Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[C:1]12([C:6]3[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:25][CH:5]1[CH2:4][CH2:3][CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cccc(C2=CCCC2)c1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(C23CCCC2O3)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5 g (23 mmol) of ethyl 3-cyclopent-1-ylbenzoate (4a) and 100 ml of methylene chloride are introduced into a round-bottomed flask. The solution is cooled to 0° C. and 9 g (28 mmol) of meta-chloroperbenzoic acid are added in portions. The mixture is stirred for 30 minutes at 0° C. and then for 4 hours at room temperature. The mixture is filtered. The filtrate is successively washed with a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution. The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 95:5). The title product is obtained in the form of a colorless oil (4.8 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][CH:11]([C:15](O)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].S(Cl)(Cl)=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH:11]([CH2:15][OH:16])[CH2:12][C:13]2=[O:14])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N2CC(C(=O)O)CC2=O)cc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1ccc(N2CC(CO)CC2=O)cc1
Yield: 81.1 %

Procedure:
1-(4-Ethylphenyl)-5-oxo-3-pyrrolidinecarboxylic acid (5.00 g) is suspended in carbon tetrachloride (15 ml) and thereto is added thionyl chloride (2.32 ml). The reaction mixture is heated with stirring under refluxing for 1 hour and concentrated under reduced pressure. The residue is dissolved in tetrahydrofuran (25 ml) and thereto is added dropwise a solution of sodium boron hydride (1.61 g) in dimethylformamide (about 16 ml) under ice-cooling. The mixture is further stirred for 1 hour. Methanol (13 ml) and conc. hydrochloric acid (1.87 ml) are successively added dropwise into the reaction mixture and the mixture is concentrated under reduced pressure. Ethyl acetate (120 ml) is added to the residue and the mixture is washed with water three times, dried over anhydrous magnesium sulfate, and then concentrated again under reduced pressure. To this residue is added a mixed solvent (about 50 ml) of ethyl acetate/hexane [1:20 (v/v)]. The mixture is allowed to stand and the precipitated crystal is collected by filtration to give the desired product (3.81 g).
Reaction SMILES: [C:1](=[O:13])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:2][CH:3](Cl)[CH3:4].[Br-:14].C[SiH](C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1](=[O:13])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:2][CH:3]([Br:14])[CH3:4]
Reactant: [Br-]
Reactant: CC(Cl)OC(=O)Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[SiH](C)C
Product: CC(Br)OC(=O)Oc1ccccc1
Temperature: 90 °C

Procedure:
15.4 g (0.077 mol) of 1-chloroethyl phenyl carbonate, 0.44 g (0.0014 mol) of tetrabutylammonium bromide and 13.7 g (0.090 mol) of trimethylsilane bromide are introduced into a distillation apparatus equipped with a 15 cm Vigreux column, a thermometer and a stirrer. The mixture is heated at 90° C. for 24 h and the trimethylsilane chloride released is removed by distillation. The product expected is then distilled. 17.2 g (Yld=91%) are obtained.
Reaction SMILES: [S:1](=[O:3])=[O:2].[S:4]([O-:7])([O-:6])=[O:5].[Mg+2:8]>>[S:4](=[O:5])([OH:7])[O-:6].[Mg+2:8].[S:1](=[O:5])([OH:3])[O-:2]
Reactant: O=S=O
Reactant: O=S([O-])[O-]
Agent: [Mg+2]
Product: O=S([O-])O

