Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[C@H:11]([OH:14])[C@@H:10]([OH:15])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([OH:14])[C@@H:10]([OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H](O)[C@@H](O)C(=O)N1Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a mixture of (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (44 g, 199 mmol, 1.0 eq) and THF (176 mL) at 20° C. (vessel jacket temperature) was added borane-tetrahydrofuran complex (1.0 mol/L) in THF (800 mL, 800 mmol, 1.0 mol/L, 4.0 eq) at a rate to maintain the temperature between 20° C. and 25° C. Over 1 hr, the jacket temperature was ramped to 60° C. and then held for 1 hr. Upon completion, the reaction was cooled to 30° C. and quenched by the slow dropwise addition of MeOH (97 mL, 12 eq) to the mixture at a rate to control off gassing. The reaction mixture was then heated to reflux and concentrated to a low stir volume. The reaction solvent THF was then replaced by a constant volume displacement with MeOH (total of 1.5 L). Once the THF content had been reduced to less than 1 wt %, MeOH was replaced by a constant volume displacement with EtOAc (total of 1.5 L) to reduce the MeOH content to less than 1 wt %. The total volume of EtOAc was then readjusted to about 250 mL (6 vol) and then cooled to 5° C. to crystallize the product. The desired product was isolated by filtration, washed with cold EtOAc (88 mL) and dried to give title compound (27.0 g, 140 mmol, 70%). A second crop of product was isolated by concentration of the combined filtrate and cake wash to half volume, which was then cooled to 5° C., filtered and washed with cold EtOAc (50 mL) to afford additional title compound (4.5 g, 23 mmol, 12%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.26 (m, 4 H) 7.25-7.20 (m, 1 H) 4.48 (d, J=4.8 Hz, 2 H) 3.38-3.31 (m, 2 H), 3.57 (d, J=13.0 Hz, 1 H) 3.46 (d, J=13.0 Hz, 1 H) 2.74 (dd, J=9.4, 5.9 Hz, 2 H) 2.30 (dd, J=9.4, 4.4 Hz, 2 H). m/z (EI+) for C11H15NO2 194.2 (M+H)+.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].C(O[C:13]1([CH3:23])[CH:20]2[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:22][CH:14]1[CH2:15]3)[CH2:19]2)(=O)C(C)=C>C1(C)C=CC=CC=1>[CH2:23]=[C:13]1[CH:14]2[CH2:22][CH:18]3[CH2:17][CH:16]([CH2:21][CH:20]1[CH2:19]3)[CH2:15]2
Reactant: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: C=C1C2CC3CC(C2)CC1C3
Reaction time: 3 h

Procedure:
A reaction was conducted at a refluxing temperature for 3 hours using no magnesium sulfate but using a Dean-Stark dehydrating apparatus. Toluene was used as a solvent. The other operating conditions were the same as in Example 16, and a reaction, a post-treatment, etc. were conducted. 1.0 g of a crude product was obtained. However, the purity of 2-methyl-2-adamantyl methacrylate in the crude product was 15% and 2-methyleneadamantane was formed by 80%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([N+:16]([O-])=O)[CH:8]=1)#[CH:2]>[OH-].[NH4+].O1CCCC1.[Zn]>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH2:16])[CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Product: C#Cc1cccc(Oc2ccc(N)c(N)c2)c1
Reaction time: 0.5 h

Procedure:
To a rapidly stirred suspension of 25 g (0.38 g atom) of powdered zinc in 25 ml of concentrated ammonium hydroxide was added a solution containing 5.0 g (17.6 mmoles) of 4-(3-ethynylphenoxy)-o-dinitrobenzene dissolved in 25 ml of tetrahydrofuran. The mixture was stirred at room temperature for 1/2 hour, at which time an additional 5 ml of ammonium hydroxide was added, and the solution stirred an additional half hour. At that time, the reaction mixture was filtered by suction, and the residue was washed with several portions of tetrahydrofuran. The filtrate was extracted with several portions of ether, and the combined ether extracts washed with water. Evaporation of the organic layer in vacuo yielded a dark red oil. Chromatography of the residue on 1 × 12 inch dry column of silica gel afforded an initial red band (elution with methylene chloride) of side-product. Further elution using ethyl acetate produced a second band of desired product. Evaporation of solvent in vacuo yielded 3.3 g (84%) of 4-(3-ethynylphenoxy)-o-phenylenediamine as a dark orange oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[CH2:16]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])[CH3:17].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:21][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:23])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 111.3 %

