Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CN(C)C=O>[CH2:18]([O:9][C:8]([C:6]1[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)=[O:10])[CH3:19]
Reactant: O=Cc1ccc(C(=O)O)o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.3 %

Procedure:
5-Formyl-2-furancarboxylic acid (2.9 g) was dissolved in N,N-dimethylformamide (30 ml), and potassium carbonate (2.9 g) and iodoethane (3.6 g) were added. The mixture was stirred at room temperature for 12 hours, poured into ice water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-formyl- 2-furancarboxylic acid ethyl ester (1.3 g). 5-Formyl-2-furancarboxylic acid ethyl ester (1.3 g) in methylene chloride (5 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.3 g) in methylene chloride (5 ml) at room temperature. The mixture was stirred at room temprature for 30 minutes, and water was added to the mixture. The resulting mixture was extracted with diethyl ether, and the extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-difluoromethyl-2-furancarboxylic acid ethyl ester (0.7 g). 5-Difluoromethyl-2-furancarboxylic acid ethyl ester (2.3 g) synthesized in this manner was dissolved in ethanol (20 ml), and 1N aqueous sodium hydroxide (15 ml) was added. The mixture was stirred at room temperature and concentrated under reduced paressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with hexane-isopropyl ether to give 5-difluoromethyl-2-furancarboxylic acid (1.2 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].C1N2CCN(CC2)C1.[C:22](#[N:25])[CH:23]=[CH2:24]>C(OCC)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]([OH:13])[C:23]([C:22]#[N:25])=[CH2:24]
Reactant: COC(=O)c1ccc(C=O)c(Cl)n1
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C#N)C(O)c1ccc(C(=O)OC)nc1Cl

Procedure:
To a mixture of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 mmol, 1.99 g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜4-5 min.) was diluted with diethyl ether (300 ml.) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (2.50 g.).
Reaction SMILES: C(=O)([O-])O.[K+].[OH:6][C:7]1[C:8]([O:21][CH3:22])=[CH:9][C:10]2[O:15][C:14](=[O:16])[C:13]3[CH2:17][CH2:18][CH2:19][C:12]=3[C:11]=2[CH:20]=1.Cl[CH2:24][CH2:25][CH2:26][OH:27]>C(O)(C)C>[OH:27][CH2:26][CH2:25][CH2:24][O:6][C:7]1[C:8]([O:21][CH3:22])=[CH:9][C:10]2[O:15][C:14](=[O:16])[C:13]3[CH2:17][CH2:18][CH2:19][C:12]=3[C:11]=2[CH:20]=1
Reactant: OCCCCl
Reactant: COc1cc2oc(=O)c3c(c2cc1O)CCC3
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCO)CCC3
Yield: 58 %

Procedure:
Method J (but using potassium hydrogencarbonate); Starting materials: 2,3-dihydro-8-hydroxy-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 109) and 3-chloro-1-propanol; yield 58%; fusion point 213°-215° C. (from isopropanol).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:31]([O-])=O)[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C:17]([OH:22])([CH3:21])[C@H:16]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]>C(O)(=O)C.CCOC(C)=O.[Fe]>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:31])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C:17]([OH:22])([CH3:21])[C@H:16]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@H](C)C(C)(O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C(C)(O)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
4-{(3R,5S)-3-[(tert-Butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (198 mg, 0.426 mmol) was dissolved in acetic acid (2.8 mL), and iron powder (0.36 g, 6.4 mmol) was added to the solution. Reaction was stirred at room temperature for 2 h. The mixture was diluted with 30 mL of EtOAc, filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and the resulting residue was dissolved in EtOAc, and neutralized with NaHCO3. The layers were separated, and the aqueous layer was extracted with further EtOAc. The combined organic layers were dried and concentrated under reduced pressure to give the sub-title compound as a white solid (176 mg, 95%), which was used in the next step without further purification. LCMS calc. for C22H35N4O5 (M+H)+ m/z=435.3. found 435.1.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]4[N:36]=[CH:37][N:38]=[C:12]34)[CH2:7][CH2:6]2)[O:4][CH2:3]C1.Cl.CI.[H-].[Na+]>C(OCC)(=O)C.CN(C)C=O.O1CCCC1>[CH3:3][O:4][CH:5]1[CH2:6][CH2:7][CH:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OC)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h
Yield: 11.1 %