Procedure:
U.S. Pat. No. 4,388,238 to Abrams, et al. describes how sulfur dioxide is contacted with a magnesium sulfite solution in a scrubbing zone at a pH in the range of about 6 to 7.5 in order to produce magnesium bisulfite. It also teaches providing a minor regeneration stream which is subjected to oxidation to oxidize bisulfite and sulfite to sulfate. This reference also teaches the use of a type S hydrated dolomitic lime for the spray dryer at a weight percent of 3-15% suspended solids and at a stoichiometric ratio of 1.1 to 1.5 and injected at a temperature of 145° to 165° F. The product is calcium sulfite and sulfate, magnesium sulfite and sulfate, unreacted lime, and flyash. However, the presence of calcium sulfite and sulfate and magnesium sulfate is undesirable.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20]O)=[CH:16][N:15]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[CH2:43]([NH:47][CH2:48][CH:49]([CH3:51])[CH3:50])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][N:47]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:16][N:15]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCO)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Reactant: CC(C)CNCC(C)C
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(Cn2cc(C#CCN(CC(C)C)CC(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Reaction time: 72 h

Procedure:
A solution of N-[4-chloro-5-(3-hydroxy-prop-1-ynyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (9.0 g, 19.7 mmol) and Et3N (2 mL) in DCM (50 mL) was treated with MsCl (15.3 mL, 19.7 mmol) at 0° C. for 20 min and evaporated to give a yellow solid, containg mostly the desired mesylate (10.7 g). An aliquot of this solid (106.8 mg, 0.2 mmol) was treated with diisobutylamine (25.9 mg, 24.8 μL) in DCM (2 mL) at 0° C. for 10 h, and then at 25° C. for 3 days. Evaporation and prepartive plate chromatography gave the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([N+:10]([O-])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14]>O1CCCC1.[Ni]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([NH2:10])=[CH:4][C:3]=1[C:13]([F:15])([F:16])[F:14]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(F)c(F)c1F
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)c(F)c(F)c1F
Yield: 87.9 %

Procedure:
35 g of 2,3,4-trifluoro-5-nitro-benzotrifluoride in 150 ml of tetrahydrofuran were initially introduced into a hydrogenation apparatus, 3 g of Raney nickel were added and, after flushing with nitrogen, the mixture was hydrogenated to constant pressure with 30 bar of hydrogen at 25° to 45° C. After completion of the hydrogen uptake, the pressure was released and the reaction solution was filtered and subsequently fractionally distilled. 27 g of 2,3,4-trifluoro-5-amino-benzotrifluoride were obtained with a boiling point of 82° to 83° C. at 15 mbar.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][P:8]([CH2:28][NH2:29])([CH2:10][CH:11]([C:16](=[O:27])[NH:17][C@H:18]([C:23](=[O:26])[NH:24][CH3:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH3:6].[C:30]1([C:36]2=[C:37]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:38]([O:40][C:41]2=O)=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:5]([O:7][P:8]([CH2:28][N:29]1[C:41](=[O:40])[C:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:37]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:38]1=[O:39])([CH2:10][CH:11]([C:16](=[O:27])[NH:17][C@H:18]([C:23](=[O:26])[NH:24][CH3:25])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH3:6]
Reactant: O=C1OC(=O)C(c2ccccc2)=C1c1ccccc1
Reactant: CCOP(=O)(CN)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Solvent: CC(=O)O
Product: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)C(c2ccccc2)=C(c2ccccc2)C1=O
Yield: 80.2 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.52 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester acetate and 0.34 g of diphenylmaleic anhydride, there was obtained 0.581 g of [(2,3-diphenylmaleimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester in the form of a yellow-green foam.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CC(C)=O>O>[CH2:1]([O:3][CH:4]1[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CCOC1CCC(=O)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 8-Ethoxy-1,4-dioxa-spiro[4.5]decane (Compound 166F, 2 gm, 10.7 mmol) and pyridinium p-toluene sulfonate (5.4 gm, 21.5 mmol) was taken up in a 1:1 mixture of acetone and water (150 mL) and stirred at 50° C. overnight. The acetone was subsequently removed under reduced pressure and the aqueous solution was extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4), and evaporated to give the crude material which was used in the next step without further purification. Yield: 0.8 gm (53%). 1H NMR (CDCl3, 500 MHz): δ 1.24 (t, J=7.1 Hz, 3H), 1.95 (m, 2H), 2.05 (m, 2H), 2.24 (m, 2H), 2.6 (m, 2H), 3.6 (q, J=7.1 Hz 2H), 3.7 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:16]([I:18])[CH3:17].C(OCC)C>C(#N)C>[I-:18].[CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][N+:12]([CH2:16][CH3:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCI
Reactant: CN(C)c1ccc(-c2ccncc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CC[n+]1ccc(-c2ccc(N(C)C)cc2)cc1
Product: [I-]
Yield: 18 %

