (24.9 mmol) of adenine. The mixture was heated at 80° for 1 hr. and then cooled to 30° and 6.30 g (20.7 mmol) of 4-(diethylphosphonomethoxy)-1-bromobutane was added and the mixture was warmed to 60° and stirred for 2 hrs. The solvent was then removed under high vacuum and the residue was triturated three times with 100 ml of CH2Cl2 and filtered. The combined filtrates were evaporated and purified by SiO2 chromatography to give 4.9 g (66%) of Ia product as a white crystalline material mp 67°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>Cl>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[CH:3][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1N
Agent: Cl
Product: COc1ccc(C(=O)OCc2ccccc2)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Benzyl 3-amino-4-methoxybenzoate (300 mg, 1.17 mmol) was dissolved in Py (5 ml). Methanesulfonyl chloride (140 mg, 1.22 mmol) was added at 0° C. and under Argon atmosphere. The mixture was stirred at RT for 1 hour, then it was diluted with HCl 1N and extracted with EtOAc. The organic phase was washed with HCl 1M, dried over Na2SO4 and concentrated under vacuum to give benzyl 4-methoxy-3-(methylsulfonamido)benzoate (247 mg, 63.2% yield).
Reaction SMILES: [S:1]([O:6]C)([O:4][CH3:5])(=[O:3])=[O:2].C([C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)CCC.[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CO>[CH2:5]([O:4][S:1]([O-:6])(=[O:3])=[O:2])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH2:21]([N+:16]1[CH:15]=[CH:14][N:13]([CH3:5])[CH:12]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCO
Reactant: CCCCc1ncc[nH]1
Reactant: COS(=O)(=O)OC
Solvent: CO
Product: CCCCCCCCOS(=O)(=O)[O-]
Product: CCCC[n+]1ccn(C)c1

Procedure:
In a 250 ml Schlenk flask, 48.04 g (0.381 moles) of dimethyl sulfate was slowly added dropwise to 47.31 g (0.381 moles) of butylimidazole with ice cooling and under a blanket gas. Stirring of the mixture was continued at room temperature over night. After the addition of 62.72 g (0.482 moles; 1.26 equ.) of 1-octanol and 0.67 g of Dowex ion-exchanger washed with acetone and dried under high vacuum, the mixture was allowed to react over night at 140° C., and at the same time, the by-product methanol formed was removed from the reaction mixture by sparging with an argon stream. The remaining volatile fractions were subsequently removed under high vacuum at 80° C. The product, 1-butyl-3-methylimidazolium 1-octyl sulfate, was obtained as a viscous, slightly yellow liquid in quantitative yield. The product does not contain any detectable amounts of Cl− contamination (AgNO3 test; <3 ppm).