Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:15]([CH3:24])[N:14]=[N:13][C:12]=1[CH3:25].C(OCC)(=O)C>CN(C=O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[C:11]([N:5]3[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]3)=[C:12]([CH3:25])[N:13]=[N:14][C:15]=2[CH3:24])=[CH:22][CH:21]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)n(-c2c(C)nnc(C)c2-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
70 mg of sodium hydride (55% oil dispersion) was added to 1 ml of N,N-dimethylformamide (hereinafter, described as DMF) To this was added 0.17 g of 3,5-dimethylpyrazole, and the mixture was stirred for 1 hour at room temperature. To the resultant mixture was added a solution of 0.15 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine in 2 ml of DMF, and the mixture was stirred for 7 hours on an oil bath of 60° C. To the reaction mixture was added ethyl acetate and the mixture was washed with brine five times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. To 0.33 g of the resultant residue was added 50 ml of ethyl acetate, and washed with 50 ml of 1 mol/L hydrochloric acid and brine sequentially, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.21 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.12 g of 5-(4-chloro-phenyl)-4-(3,5-dimethyl-1-pyrazolyl)-3,6-dimethylpyridazine (hereinafter, described as compound (3) of the present invention).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=[O:23])[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=1)[CH3:2].[CH2:27]([O:29]C(C1C2C=CC(O)=CC=2OC=1)=O)[CH3:28].C(OCCBr)C>>[CH2:27]([O:29][CH2:2][CH2:1][O:3][C:4]1[CH:26]=[CH:25][C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=[O:23])[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=1)[CH3:28]
Reactant: CCOC(=O)c1coc2cc(O)ccc12
Reactant: CCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Agent: CCOCCBr
Product: CCOCCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1

Procedure:
4-[6-(2-Ethoxy-ethoxy)-benzofuran-3-ylmethoxy]-1H-indole-2-carboxylic acid (30c) is synthesized analogous to 30a from 6-hydroxy-benzofuran-3-carboxylic acid ethyl ester (26) and 2-bromoethyl ethyl ether.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:31]=[C:30]([CH3:32])[O:29][C:28]=1[C:33]([F:36])([F:35])[F:34])=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:31]=[C:30]([CH3:32])[O:29][C:28]=3[C:33]([F:36])([F:34])[F:35])[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1cc(N=C=O)c(C(F)(F)F)o1
Product: COc1cccc2c1ncc1c(=O)n(-c3cc(C)oc3C(F)(F)F)c(=O)n(C3CCCC3)c12
Yield: 54.4 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(5-methyl-2-trifluoromethyl-furan-3-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (25 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 3-isocyanato-5-methyl-2-trifluoromethyl-furan (0.5 mmol) following general procedure C. LCMS: m/z 460 [M+1]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([NH:22][C:23](=[O:28])[CH2:24][C:25]([OH:27])=O)[CH:18]=2)=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)=[O:59]>CN(C=O)C>[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]([N:60]1[CH2:61][CH2:62][N:63]([C:25](=[O:27])[CH2:24][C:23]([NH:22][C:19]2[CH:18]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=3)[O:21][N:20]=2)=[O:28])[CH2:64][CH2:65]1)=[O:59]
Reactant: O=C(O)CC(=O)Nc1cc(-c2ccc(F)cc2)on1
Reactant: O=C(c1ccccc1Br)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1cc(-c2ccc(F)cc2)on1
Reaction time: 0.03 h
Yield: 28.5 %

