Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:14]([Zn]CC)[CH3:15]>O1CCOCC1>[Cl:13][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH2:14][CH3:15])[CH:3]=[N:4][CH:5]=1
Reactant: CC[Zn]CC
Reactant: CCOC(=O)c1c(Cl)cncc1Br
Solvent: C1COCCO1
Product: CCOC(=O)c1c(Cl)cncc1CC
Temperature: 70 °C
Yield: 54.9 %

Procedure:
To a solution of ethyl 3-bromo-5-chloropyridine-4-carboxylate (5.84 g, 22.08 mmol) in anhydrous dioxane (40 mL) at room temperature was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (323 mg, 0.441 mmol). Then, diethylzinc (2.72 g, 18 mL, 22.09 mmol, 15% solution in toluene) was added dropwise and the reaction was heated at 70° C. for 45 minutes. The reaction mixture was cooled to room temperature and then was quenched with MeOH. The resulting mixture was extracted with ethyl acetate (2×100 mL), and the organic layer was washed with water, 0.1 N HCl, and brine. The organic layer was then dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated, and the residue was purified by CombiFlash using 0-30% ethyl acetate and hexane to provide ethyl 5-chloro-3-ethylpyridine-4-carboxylate as a pale yellow oil (2.59 g, 55% yield); 1H NMR (400 MHz, CDCl3): δ 1.25 (t, 3H), 1.45 (t, 3H), 2.65 (q, 2H), 4.47 (q, 2H), 8.41 (s, 1H), 8.49 (s, 1H); M+ 214.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][N:14]([C:16]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[CH2:15][C:10]2=[N:9][N:8]=1.C(Cl)(Cl)Cl.CC#N.I([O-])(=O)(=O)=[O:33].[Na+]>O.O.[Ru](=O)=O>[O:33]=[C:15]1[N:14]([C:16]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[CH2:13][CH2:12][N:11]2[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=[C:10]12
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[Si](C)(C)CCOC(=O)N1CCn2c(nnc2-c2cnccn2)C1
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC#N
Product: C[Si](C)(C)CCOC(=O)N1CCn2c(nnc2-c2cnccn2)C1=O
Reaction time: 4 h
Yield: 367.9 %

Procedure:
To a vigorously stirred solution of 2-(trimethylsilyl)ethyl 3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (172 mg, 0.5 mmol) in 1:1 CHCl3:MeCN (3.8 mL) was added a solution of ruthenium (IV) oxide hydrate (9.8 mg, 0.07 mmol) and sodium metaperiodate (504 mg, 2.3 mmol) in water (4.7 mL). After 4 h, the reaction mixture was diluted with water and extracted with CHCl3 (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford a green oil. Purification by chromatography (SiO2; EtOAc—10% IPA/EtOAc) provided the desired product as a white solid (663 mg, 63%). MS (ESI): mass calcd. for C15H20H6O3Si, 360.1; m/z found, 361.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.59 (d, J=1.5 Hz, 1H), 8.63 (d, J=2.5 Hz, 1H), 8.55 (dd, J=2.5, 1.6 Hz, 1H), 4.88-4.75 (m, 2H), 4.47-4.33 (m, 2H), 4.33-4.24 (m, 2H), 1.18-1.04 (m, 2H), 0.04-(−0.02) (m, 9H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=O)=[CH:19][C:18]=3[CH:29]=2)=[CH:10][CH:9]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:34][N:35]([CH:37]=O)[CH3:36]>>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([NH:23][C:17]4[CH:18]=[CH:29][C:14]([CH2:37][N:35]([CH3:34])[CH:36]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:15][CH:16]=4)=[O:28])=[CH:19][C:18]=3[CH:29]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Solvent: O=S(Cl)Cl
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In DMF (5 ml) was dissolved 7-[4-(3-ethoxypropoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.25 g). To the solution was added, under ice-cooling, thionyl chloride (0.12 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (15 ml). The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.16 g) and triethylamine (0.44 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-(3-ethoxypropoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 2) (0.29 g) as colorless crystals.
Reaction SMILES: [C:1]1([NH:7][CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][C:25](=[O:38])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:28][CH:27]=3)=[CH:17][CH:16]=2)[C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([NH:7][CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][C:25](=[O:38])[C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:30][CH:31]=3)=[CH:17][CH:16]=2)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCCOc1ccc(CC(Nc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1

Procedure:
Ethyl 2-phenylamino-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate is hydrolyzed by sodium hydroxide in methanol to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:17].Br>C(O)(=O)C>[CH3:17][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:3]=1[OH:2])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: COc1ccc(C(=O)c2ccccc2)cc1C
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(C(=O)c2ccccc2)ccc1O
Yield: 50.1 %