Procedure:
Was prepared by refluxing N,N-dimethyl-4-(pyridine-4-yl)aniline (II) in acetonitrile in the presence of ethyl iodide. Upon cooling diethyl ether was added and the product crystallized resulting in a 18% yield of 4-(4-(dimethylamino)phenyl)-1-ethylpyridinium iodide (IDT321) (IV).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:16]3[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)=[N:4][O:5][N:6]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([O:22][C:18]2[CH:17]=[C:16]([N:8]3[C:9]4[CH:14]=[CH:13][N:12]=[CH:11][C:10]=4[N:15]=[C:7]3[C:3]3[C:2]([NH2:1])=[N:6][O:5][N:4]=3)[CH:21]=[CH:20][CH:19]=2)[CH2:26][CH2:25]1
Reactant: CN1CCC(O)CC1
Reactant: Nc1nonc1-c1nc2cnccc2n1-c1cccc(O)c1
Product: CN1CCC(Oc2cccc(-n3c(-c4nonc4N)nc4cnccc43)c2)CC1

Procedure:
The title compound was prepared from the product of Example 39 using the general method of Example 50 using N-methyl-4-hydroxy-piperidine. MS (ES+) m/e 392 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.O1CC[CH2:19][CH2:18]1.CC(C)([O-])C.[Na+].C(Br)C>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:6]([N:7]([CH2:18][CH3:19])[C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCBr
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(C(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 58 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a 3-neck, 100-mL round bottom flask was charged N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1.66 g, 7.0 mmol) and tetrahydrofuran (16 mL). Sodium tert-butoxide (0.843 g, 8.77 mmol, 1.25 eq) and ethyl bromide (0.78 mL, 10.52 mmol, 1.5 eq) were added and the reactor was capped with a septa. The reaction was stirred at 58° C. for 24 hours, at which point HPLC analysis indicated that only 1.97% starting material remained. The mixture was concentrated to give a brown residue, which was dissolved in water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organics were concentrated to dryness. The residue was passed through a silica gel plug (40 g silica) and eluted with ethyl acetate (200 mL). The filtrates were concentrated to dryness and further dried under vacuum at 20° C. to afford a yellow solid (1.68 g, 89%). Characterization matched sample prepared by previous method.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[C:14]([CH3:16])[CH3:15])[C:6]=1[C:7]#[N:8])([O-])=O>CCO.[Fe]>[NH2:2][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[C:14]([CH3:16])[CH3:15])[C:6]=1[C:7]#[N:8]
Reactant: CC(C)=Cc1cccc([N+](=O)[O-])c1C#N
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC(C)=Cc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
Concentrated HCl (65.5 mL) was added slowly to a solution of 2-nitro-6-(2-methylprop-1-enyl)benzonitrile (Example 129c) (2.00 g; 9.89 mmol) in EtOH (120.2 mL) at room temperature. Then, the obtained mixture was treated with iron powder (5.52 g; 98.91 mmol), added in small portions at the same temperature. The mixture was stirred at room temperature for 15 min, and then heated at reflux for 30 min. The mixture was cooled to room temperature, EtOH was evaporated and the pH was adjusted to pH˜10 with aqueous NaOH (2.0M). The basified mixture was extracted with EtOAc (4×100 mL) and the combined extract was dried with anhydrous MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using gradient hexanes to hexanes/EtOAc (8:2), to afford 1.32 g (77%) of the title compound as yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ 7.19-7.25 (m, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.46 (d, J=7.2 Hz, 1H), 6.23 (broad s, 1H), 5.91 (broad s, 2H), 1.86-1.88 (m, 3H), 1.72-1.74 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:23][C:22]([CH3:24])=[N:21][C:4]=2[N:5]([CH3:20])[C:6](=[O:19])[C:7]=1[C:8]([NH:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[O:9].C(N(CC)C(C)C)(C)C.OC1C2SC(C)=NC=2N(C)C(=O)C=1C(OCC)=O>O1CCOCC1>[OH:1][C:2]1[C:3]2[S:23][C:22]([CH3:24])=[N:21][C:4]=2[N:5]([CH3:20])[C:6](=[O:19])[C:7]=1[C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9]
Reactant: Cc1nc2c(s1)c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n2C
Agent: CCOC(=O)c1c(O)c2sc(C)nc2n(C)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc2c(s1)c(O)c(C(=O)NCC(=O)O)c(=O)n2C
Temperature: 25 °C