Procedure:
DIPEA (57 mg, 0.078 mL, 0.45 mmol) was added dropwise to N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-malonamic acid (40 mg, 0.15 mmol) in DMF (2 mL) followed by EDCI (35 mg, 0.18 mmol) and HOBT (24 mg, 0.18 mmol). After 2 minutes, (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride (55 mg, 0.18 mmol) was added and stirring was continued at room temperature overnight. The reaction mixture was quenched with cold water and was then extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by preparative HPLC afforded 22 mg (28.27% yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-3-oxo-propionamide. LC/MS [M+H]+: 515.07, 96.02%. 1H NMR (300 MHz, DMSO-d6): δ 11.4-11.2 (m, 1H), 7.8 (m, 2H), 7.6 (d, 1H), 7.4-7.2 (m, 5H), 7.1 (t, 2H), 6.6 (d, 1H), 4.1-3.9 (m, 2H), 3.8-3.2 (m, 10H).
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:9][C:10]([NH:12][CH:13]([CH2:18][CH:19]=C)[C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH:7]=[CH2:8].[CH2:21](Br)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:17][O:16][C:14](=[O:15])[C@H:13]([CH:18]([CH3:19])[CH3:21])[NH:12][C:10]([O:9][CH2:6][C:7]1[CH:8]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: C=CCOC(=O)NC(CC=C)C(=O)OC
Reactant: BrCc1ccccc1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran solution (1.0 ml) of the compound prepared in Example 4 (130 mg, 0.42 mmol), were successively added dropwise at 0° C. in a nitrogen atmosphere benzyl bromide (0.101 ml, 0.84 mmol) and a tetrahydrofuran solution of tetrabutyl ammonium fluoride (0.42 ml, 0.42 mmol). The mixture was stirred for 1 hour at 0° C., poured into water and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under vacuum. The resulting reaction mixture was subjected to column chromatography on silica gel and eluted with a 1:4 mixture of ether and hexane, to give the titled compound in an amount of 95.1 mg (yield, 85% based on the starting materials used in Example 4).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:25])=O>ClCCl>[Cl-:25].[N:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O-:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C([O-])C1CCN(c2ccncc2)CC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7 g (34 mmol) of 1-(pyridine-4-yl)-piperidine-4-carboxylate hydrochloride was stirred in 340 ml of dichloromethane, and 1 ml of dimethylformamide and 10.4 ml (109 mmol) of oxalyl dichloride were added thereto and stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was dried with a vacuum pump to obtain the title compound.
Reaction SMILES: [CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[N:29]1([CH2:35][CH2:36]O)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[ClH:69]>C(Cl)Cl.CO>[ClH:69].[CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:36][CH2:35][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:25][CH:26]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CCC[C@H](C)NC(=O)Nc1nc2nccc(-c3ccc(O)cc3)n2n1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)CCC[C@H](C)NC(=O)Nc1nc2nccc(-c3ccc(OCCN4CCOCC4)cc3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-1-(1,5-dimethylhexyl)-3-[7-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]urea (the compound obtained in Example 255; 20 mg) was dissolved in methylene chloride (1 ml) in an argon atmosphere. Thereafter, 2-morpholin-4-ylethanol (21 mg) and triphenylphosphine (41 mg) were added to the obtained solution, and the obtained mixture was stirred at a room temperature for 30 minutes. Thereafter, the reaction solution was cooled on ice, and diethyl azodicarboxylate (27 mg) was then added thereto, followed by stirring the mixture at the same temperature for 30 minutes. The reaction solution was further stirred at a room temperature overnight. Thereafter, the reaction solution was concentrated under a reduced pressure. Thereafter, ethyl acetate (3 ml) and 1 M hydrochloric acid (3 ml) were added thereto, and the obtained mixture was separated. After the obtained water layer was washed with ethyl acetate (3 ml), an aqueous 6 M sodium hydroxide solution was added thereto to convert the solution to be alkaline. After extraction with methylene chloride (5 ml), the organic layer was washed with distilled water (5 ml×2), and the solvent was then distilled off under a reduced pressure. The residue was washed by suspension in a mixed solvent (2 ml) consisting of 50% ethyl acetate and hexane to obtain the captioned compound in the form of a free body (18 mg). Thereafter, methanol (1 ml) and 1 M hydrochloric acid (0.2 ml) were added to the obtained compound and dissolved therein, and the obtained mixture was then concentrated under a reduced pressure. The obtained residue was washed by suspension in acetone (0.5 ml) to obtained the captioned compound (17 mg).
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]3[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34])[CH:27]=4)=[CH:24][N:25]=[C:19]3[CH:18]=2)[N:12]=1)(=O)=O.CO.Cl>CCO>[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]3[C:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33]([NH:35][CH2:36][C:37]([F:38])([F:40])[F:39])=[O:34])[CH:29]=[CH:30][CH:31]=4)=[CH:24][N:25]=[C:19]3[CH:18]=2)[N:12]=1
Reactant: CN(C)S(=O)(=O)n1ccnc1-c1ccnc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)n1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4nccc(-c5ncc[nH]5)n4)ccn23)c1
Temperature: 60 °C
Yield: 18.2 %