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2 g), 6N hydrochloric acid (20 mL) and tetrahydrofuran (30 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (30 mL), sodium borohydride (0.18 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in N,N-dimethylformamide (10 mL), methyl iodide (0.13 mL) and sodium hydride (0.05 g) were added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.21 g, 28%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1>[Ni]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(CNc2ncccn2)cc1
Agent: [Ni]
Product: Nc1ccc(CNc2ncccn2)cc1

Procedure:
Prepared analogously to Example 55 by catalytic hydrogenation of 4-(pyrimidin-2-ylaminomethyl)-nitrobenzene with Raney nickel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:12][C:13]1[CH:20]=[C:19](F)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:10][C:19]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([Cl:12])[CH:20]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: N#Cc1cc(Br)cc(F)c1O
Product: N#Cc1ccc(Oc2c(F)cc(Br)cc2C#N)cc1Cl

Procedure:
The title compound was prepared according to the method described for Preparation at 120° C. for 68 hours using 5-bromo-3-fluoro-2-hydroxybenzonitrile (WO 2006022374) and 2-chloro-4-fluorobenzonitrile.
Reaction SMILES: [C:1]1(=[CH:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1([CH3:22])[C:14]([CH3:16])([CH3:15])[O:13][B:12]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[O:11]1.N12CCCN=C1CCCCC2>C(#N)C>[CH3:9][C:10]1([CH3:22])[C:14]([CH3:15])([CH3:16])[O:13][B:12]([C:17]2[CH:21]=[N:20][N:19]([C:1]3([CH2:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:18]=2)[O:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CC=C1CCCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C3(CC#N)CCCC3)c2)OC1(C)C
Temperature: 25 °C
Yield: 17.2 %

Procedure:
A mixture of cyclopentylideneacetonitrile (0.65 g, 0.0061 mol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.60 g, 0.0031 mol, Aldrich, Cat. 525057), and 1,8-diazabicyclo[5.4.0]undec-7-ene (47 mg, 0.00031 mol, Aldrich, Cat. No. 139009) in acetonitrile (7 mL) was stirred at 60° C. overnight. After cooling to r.t., the reaction mixture was concentrated. The crude residue was purified by flash column chromatography on a silica gel column using 40% ethyl acetate in hexane as eluent to afford the desired compound (161 mg, 17.29%). LCMS (M+H)+: m/z=302.4.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[NH2:14][C@H:15]([CH3:18])[CH2:16][OH:17]>O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[NH:7][C:6]=2[CH:8]=1
Reactant: C[C@@H](N)CO
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Solvent: O
Product: C[C@H](CO)NC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide and (R)-(-)-2-amino-1-propanol by a procedure analogous to the procedure described in example 1Bb; mp 203°-204° C. (water), 1H-NMR (DMSO-d6): δ 1.11 (d, 3H), 3.4 (d, 2H), 3.78 (m, 1H), 4.95 (br. s, 1H), 7.05 (br. s, 1H), 7.09 (s, 1H), 10.8 (br. s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[CH3:24][S:25]([N:28]1[CH2:29][CH2:30][CH:31]([NH:34][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:32][CH2:33]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: Clc1ncc2c(-c3ccccc3)n[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ncc3c(-c4ccccc4)n[nH]c3n2)CC1
Yield: 21 %

Procedure:
The compound was prepared from 6-chloro-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (Example 14) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid in an analogous manner as described in Example 4 and was purified by HPLC (Gilson) to give a free base (21% yield). MS (M+H)+, 373.24.
Reaction SMILES: [C:1]1([S:7](N)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)(Cl)(Cl)Cl.Cl>CO.C(O)(=O)C>[C:1]1([S:7]([C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:2][C:1]=3[S:7](=[O:8])[N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: O=S1N=C(S(=O)(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
31.44 G. (0.2 mole) of benzenesulfonamide was dissolved in 80 ml. of dry pyridine to obtain a clear, straw-colored solution, which was placed in a cold water bath. To this pyridine solution was added the carbon tetrachloride solution produced in Part B above. An exothermic reaction ensued with formation of a white slurry, which was stirred at ambient temperature for 45 minutes and then poured into 600 ml. of 2N hydrochloric acid. The aqueous phase of the resultant mixture was decanted from the lower organic phase, which was cooled in ice water and filtered to remove carbon tetrachloride. The white solid thus obtained was slurried in 600 ml. of hot acetic acid, cooled and filtered to obtain a white solid, which was dried under vacuum to yield 49.7 g. of product having an infra-red spectrum consistent with the expected structure. The ultraviolet spectrum of the product in methanol showed peaks at 202 nm (ε=17,000), 232 nm. (ε=31,000) and 332 nm. (ε=4,000).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:23][C:24](O)=[O:25])=[C:7]([CH3:22])/[C:8]/2=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:27][CH3:28].C(Cl)(=O)C([Cl:32])=O>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:23][C:24]([Cl:32])=[O:25])=[C:7]([CH3:22])/[C:8]/2=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2c(cc1F)/C(=C\c1ccc(S(C)(=O)=O)cc1)C(C)=C2CC(=O)O
Solvent: C1CCOC1
Product: COc1cc2c(cc1F)/C(=C\c1ccc(S(C)(=O)=O)cc1)C(C)=C2CC(=O)Cl