Procedure:
tert-Butyl 2-(7-hydroxy-2,4-dimethyl-5-oxo-4,5-dihydrothiazolo[4,5-b]pyridine-6-carboxamido)acetate. N,N-diisopropylethylamine (0.25 g, 2.0 mmol), tert-butyl glycine ester hydrochloride (0.33 g, 2.0 mmol) and ethyl 7-hydroxy-2,4-dimethyl-5-oxo-4,5-dihydrothiazolo[4,5-b]pyridine-6-carboxylate (0.35 g, 1.31 mmol) were heated at 90° C. for 5 hours in 1,4-dioxane (5 mL). The mixture was cooled to room temperature and concentrated to about ¼ of the original volume. Et2O (5 mL) was added, and the resulting suspension was filtered and washed with Et2O to give a solid. This material was washed with cold MeOH (0.5 mL) to give the title compound. MS (ESI) m/z: Calculated; 353.1: Observed; 298.1 (M-tert-butyl+H+). 1H NMR (400 MHz, CDCl3) δ ppm 10.52-10.83 (1H, m), 4.11 (2H, d, J=5.3 Hz), 3.81 (3H, s), 2.83 (3H, s), 1.52 (9H, s)
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23].C(=O)([O-])[O-].[K+].[K+].[Br:30]Br>ClCCCl>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Br:30])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)cc2)c(C)c(N)c1Cl
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(Br)cc2)c(C)c(N)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.5 %