Procedure:
2-[2-(3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridin-7-yl)-pyrimidin-4-yl]-imidazole-1-sulfonic acid dimethylamide (140 mg, 0.23 mmol) dissolved in EtOH (5 ml) and MeOH(1 ml) treated with 2M HCl (1 ml) heated at 60° C. for 2 hours. Reaction mixture concentrated under reduced pressure and was purified by preparative HPLC to give product (20 mg).
Reaction SMILES: [OH-].[K+].O.[C:4]([OH:13])(=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[SH:7].I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.C1C=CC=CC=1>[C:15]1([S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]([OH:13])=[O:12])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1ccccc1
Reactant: O=C(O)c1ccccc1S
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)c1ccccc1Sc1ccccc1
Reaction time: 18 h
Yield: 82.5 %

Procedure:
5.6 g (0.10 mol) potassium hydroxide, 7 ml water, 30 ml benzene and 7.7 g (0.05 mol) thiosalicyclic acid were combined and heated at reflux under a Dean Stark trap. After the water had been collected, 50 ml of dimethylformamide was added and the mixture slowly heated to 140°-150° C. to remove the benzene. An additional 10 ml of dimethylformamide and 0.25 g (1.75 mmol) of cuprous oxide were then added. 5.8 ml (0.051 mol) of iodobenzene was slowly added over a period of 20 minutes while the temperature was maintained at 140°-150° C. The reaction mixture gradually became a solution and gentle reflux was continued for 18 hours. The mixture was then cooled and poured over ice. The pH was adjusted to 10.0 and precipitated solids removed by filtration. The filtrate was washed with two portions of ethyl acetate (the organics were discarded) and adjusted to pH 2.5 with 1N HCl. A precipitate formed which was collected by filtration and then recrystallized from aqueous isopropanol to yield 9.5 g (83%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.[ClH:12].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:36][NH:37][O:38][CH3:39]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:12][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:37]([O:38][CH3:39])[CH3:36])=[O:8])=[CH:5][CH:4]=1
Reactant: CNOC
Reactant: Cl
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CON(C)C(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 53 h
Yield: 30.4 %

Procedure:
To a solution of 4-(bromomethyl)benzoic acid (10.7 g) in chloroform (200 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.5 g), 1-hydroxybenzotriazole monohydrate (8.38 g), N,O-dimethylhydroxylamine hydrochloride (4.85 g), and triethylamine (6.94 mL) were added. After stirring the mixture at room temperature for 53 hours, chloroform (200 mL) was added. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, a saturated aqueous solution of ammonium chloride, and saturated brine successively. After passage through a phase separator, the washed mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-40:60) to give 4-(chloromethyl)-N-methoxy-N-methylbenzamide as a colorless oil (3.23 g).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:17][CH:18]=2)=[CH:7][CH:6]=1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27]>C1COCC1>[C:19]1([C:16]2[O:17][CH:18]=[C:14]([CH2:13][CH2:12][O:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]4[NH:25][C:26](=[O:27])[O:1][N:2]=4)=[CH:10][CH:9]=3)[N:15]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N=C(Cc1ccc(OCCc2coc(-c3ccccc3)n2)cc1)NO
Solvent: C1CCOC1
Product: O=c1[nH]c(Cc2ccc(OCCc3coc(-c4ccccc4)n3)cc2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
A mixture of 4.06 g of the amidoxime from Example 14 Part A, 150 mL of THF and 1.98 g of carbonyldiimidazole was heated at reflux for 7 hours, cooled to 25° C., and stirred another 16 hours. The solvent was removed in vacuo. The residue was dissolved in 600 mL of EtOAc, washed with H2O and dried over anhydrous Na2SO4. The residue, obtained after filtration and evaporation of the solvent, was recrystallized from EtOH to give 3.11 g of 3-[(4-(2-(2-phenyl-4-oxazolyl)ethoxy)phenyl)-methyl]1,2,4-oxadiazolin-5-one, (71% mp 154.5°-157.5° C.).
Reaction SMILES: CC(OI1(O[C:20]([CH3:22])=[O:21])(OC(C)=O)OC(=O)[C:11]2[CH:10]=C[CH:8]=[CH:7][C:6]1=2)=O.[C:23](OCC)(=O)C.ClCCl>>[CH3:23][C:20]([CH3:22])=[O:21].[CH3:10][CH2:11][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(C)=O
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)=O
Product: CCCCC
Yield: 46 %