Procedure:
(Z)-6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 70 mmol) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:26])[C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([C:22](O)=[O:23])[C:16]=2[Cl:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:69][CH2:70][C:71]1[C:72](=[O:79])[NH:73][C:74]([CH3:78])=[CH:75][C:76]=1[CH3:77]>CN(C=O)C>[Cl:25][C:16]1[C:17]([C:22](=[O:23])[NH:69][CH2:70][C:71]2[C:72](=[O:79])[NH:73][C:74]([CH3:78])=[CH:75][C:76]=2[CH3:77])=[N:18][C:19]([Cl:21])=[CH:20][C:15]=1[N:14]([CH3:26])[CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CN(c1cc(Cl)nc(C(=O)O)c1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2nc(Cl)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}(methyl)amino)-3,6-dichloropyridine-2-carboxylic acid (75 mg, 0.19 mmol) in DMF (2 ml) cooled to 0° C. h was added DIPEA (48 μl, 0.28 mmol) followed by PyBOP (116 mg, 0.22 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89% purity, 35 mg, 0.2 mmol). The reaction mixture was then stirred at room temperature for 16 h after which the reaction was poured onto water (30 ml) and extracted with EtOAc (3×50 ml) after which the combined organics were washed with brine (50 ml) and dried (Na2SO4) and evaporated. The crude product was purified using a 5 g silica Isolute column eluting with a gradient of 0% to 100% EtOAc in heptane to afford the title compound as a white solid which contained ˜45% w/w tripyrrolidinophosphene oxide by NMR—this compound was used in the next stage of the synthesis without any further purification. LC-MS 93%, 1.97 min (3.5 minute LC-MS method), m/z=538.0/539.45/542.05, 1H NMR (500 MHz, Chloroform-d) δ 10.03 (br. s, 1H), 8.13-7.97 (m, 1H), 6.79 (s, 1H), 5.87 (s, 1H), 4.50 (d, J=6.1 Hz, 2H), 4.16 (br. m, 2H), 3.78-3.62 (m, 1H), 2.72 (s, 3H), 2.65 (br. m, 2H), 2.35 (s, 3H), 2.22 (s, 3H), 1.73-1.63 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([C:3]([NH:6][C:7]([CH:9]([NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:8])([CH3:5])[CH3:4])#[N:2].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.[Na]>C1COCC1>[C:1]([C:3]([NH:6][C:7]([CH:9]([NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:18][CH:17]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:8])([CH3:5])[CH3:4])#[N:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)CC(NC(=O)c1ccc(CBr)cc1)C(=O)NC(C)(C)C#N
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)c1ccc(Cn2ccnc2)cc1)C(=O)NC(C)(C)C#N
Temperature: 25 °C