Procedure:
4-Chloro-3-nitroquinoline (76.1 g, 365 mmol) was treated with β-alanine ethyl ester hydrochloride (50.0 g, 326 mmol) in the presence of triethylamine (94.5 mL, 678 mmol) and potassium carbonate (37.45 g, 271.2 mmol) according to a modification of the method described in Part A of Example 15. Before the addition of β-alanine ethyl ester hydrochloride, the reaction was cooled to 0° C. After this addition, the reaction was stirred for four hours at ambient temperature and subjected to the work-up procedure to provide 105 g of ethyl N-(3-nitroquinolin-4-yl)-β-alaninate.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[NH:43]1[CH2:57][CH2:56][CH2:55][C@H:44]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46].C([O-])(O)=O.[Na+]>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:43]1[CH2:57][CH2:56][CH2:55][C@H:44]1[C:45]([O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Boc-Ile-OH (12.01 g, 0.05 mole) in DMF (50 ml) was cooled to 0° C. and NMM (5.49 ml) was added. After cooling the solution to -15° C. isobutylchloroformate (6.48 ml) was added slowly while maintaining the temperature at -15° C. and stirred for 10 minutes at which time HOBt (7.65 g) was added and stirring was continued for additional 10 minutes. A pre-cooled solution of HCl-H-Pro-OBzl (12.09 g, 0.05 mole) in DMF (50 ml) and NMN (5.49 ml) was added to the above solution and the completeness of the reaction was followed by TLC. The reaction mixture was poured into a cold saturated NaHCO3 solution and stirred for one hour. The peptide was extracted into CHCl3 and washed with acid and base (0.5 N NaOH to remove HOBt), and on evaporating the solvent the product was obtained as an 92% yield. Rf1, 0.65. Anal. Calcd. for C23H34N2O5 : C 66.00, H 9.19, N 6.69%. Found: C 65.58, H 8.28, N 7.13%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:18]([O:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:14](=[O:16])[C@H:9]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 93.1 %

Procedure:
N-t-butyloxycarbonyl-L-isoleucine 1/2 hydrate 36.05 g, 150 mmole), L-proline benzylester hydrochloride 36.26 g, 150 mmole) and HOBT (20.26 g, 150 mmole) were dissolved in methylene chloride (500 ml), and triethylamine 18 g, 150 mmole) and WSC hydrochloride (28.76 g, 150 mmole) were added thereto at -30° C. The mixture was stirred for 2 hours at less than 0° C. and then overnight at room temperature, and the solution was washed with 5% aqueous sodium bicarbonate (500 ml, twice), 5% aqueous citric acid (500 ml, twice) and water (508 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-t-butyloxycarbonyl-L-isoleucyl-L-proline benzylester(yield: 58.43 g, 93.1%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12](Cl)(Cl)=[S:13].C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:12]=[S:13])=[CH:5][CH:4]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(N=C=S)cc1