Procedure:
The title derivative was prepared from the compound of Example 11, Step A, using the Dess-Martin oxidation method given in Example 2, Step C (but with a larger excess of periodinane). It was purified by flash chromatography (silica gel, ethyl acetate/dichloromethane: 2/8, Rf: 0.35) and crystallization from acetone/pentane (46% yield). Analysis calculated for C38H38N4O8N2 : C, 63.38; H, 5.54; N, 7.82. Found: C, 63.49; H, 5.33; N, 7.75.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([OH:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])[CH3:2].[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:30]=CC=C[CH:26]=1.C(O)(C)C.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH:25]([CH3:30])[CH3:26])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(O)cc2C)c1C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(OC(C)C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.1 %

Procedure:
To a solution of 4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenol (58 mg, 0.176 mmol) in 3 ml of dry THF was added triphenylphosphine (70 mg, 0.264 mmol) and isopropanol (60 mg, 0.22 mmol). The resulting mixture was stirred at room temperature for 5 min, diethyl azodicarboxylate (46 mg, 0.264 mmol) was added. The mixture was stirred at room temperature overnight. An additional 20 mg of diethyl azodicarboxylate was added and the mixture was stirred for an additional 4 hours. The mixture was quenched with water and extracted with methylene chloride. The organic layer was dried and concentrated to give an oil. The oil residue was purified through silica gel column chromatography using 1:1 hexane:chloroform to 1:2 hexane: chloroform as eluent to give 38 mg (58%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ6.60 (s, 2H), 6.28 (s, 1H), 4.50 (m, 1H), 4.18 (m, 1H), 2.20 (s, 3H), 2.19 (s, 3H), 2.079s,6H), 1.71 (m, 4H), 1.34 (d, 6H), 0.98 (t, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Si:21]([O:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[N:36][CH:37]=1)[NH2:31])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C>C(#N)C>[Si:21]([O:28][CH2:29][C@@H:30]([NH:31][C:17]1[C:12]2[CH2:11][N:10]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=3[C:7]#[N:8])[CH2:20][CH2:19][C:13]=2[N:14]=[CH:15][N:16]=1)[C:32]1[CH:37]=[N:36][C:35]([CH3:38])=[N:34][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Reactant: Cc1ncc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc([C@@H](CO[Si](C)(C)C(C)(C)C)Nc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (150 mg, 0.49 mmol) and (S)-2-(tert-butyldimethylsilyloxy)-1-(2-methylpyrimidin-5-yl)ethanamine (144 mg, 0.54 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (0.5 mL, 3 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC to yield the product as a yellow solid.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54]O)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54][O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CO[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@H]1O[C@H](COS(=O)(=O)C(F)(F)F)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of dry pyridine (0.46 mL) in methylene chloride (17.5 mL) cooled to -15° C. was added trifluoromethanesulfonic anhydride (0.87 mL). The mixture was stirred during 15 min at -10° C., then methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (1.2 g, 2.58 mmol) in methylene chloride (5 mL) was added (P. Kovac, V. Sklenar and C. Glaudemans, Carbohydr. Res. 175, 201 (1988)). The mixture was stirred during 1.5 h at -10° C. The reaction mixture was washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 7:3 mixture of hexane and ethyl acetate afforded the expected compound methyl 2,3,4-tri-O-benzyl-6-O-trifluoromethylsulfonyl-α-D-glucopyranoside which was crystallized from hexane (1.43 g, 93%); m.p. 44°-45° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:36]=[CH:35][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:34])[C:15]([CH2:25][CH2:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:37](Cl)([CH3:40])(=[O:39])=[O:38].N1C=CC=CC=1>CC(C)=O>[CH:28]1([CH2:27][CH2:26][CH2:25][C:15]2([CH3:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]([OH:23])=[C:13]([C:8]3[NH:7][C:6]4[CH:35]=[CH:36][C:3]([NH:2][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:4][C:5]=4[S:10](=[O:12])(=[O:11])[N:9]=3)[C:14]2=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 88 %

Procedure:
A solution of Example 38B (0.357 g, 0.674 mmol), mesyl chloride (0.209 mL, 2.69 mmol), and pyridine (0.436 mL, 5.39 mmol) in acetone (15 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.339 g, 88%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:23][C:24]3[S:25][CH:26]=[C:27]([CH3:29])[N:28]=3)[N:3]=[CH:4][C:5]=2[C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[N:10]=1
Reactant: Cc1csc(N)n1
Reactant: OB(O)c1ccncc1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Product: Cc1csc(Nc2ncc(-c3ccncc3)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=334.1 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 4-pyridineboronic acid and 2-amino-4-methylthiazole.