Procedure:
A mixture of 6.17 g of 4-methoxy-3-methylbenzophenone. 65 ml of glacial acetic acid and 103 ml of a 62 percent hydrobromic acid solution is heated to boiling under reflux for 3 hours. The dark solution obtained is concentrated, extracted with ethyl acetate and the organic phase is dried and evaporated. The residue is chromatographed on silica gel with hexane:ethyl acetate (7:3). There are obtained 2.90 g (50%) of 3-methyl-4-hydroxybenzophenone as a yellowish solid with a m.p. of 170°-173°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][C:15]([CH2:19][NH:20]C(=O)OCC)([OH:18])[CH2:14][CH2:13]3)[C:6]=2[CH:26]=1.FC1C=CC2OC=C(CCBr)C=2C=1>>[NH2:20][CH2:19][C:15]1([OH:18])[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]2[C:6]3[CH:26]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:9][CH:8]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)NCC1(O)CCN(CCc2coc3ccc(F)cc23)CC1
Agent: Fc1ccc2occ(CCBr)c2c1
Product: NCC1(O)CCN(CCc2coc3ccc(F)cc23)CC1

Procedure:
The product is obtained according to the process of Preparation 17, using ethyl N-{1-[2-(5-fluoro-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidylmethyl}carbamate as substrate, which is prepared as for the product of Step C of Preparation 16 starting from 2-(5-fluoro-benzofuran-3-yl)-1-bromoethane.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:10]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH2:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)[C@@H](N)CC(C)C
Yield: 97.4 %

Procedure:
L-Leucine (5.0 g, 0.038 mol), 1-octanol (5.0 g, 0.038 mol) and p-toluenesulfonic acid monohydrate (8.0 g, 0.042 mol) were suspended in toluene (200 ml) in a flask equipped with a Dean-Stark trap and refluxed for 20 h. Subsequently, the solvent was removed in vacuo and the remaining white solid was dissolved in CHCl3 (150 ml). This solution was extracted with 10%1/sodium carbonate, water and brine and dried Over MgSO4, Evaporation of the solvent in vacuo yielded a colourless oil (9.0 g, 0.037 mol, 97%). 1H NMR (CDCl3): δ=4.18 (t, 2H, 3J=7.0 Hz), 3.63 (dd, 1H, 3JAB=8.4 Hz, 3JAB=5.9 Hz), 1.85 (m, 1H), 1.74-3.18 (m, 6H), 1.37 (s, 10H, 0.99 (t's, 9H); 13C NMR (CDCl3): δ=176.98, 64.82, 52.79, 44.06, 31.64, 29.04, 28.47, 25.76, 24.66, 22.81, 22.51, 21.77, 13.96
Reaction SMILES: [NH2:1][OH:2].Cl.[CH:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]3[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[NH:18][C:17]([CH3:24])=[C:16]3[C:25]#[N:26])[CH:13]=2)[NH:8][N:7]=1)=O>N1C=CC=CC=1>[OH:2]/[N:1]=[CH:4]/[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]3[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[NH:18][C:17]([CH3:24])=[C:16]3[C:25]#[N:26])[CH:13]=2)[NH:8][N:7]=1
Reactant: NO
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(C=O)c3c2)C(C#N)=C(C)N1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(/C=N/O)c3c2)C(C#N)=C(C)N1
Yield: 68.1 %

Procedure:
A mixture of NH2OH.HCl (229 mg, 3.3 mmol) and 4-(3-formyl-1H-indazol-5-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarbonitrile (200 mg, 0.66 mmol), from Synthetic Example 10B, in pyridine (5 mL) was stirred at rt overnight. After removal of pyridine under vacuum, the residue was treated with a saturated solution of NaHCO3 and extracted with CH2Cl2. The organic phases were combined, washed with brine, and concentrated. The residue was purified by column to give 1,4-dihydro-4-[3-[(E)-(hydroxyimino)methyl]-1H-indazol-5-yl]-2,6-dimethyl-3,5-pyridinedicarbonitrile (143 mg, 68%) as a powder (Cpd. No. 149, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=11.42 (s, 1H), 9.55 (s, 1H), 8.36 (s, 1H), 7.85 (s, 1H), 7.60 (d, 1H), 7.38 (d, 1H), 4.58 (s, 1H), 2.03 (s, 6H) ppm.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH2:18]([NH2:21])[CH2:19][CH3:20]>C(#N)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:21][CH2:18][CH2:19][CH3:20])#[N:2]
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Reactant: CCCN
Solvent: CC#N
Product: CCCNC(=NC#N)NC1CCCc2ccccc21
Reaction time: 20 h