Procedure:
To methyl 4-amino-3-chloro-5-methyl-6-(4-(trimethylsilyl)phenyl)picolinate (150 mg, 0.43 mmol) and potassium carbonate (215 mg, 1.56 mmol) in 1,2-dichloroethane (DCE, 2.9 mL) was added bromine (0.03 mL, 0.58 mmol) and stirred at room temperature for 18 h. The DCE was concentrated off under vacuum and the crude material was partitioned between ethyl acetate and aqueous potassium carbonate. The aqueous layer was extracted with ethyl acetate (3×), washed with water, dried over anhydrous magnesium sulfate, filtered, and adsorbed onto silica gel. Purification by flash chromatography (0-40% ethyl acetate/hexanes) afforded the title compound as a yellow solid (68 mg, 45%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[N:3]=1.C([Li])CCC.[O:18]1[CH2:21][C:20](=[O:22])[CH2:19]1>O1CCCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[N:3]=[C:2]([C:20]2([OH:22])[CH2:21][O:18][CH2:19]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(C2OCCO2)n1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cccc(C3OCCO3)n2)COC1
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
To a solution of 2-bromo-6-(1,3-dioxolan-2-yl)pyridine (2.49 g, 10.8 mmol) in anhydrous tetrahydrofuran (40 mL) was added a solution of n-butyllithium (2.5 M, 4.3 mL, 10.8 mmol) at −78° C. After stirring for 30 min., a solution of oxetan-3-one (0.6 g, 8.32 mmol) in anhydrous tetrahydrofuran (12 mL) was added slowly and the mixture was stirred at that temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude compound. The crude material was purified via preparative TLC eluting with 35% ethyl acetate in petroleum ether to afford 3-(6-(1,3-dioxolan-2-yl)pyridin-2-yl)oxetan-3-ol (500 mg, 27%). MS (ES+) (M+H) 224.20; LCMS retention time: 2.76 minutes (Method S).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].Cl.[CH2:28]([NH2:31])[CH2:29][CH3:30].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:31][CH2:28][CH2:29][CH3:30])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (530 mg, 1.36 mmol) in CH3CN (7 mL) was added neat propylamine hydrochloride (260 mg, 2.72 mmol) followed by triethylamine (378 μL, 2.72 mmol) and the resulting mixture was stirred for 1 h. Saturated aqueous NaHCO3 (20 mL) was added, then the resulting mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried (MgSO4) and concentrated. The resulting crude material was purified by flash chromatography on silica gel (hexane/EtOAc 1:1) to give (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-propylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white foam (532 mg, 87% yield). 1H NMR (500 MHz, CDCl3) δ 0.97 (t, 3H, J=7.5 Hz), 1.59-1.64 (m, 2H), 1.53-1.59 (m, 2H), 2.06 (s, 3H), 2.08 (s, 3H), 2.12 (s, 3H), 2.15 (s, 3H), 3.35 (br s, 2H), 3.81-3.85 (m, 1H), 4.13-4.17 (m, 2H), 4.20-4.25 (m, 1H), 4.29 (dd, 1H, J=4.5, 12.5 Hz), 5.17-5.23 (m, 2H), 5.73 (d, 1H, J=8.5 Hz), 6.07 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-])=O)[CH2:10][CH2:9][CH2:8]2>CO.[C].[Pd]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11]([CH2:10][CH2:9][CH2:8]2)=[CH:12][C:13]=1[NH2:14]
Reactant: COCOc1cc2c(cc1[N+](=O)[O-])CCC2
Agent: [Pd]
Solvent: CO
Product: COCOc1cc2c(cc1N)CCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
4.20 g of 5-(methoxymethoxy)-6-nitroindane was dissolved in 42.0 mL of methanol, and 500 mg of 10% palladium carbon was added thereto, followed by stirring at room temperature for 6 hours under a hydrogen atmosphere. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 3.30 g of 6-(methoxymethoxy)indan-5-amine.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1C(F)(F)F
Product: O=C(Nc1ccccc1C(F)(F)F)c1ccc([N+](=O)[O-])cc1
Yield: 15.3 %

Procedure:
Using 2-trifluoromethylaniline (1.77 g, 11.0 mmol) and 4-nitrobenzoic acid (1.67 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 474 mg (15.3%) the title compound in the form of colorless powder.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]([C:14]([N:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]3[CH:40]=[CH:39][C:38](Cl)=[CH:37][CH:36]=3)[CH:29]=2)[C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[O:15])[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:42]([OH:44])=[O:43])(=O)C.C([O-])(O)=O.[Na+]>CO.O>[OH:4][C:5]1[CH:13]=[C:12]([C:14]([N:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=2)[C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[O:15])[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:42]([OH:44])=[O:43]
Reactant: CC(=O)Oc1cc(C(=O)N(Cc2cccc(Oc3ccc(Cl)cc3)c2)[C@H]2CCCc3ccccc32)c(C(=O)O)cc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Oc3ccccc3)c2)[C@H]2CCCc3ccccc32)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
The products from Example 104B (0.97 g, 1.68 mmol) in methanol (60 mL) were treated with NaHCO3 (3.9 g, 46.4 mmol) in water (30 mL) and the mixture was stirred at room temperature for 24 hours. The methanol was removed under reduced pressure and the remaining aqueous solution was acidified to pH 1 with 1N HCl. The acidified solution was extracted with ethyl acetate (5×15 mL). The organic extracts were combined, washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 9:1 CH2Cl2:methanol to 8:2 CH2Cl2:methanol) to provide the title compounds as a foamy white solid (208 mg, 23%).