Procedure:
N-{1-[(Cyano-dimethyl-methyl)-carbamoyl]-3-methyl-butyl}-4-bromomethyl-benzamide (0.18 mmol) is dissolved in THF (1 ml) and sodium-imidazol (0.41 mmol) is added and the reaction mixture stirred at RT over night. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and evaporated. An oil with Rf=0.44 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A solution of methyl[3,5-dihydroxyphenyl]acetate (2.1 g, 11.5 mmol) in acetone (100 mL) was treated with potassium carbonate (2.4 g, 17.4 mmol), potassium iodide (0.38 g, 2.31 mmol) and benzyl bromide (1.5 mL, 12.7 mmol), and the mixture was stirred at room temperature overnight. The reaction was diluted with water, and was extracted with dichloromethane (×3). Combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The crude material was purified on a Biotage™ 40 M column (silica), eluting with 40% ethyl acetate/hexane, to give methyl[3-benzyloxy-5-hydroxyphenyl]acetate (1.0 g, 33%). 1H NMR (400 MHz, CDCl3): δ 7.32-7.42 (m, 5H), 6.48 (d, J=1.4 Hz, 1H), 6.38-6.39 (m, 2H), 4.99 (s, 2H), 3.69 (s, 3H), 3.53 (s, 2H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:19]=[CH:18][C:12]([O:13][CH:14]([CH3:17])[CH2:15][OH:16])=[CH:11][CH:10]=2)O1.[Cl:21][C:22]1[CH:23]=[C:24]2[NH:31][C:30]([O:32][C@H:33]3[CH2:38][O:37][C@H:36]([CH2:39][OH:40])[C@@H:35]([OH:41])[CH2:34]3)=[N:29][C:25]2=[N:26][C:27]=1I.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.O.CCOC(C)=O>[Cl:21][C:22]1[CH:23]=[C:24]2[NH:31][C:30]([O:32][C@H:33]3[CH2:38][O:37][C@H:36]([CH2:39][OH:40])[C@@H:35]([OH:41])[CH2:34]3)=[N:29][C:25]2=[N:26][C:27]=1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:17])[CH2:15][OH:16])=[CH:18][CH:19]=1
Reactant: CC(CO)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: OC[C@H]1OC[C@H](Oc2nc3nc(I)c(Cl)cc3[nH]2)C[C@@H]1O
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(CO)Oc1ccc(-c2nc3nc(O[C@H]4CO[C@H](CO)[C@@H](O)C4)[nH]c3cc2Cl)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-1-ol (61.3 mg, 0.220 mmol), (2R,3S,5R)-5-((6-chloro-5-iodo-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol (75 mg, 0.176 mmol) and potassium phosphate tribasic (150 mg, 0.70 mmol) were dissolved in dioxane (600 μl) and water (600 μl). The mixture was sparged with N2 with for 15 min and [1,1′-Bis(Diphenyl-phosphino)Ferrocene]Dichloropalladium(II) (25.8 mg, 0.035 mmol) was added. The reaction was stirred 3 h at 80° C., then diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2), and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by mass directed reverse phase HPLC eluted with acetonitrile in water containing 0.1% formic acid. The desired fractions were combined and lyophilized to give the title compound as a white solid. LC-MS: calculated for C21H24ClN3O6 449.14 observed m/e: 449.92 (M+H)+ (Rt 1.03/2 min); 1H NMR δ (ppm) (CD3OD): 7.77 (s, 1H), 7.58 (d, 2H), 7.02 (d, 2H), 5.10 (septet, 1H), 4.57-4.54 (m, 2H), 4.32 (dd, 1H), 3.88 (d, 1H), 3.73-3.59 (m, 3H), 3.36 (t, 1H), 3.17-3.14 (m, 1H), 2.75-2.73 (m, 1H), 1.67 (dd, 1H), 1.31 (d, 3H).
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH2:3][CH3:4].C(Cl)CCl.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>O>[CH2:2]([O:5][NH:6][C:18](=[O:19])[O:20][CH2:21][CH3:22])[CH2:3][CH3:4]
Reactant: CCCON
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Product: CCCONC(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
22 g (197 mmol) of n-propoxyamine hydrochloride was dissolved in 100 ml of water, and 200 ml of ethylene dichloride was added thereto. Then, 27.2 g (197 mmol) of potassium carbonate was added in several times under cooling, and then 21.3 g (196 mmol) of ethyl chloroformate was dropwise added thereto at a temperature of not higher than 10° C. After raising the temperature to room temperature, the mixture was further stirred at the same temperature for 4 hours. The ethylene dichloride layer was separated, and then the aqueous layer was extracted twice with 100 ml of chloroform. The ethylene dichloride layer and the chloroform layer were put together, and washed with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. 27 g of ethyl N-n-propoxycarbamate was obtained by distillation under reduced pressure.
Reaction SMILES: [CH3:1][C:2](=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:15][CH2:16][CH:17]([CH2:19]O)[OH:18]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:18][CH:17]([CH2:16][OH:15])[CH2:19][O:14]1
Reactant: CCCCCCCCCCCC(C)=O
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC1(C)OCC(CO)O1
Reaction time: 24 h

Procedure:
A reactor equipped with a stirrer, reflux-condenser, thermometer and nitrogen gas inlet pipe was charged with 297 g of 2-tridecanone, 166 g of glycerol and a solvent amount of toluene, and following addition of p-toluenesulfonic acid as a catalyst, the dehydrative condensation reaction was carried out at the reflux temperature for 24 hours. The resulting crude product was washed with an aqueous solution of potassium carbonate and further with 3 portions of distilled water and finally purified by distillation under reduced pressure to provide 2-methyl-2-undecyl-4-hydroxymethyl-1,3-dioxolane.