Procedure:
A solution of 12.3 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 16 ml of n-propylamine in 100 ml of acetonitrile was heated at reflux with stirring for 20 hours. The reaction mixture was then allowed to stand in a refrigerator to give 8.63 g of N"-cyano-N-n-propyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 130.5°-131.5° C. A further quantity of the product was obtained by the concentration and subsequent cooling of the mother liquor.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1.[O:20]1[CH2:25][CH:24]=[C:23]([C:26]2[C:27](F)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1.O>CN1C(=O)CCC1>[O:20]1[CH:21]=[CH:22][CH:23]([C:26]2[C:27]([O:19][C@H:16]3[CH2:15][CH2:14][C@H:13]([NH:12][C:4]4[S:3][C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[N:5]=4)[CH2:18][CH2:17]3)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:24][CH2:25]1
Reactant: Fc1ncccc1C1=CCOCC1
Reactant: O[C@H]1CC[C@H](Nc2nc3ccccc3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C1=CC(c2cccnc2O[C@H]2CC[C@H](Nc3nc4ccccc4s3)CC2)CCO1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.054 g, 1.3 mmol, 60% dispersion in mineral oil) was added to a mixture of trans-4-(benzo[d]thiazol-2-ylamino)cyclohexanol (0.17 g, 0.67 mmol) in NMP (1.5 mL) in a microwave tube. The tube was sealed and placed under an argon atmosphere. The mixture was stirred at RT for 45 min before 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridine, as prepared in preparation 1a, step 1, (0.10 g, 0.56 mmol) was added via syringe. The reaction mixture was warmed to 120° C. and stirred for 1 h. Water was added, and the aqueous mixture was extracted with EtOAc (2×). The organic extracts were combined, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified via silica gel chromatography to give both N-(trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclohexyl)benzo[c/]thiazol-2-amine and N-(trans-4-(3-(3,4-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine as white solids. [M+1] 408.1 each. IC50 (uM): 0.007281 (Example 3b) and 0.9154 (Example 3c).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11](=O)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:11]1[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccc(F)c(F)c2)cc(C(F)(F)F)[nH]1
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1F

Procedure:
The title compound was prepared from 4-(3,4-difluoro-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (14.7 g, 0.053 mol) and phosphoroxychloride (148 mL) according to the general procedure I. Obtained as a light brown solid (15.6 g, 99%). MS (EI) 294.0 [(M)+]; mp 53° C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)=[N:14][CH:15]=[N:16]2)=[C:11]([O:28][CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[F:26])[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:28][CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:16]=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(O)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl (2R)-2-[({7-(benzyloxy)-4-[3-chloro-4-fluoroanilino]-quinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (230 mg) (obtained as described in Example 16) and 5% palladium on carbon in ethanol (5 ml) was stirred under hydrogen (5 bar pressure) at 25° C. for 16 hours. The mixture was then filtered and concentrated in vacuo to leave the tert-butyl (2R)-2-[({4-[3-chloro-4-fluoroanilino]-7-hydroxyquinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate as a light brown oil, which was used without further purification.
Reaction SMILES: [N+]([CH2:4][C@H:5]([C@@H:7]([C@H:9]([C@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6])([O-])=O.[OH-].[Na+].S(=O)(=O)(O)[OH:18].[OH-].[Ba+2].[OH-]>O>[O:18]=[CH:4][C@H:5]([C@@H:7]([C@H:9]([C@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: [Ba+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
A solution of 5 grams of 1-deoxy-1-nitro-L-glucitol dissolved in 15 ml. of 2 N sodium hydroxide was added dropwise to a stirred solution of 7.5 ml. of sulfuric acid in 9 ml. of water at room temperature. After dilution with 200 ml. of water, the solution was neutralized to Congo red indicator with warm barium hydroxide solution and the remaining sulfate ion precipitated with barium acetate solution. The barium sulfate was removed by filtration and the filtrate de-ionized by passage through 50 ml. of Dowex-50(H+) resin. The effluent and washings were concentrated at reduced pressure to a syrup. This syrup was diluted with a few drops of ethanol and allowed to crystallize. The resulting β-L-glucose was filtered with the aid of ethanol; yield 2.5 grams, mp 146°-147° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7](Cl)(=[O:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C.Cl.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]([CH:3]=[C:4]=[O:5])(=[O:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: C=C1CC(=O)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)C=C=O