Procedure:
4-(Trifluoromethyl)aniline (1.34 g), thiophosgen (0.73 ml), sodium hydrogen carbonate (5.1 g), chloroform (70 ml) and water (140 ml) were treated by the method disclosed in the literature (Burke, T. R., Jr.; Bajwa, B. S.; Jacobson, A. E.; Rice, K. C.; Streaty, R. A.; Klee, W. A. J. Med. Chem., 1984, 27, 1570-1574) to give the title compound (1.62 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:3][CH2:2]1
Reactant: OCC1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A solution of 90 g (774.8 mmol) of tetrahydropyran-4-methanol and 129.6 mL (929.76 mmol, 1.2 eq.) of triethylamine in 775 mL of anhydrous DCM was cooled to 0° C. with in an ice bath. Methanesulfonyl chloride (66.2 mL, 852.28 mmol, 1.1 eq.) of was then added dropwise over 60 minutes while maintaining the temperature around 0° C. The reaction mixture was stirred for 30 minutes at 0° C. and quenched with a saturated solution of sodium bicarbonate (800 mL). The aqueous layer was extracted with DCM (800 mL). The combined organic layers were washed with water (2×800 mL), brine (800 mL) and dried over sodium sulfate. After filtration and concentration in vacuo, a yellowish solid (146.1 g, 97%) was obtained corresponding to the methanesulfonic acid tetrahydropyran-4-ylmethyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][SH:5].[OH-].[Na+].Cl[C:9](Cl)=[CH:10][N+:11]([O-:13])=[O:12].Cl>CO.C(Cl)(Cl)Cl.O>[N+:11]([CH:10]=[C:9]1[NH:1][CH2:2][CH2:3][CH2:4][S:5]1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])C=C(Cl)Cl
Reactant: NCCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])C=C1NCCCS1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
Into 40 ml of methanol were added 5.5 g of 1-amino-3-propanethiol and 2.4 g of caustic soda, followed by stirring, to be completely dissolved therein. Then, the mixture was cooled to 0° C. While stirring the solution, a solution of 2.8 g of 2,2-dichloronitroethylene diluted in 10 ml of methanol was added dropwise slowly over 15 minutes, and the reaction was carried out for one hour. The reaction was exothermic and the liquid temperature was maintained at lower than 10° C. (about 8° C.) After the reaction, the reaction mixture was neutralized to pH 7 with 6 N aqueous hydrochloric acid, and then with addition of 30 ml of water, extraction with 50 ml of chloroform was repeated four times. The extracts were concentrated to give 2.24 g of tetrahydro-2-(nitromethylene)-1,3-thiazine (yield: 70.0%).
Reaction SMILES: C([S:8][C:9]1[N:10]=[N:11][N:12]([CH2:14][C:15]2[NH:19][N:18]=[N:17][N:16]=2)[N:13]=1)C1C=CC=CC=1>[Hg].[Pt].CN(C=O)C>[NH:16]1[C:15]([CH2:14][N:12]2[N:11]=[N:10][C:9]([SH:8])=[N:13]2)=[N:19][N:18]=[N:17]1
Reactant: c1ccc(CSc2nnn(Cc3nnn[nH]3)n2)cc1
Agent: [Pt]
Agent: [Hg]
Solvent: CN(C)C=O
Product: Sc1nnn(Cc2nnn[nH]2)n1
Reaction time: 0.14 h

Procedure:
5-Benzylthio-2-(1H-tetrazole-5-ylmethyl)-2H-tetrazole, 175 mg., prepared as described above under part C, was dissolved in 40 ml. of distilled DMF and reduced at the mercury pool cathode (14 cm2Hg pool) with a platinum wire anode. The electrodes were separated by a glass frit. The electrolyte was tetraethylammonium perchlorate, 0.1 M in the DMF solution of the substrate. The electrolysis was carried out at -2.7 to -2.85 volts for 500 seconds and at -2.80 v. for about 630 seconds.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CO>[C:1]1([S:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C1CNCCN1
Solvent: CO
Product: O=S(=O)(c1ccccc1)N1CCNCC1

Procedure:
A solution of benzenesulfonyl chloride, piperazine and methanol allows us to obtain benzenesulfonyl piperazine. This product is dissolved into methanol and replaced with compound A (N-7-bromoethyl 3-isobutyl-1-methylxanthine) to obtain compound 21. By replacing the ethyl bromide with propyl bromide, compounds 22 and 23 can be produced. By replacing p-toluene-sulfonyl chloride or o-toluenesulfonyl chloride with benzenesulfonyl chloride, compounds 24, 25, or 26 may be produced.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)(Cl)Cl.CCO>N1C=CC=CC=1>[C:23]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 0.07 h

Procedure:
A mixture of 2'-deoxyuridine (100 g, 0.44 mol) and triphenylmethyl choride (147 g, 0.53 mol) in 250 mL of pyridine was heated at 100° C. for 30 minutes. One-third of the cooled solution was added at a slow flow rate to a mixture of ice water (2:3) in a commercial blender blending for 3-5 minutes after adding the solution. The resulting white precipitate was filtered and washed twice, stirring in 2 L of water. Recrystallization was accomplished by refluxing the product in a benzene-acetone solution (1:1) for 15 minutes, yielding 128 g (62%). The compound softened at 76° C., began to melt at 152-155° C., and darkened in color at 155-159° C. Rf =0.71 (CHCl3 --EtOH, 4:1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:9][C:10]1[C:11]([F:21])=[C:12]([F:20])[C:13](F)=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:9][C:10]1[C:11]([F:21])=[C:12]([F:20])[C:13]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1F
Reactant: Nc1ccccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2-fluoroaniline (10.2 mL, 105.8 mmol) and 5-bromo-2,3,4-trifluorobenzoic acid (13.51 g, 52.9 mmol) in THF (120 mL) was added LiHMDS (158.7 mL, 1 M in THF, 158.7 mmol) dropwisely at −78° C. under nitrogen atmosphere. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with 10% HCl (aq., 100 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 13.73 g, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.01 (d, 1H), 7.26 (m, 1H), 7.01-7.16 (m, 3H).
Reaction SMILES: C([S@]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([CH3:21])[CH:11]=1)[CH3:9])=O)(C)(C)C.[ClH:22].CO>O1CCOCC1>[ClH:22].[NH2:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([CH3:21])[CH:11]=1)[CH3:9]
Reactant: Cc1cc([C@@H](C)N[S@](=O)C(C)(C)C)ccc1NS(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To N-[4-((1R)-1-{[(R)-tert-butylsulfinyl]amino}ethyl)-2-methylphenyl]methanesulfonamide (530 mg, 1.60 mmol) was added HCl-methanol (2.0 M, 5.0 mL) and 1,4-dioxane (5.0 mL). The solution was stirred at room temperature for 30 minutes and then concentrated in vacuo. Diethyl ether was added to precipitate amine hydrochloride. The precipitate was then filtered and washed with diethyl ether (450 mg, quant) to furnish the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6].[NH3:14]>[Cl-].[Na+].O>[NH2:14][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6]
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Reactant: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)c(N)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A closed pressure tube charged with 3-fluoro-4-(trifluoromethyl)benzonitrile (10.0 g; 52.9 mmol) and liquid NH3 (60 mL) was heated for 6 days at 90° C. The tube was cooled to −60° C. and opened. The mixture was allowed to stir for 1 h at rt. The residue was treated with brine and extracted with EtOAc to give the crude sub-title compound (10.2 g).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1([F:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(CN)O>>[NH2:3][CH2:12][C:13]1([F:26])[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CN2C(=O)c3ccccc3C2=O)CC1
Solvent: NCCO
Product: CC(C)(C)OC(=O)N1CCC(F)(CN)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 3-3 (11.0 g) and 25 mL ethanolamine was stirred at 60° C. for 1 h. The reaction was then allowed to cool to room temperature, poured into ice-water (100 mL), and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine (150 mL), dried over MgSO4, filtered, and concentrated in vacuo, giving 5.82 g of crude 3-4 as a viscous amber oil. 1H NMR (CDCl3, 300 MHz): 3.94 (br, 2H), 3.08 (m, 2H), 1.85 (m, 2H), 1.51 (m, 4H), 1.44 (s, 9H); MS (Electrospray): m/z 218.2 (M−Me+H), 177.2 (M−t−Bu+H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C>C(#N)C>[NH2:1][C:2]1[N:3]([C@@H:17]2[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 15.5 %