Procedure:
For this example, the alkyl ketene dimer used was palmitoyl (C16) ketene dimer, a typical fatty acid ketene dimer. The ketene dimer was prepared by dissolving 27.5 grams palmitoyl chloride in 200 mL ethyl acetate in a 500 mL Erlenmeyer flask. Then, 10.1 grams triethylamine was dissolved in 50 mL ethyl acetate and placed into an addition funnel. The solution of triethylamine was dripped slowly into the stirring acid chloride solution. A white precipitate began to form almost immediately; this white precipitate was triethylamine hydrochloride. The solution was stirred for one hour after all of the triethylamine was added. The triethylamine hydrochloride was filtered out of the solution, and the filtrate, a clear, golden-yellow solution, was evaporated under reduced pressure to yield a light yellow, waxy solid, palmitoyl ketene dimer. The yield was virtually quantitative.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[NH:13][CH:12]=[N:11][N:10]=1.Cl.[O:15]=[C:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[N:17]1[CH2:26][C:27](O)=[O:28]>>[C:7]([C:4]1[C:3]([C:9]2[N:13]=[CH:12][NH:11][N:10]=2)=[C:2]([NH:1][C:27](=[O:28])[CH2:26][N:17]2[C:18]3[C:23](=[N:22][CH:21]=[CH:20][CH:19]=3)[CH2:24][CH2:25][C:16]2=[O:15])[S:6][CH:5]=1)#[N:8]
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Reactant: N#Cc1csc(N)c1-c1nnc[nH]1
Agent: Cl
Product: N#Cc1csc(NC(=O)CN2C(=O)CCc3ncccc32)c1-c1nc[nH]n1

Procedure:
The title compound was synthesized according to protocol A from 5-amino-4-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (69 mg, 0.364 mmol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid hydrochloride (89 mg, 0.367 mmol). HPLC purification afforded desired product as a white solid. LCMS method [11], retention time=6.22 min; MS(ESI) 380.1 (MH+); 1H NMR (300 MHz, CD3OD) δ 8.52 (s, 1H), 8.28 (d, J=5.2 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4, 5.3 Hz, 1H), 5.01 (s, 2H), 3.37 (t, J=7.6 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CC([O-])(C)C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CC#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Cc1cc2c(cc(NCCN3CCOCC3)c3nnc(C)n32)n1Cc1ccccc1
Temperature: 100 °C

Procedure:
A degassed mixture of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25 mg, 0.080 mmol, from Example 228, Step 7), N-(2-aminoethyl)morpholine (42 μL, 0.32 mmol, Aldrich), NaOtBu (15 mg, 0.16 mmol, Aldrich), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (9.3 mg, 0.016 mmol, Aldrich) and tris(dibenzylideneacetone)dipalladium(0) (7.4 mg, 0.0080 mmol, Aldrich) in toluene (1.2 mL) was heated at 100° C. overnight. Upon cooling, the reaction mixture was diluted with MeCN, filtered and purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (4.8 mg, 15%).
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:41])[C@@H:10]([NH:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([Cl:39])[C:32]=1[CH3:40])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si](C(C)(C)C)(C)C)=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:39][C:33]1[C:32]([CH3:40])=[C:31]([NH:30][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)=[N:14][N:15]=2)[C@H:9]([OH:8])[CH3:41])[CH:38]=[CH:37][C:34]=1[C:35]#[N:36]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@@H](C)O)ccc(C#N)c1Cl

Procedure:
4-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-(tert-butyldimethylsilyloxy)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (intermediate 10c) (146 mg, 0.24 mmol) was deprotected in a similar manner to that for example 7 using tetrabutylammonium fluoride (1.0 M solution in THF, 0.95 mL, 0.95 mmol). After column chromatography (80% EtOAc/hexanes) the title compound was isolated as a white solid (90 mg, 98%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.01 (s, 1H), 7.84 (AA′XX′, J=8.9 Hz, 2H), 7.48 (d, J=8.7 Hz, 1H), 6.97 (AA′XX′, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 1H), 5.85 (d, J=8.8 Hz, 1H), 5.0 (dd, J=5.5, 8.7 Hz, 1H), 4.50 (m, 1H), 2.35 (s, 3H), 1.41 (d, J=6.4 Hz, 3H).
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[C:17]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:22]=[CH:21][C:20]([C:23]2[C:31]3[C:30](=[O:32])[NH:29][C:28]([C:33](OCC)=[O:34])=[N:27][C:26]=3[S:25][CH:24]=2)=[CH:19][CH:18]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:87]2[CH:91]=[N:90][C:89]([O:92][CH2:93][CH2:94][O:95][C:96]3[CH:97]=[C:98]([CH2:102][NH2:103])[CH:99]=[CH:100][CH:101]=3)=[N:88]2)C=CC=CC=1>>[C:17]1([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:22]=[CH:21][C:20]([C:23]2[C:31]3[C:30](=[O:32])[NH:29][C:28]([C:33]([NH:103][CH2:102][C:98]4[CH:99]=[CH:100][CH:101]=[C:96]([O:95][CH2:94][CH2:93][O:92][C:89]5[N:90]=[CH:91][NH:87][N:88]=5)[CH:97]=4)=[O:34])=[N:27][C:26]=3[S:25][CH:24]=2)=[CH:19][CH:18]=1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3ccc(-c4ccccc4)cc3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccc(-c4ccccc4)cc3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-biphenyl-4-yl-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 136 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (155.4 mg, 85%).