Procedure:
2-Amino-5,6-dichlorobenzimidazole (4) (3 g, 16 mmole) was dissolved in dry acetonitrile (150 ml) and stirred in an inert atmosphere at 60° C. BSA (4.37 ml, 17 mmole) was added and the mixture was stirred for 10 minutes. 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (5.09 g, 16 mmole) and TMSTF (3.29 ml, 17 mmole) were added to the clear solution and the mixture was allowed to stir at 60° C. for 1 hr. The mixture was concentrated under reduced pressure and separated on a silica column to yield 1.14 g (15%) of 2-amino-5,6-dichloro-1-(2,3,5,tri-O-acetyl-β-D-ribofuranosyl) benzimidazole (43). 13C NMR (CDCl3): d 170.04 ppm, 169.56, 169.11, 154.57, 141.64, 132.53, 125.90, 1123.45, 117.72, 109.49, 85.78, 80.99, 70.95, 69.83, 62.91, 20.74, 20.54, 20.20. 1H NMR (CDCl3): d 0.96 ppm (s, 3H), 1.09 (s, 3H), 1.13 (s, 3H), 3.75 (m, 2H), 4.08 (dd, 1H), 5.00 (dd, 1H), 5.13 (t, 1H), 5.42 (s, 2H), 5.61 (d, 1H), 7.27 (s, 1H), 7.42 (s, 1H). MS (FAB): m/e 758, 718, 676, 460, 426, 259, 217, 139.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:15][CH:16]=O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:15]=[CH:16][N:8]=[C:4]2[CH:3]=1
Reactant: O=CCCl
Reactant: Nc1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Clc1ccn2ccnc2c1
Yield: 86.5 %

Procedure:
To a solution of 4-Chloro-pyridin-2-ylamine (12.8 g, 100 mmol, 1.0 equiv) in EtOH (170 ml) was added NaHCO3 (16.8 g, 200 mmol, 2.0 equiv) followed by chloroacetaldehyde (19.0 ml, 150 mmol, 1.5 equiv). The mixture was refluxed for 6 h. Solvents removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by column chromatography (SiO2, eluted with 50% EtOAC-petrol) to afford 13.2 g of product. MS: [M+H]+=153.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.C(OCC)(=O)C>O1CCCC1.O>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:5][C:3]#[N:4])[CH:15]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC=Cc1cccnc1

Procedure:
To a suspension of sodium hydride (62% oil, 10.87 g) in tetrahydrofuran (200 ml) was added successively diethyl cyanomethylphosphonate (43.25 ml) and pyridine-3-carbaldehyde (24 ml) at 0° C. Then, the reaction mixture was heated to refluxing temperature. After 5 hours the reaction mixture was poured into a mixture of ethyl acetate (1 l) and water (200 ml). The organic layer was separated, washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (600 ml) eluting with ethyl acetate to give 3-(3-pyridyl)acrylonitrile (23.9 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH:8]([CH3:10])[CH3:9].O.[OH-].[Na+]>C(OCC)C>[CH2:7]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:17][CH:18]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)Cc1ccc(C=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)Cc1ccc(CO)cc1
Yield: 94.2 %

Procedure:
Lithium aluminum hydride (586 mg, 15.4 mmol) was slurried in diethyl ether (50 mL) and cooled in an ice bath. A solution of 4-isobutylbenzaldehyde (5.00 g, 30.9 mmol) in diethyl ether (30 mL) was added dropwise over 10 min and the mixture was stirred for 30 min before successive addition of water (0.6 mL), 15% aq NaOH (0.6 mL), and water (1.8 mL). The resulting precipitate was removed via filtration and the filtrate was dried (MgSO4), filtered, and evaporated in vacuo to give 4-isobutylbenzyl alcohol (4.78 g, 94%). 1H NMR (CDCl3) 7.28 (d, 2H), 7.13 (d, 2H), 4.63 (s, 2H), 2.45 (d, 2H), 1.85 (m, 1H), 0.90 (d, 6H).