Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4]([CH3:14])[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[Cl:15]N1C(=O)CCC1=O>C(#N)C>[Cl:15][C:7]1[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]([CH3:14])[C:3]=1[NH:2][CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNc1cc(-c2cccnc2)nn1C
Solvent: CC#N
Product: CNc1c(Cl)c(-c2cccnc2)nn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A mixture of methyl-(2-methyl-5-pyridin-3-yl-2H-pyrazol-3-yl)-amine (0.35 g, 1.8 mmol) and N-chlorosuccinimide (0.273 g, 2 mmol) was combined in acetonitrile (3 mL), stirred at room temperature for 30 minutes, concentrated under reduced pressure and purified using silica gel chromatography eluting with a gradient of EtOAc in hexanes to yield the title compound as a yellow oil (0.096 g, 23%): IR (thin film) 1581.6 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J=1.5 Hz, 1H), 8.57 (dd, J=4.8, 1.3 Hz, 1H), 8.15 (ddd, J=7.8, 2.0, 2.0 Hz, 1H), 7.33 (dd, J=8.1, 5.1 Hz, 1H), 3.80 (s, 3H), 2.91 (d, J=5.8 Hz, 3H); ESIMS (m/z) 225.6 [M+2].
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH:9]([CH3:12])[CH:10]=[O:11].[CH3:14][C:15]([CH3:18])([O-])[CH3:16].[K+].C(Cl)C(=C)C>CN(C=O)C>[CH3:12][C:9]([CH:6]1[CH2:5][CH2:4][CH:3]2[CH2:8][CH:7]1[C:2]2([CH3:13])[CH3:1])([CH2:16][C:15]([CH3:18])=[CH2:14])[CH:10]=[O:11]
Reactant: CC(C=O)C1CCC2CC1C2(C)C
Reactant: CC(C)(C)[O-]
Agent: C=C(C)CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CC(C)(C=O)C1CCC2CC1C2(C)C
Yield: 72.4 %

Procedure:
In a similar manner to Example 6, 100 g of the aldehyde from Example 58 at a purity of 85% (0.47 mole) in 75 ml of DMF, 82 g of potassium t-butoxide (0.69 mole) in 500 ml of DMF, and 78 g of methallyl chloride (0.86 mole) in 50 ml of DMF were reacted in the usual way. In this way 116.2 g of crude O- and C-alkylates (58.1:33.8) were obtained. The crude product was heated at 165°-170° C. for 2 hours. The crude aldehyde was distilled to afford 94.1 g of purified product (85% yield). BP 85° C./0.05 mmHg; 1H-NMR (300 MHz), δ 0.95 (3H, s), 0.96 (3H, s), 1.18 (3H, s), 1.2-1.4 (2H, m), 1.59 (3H, s), 1.7-2.5 (9H, m), 4.64 (1H, s), 4.80 (1H, s), 9.57 (1H, s); 13C-NMR (75 MHz), spectra consistent with assigned structures; IR (Neat), 2960, 2700, 1725, 1645, 1470, 1370, 895 cm-1 ; MS (m/e), 234 (M+), 219, 203, 191, 177, 163, 151, 135, 123, 109, 97, 81, 41 (Base);
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][CH3:22])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:21]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:16][CH2:17][N:18]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH2:19][CH2:20]2)[CH2:5][CH2:4]1)[CH3:22]
Reactant: CCC1(CC)CCC(c2ccccc2N2CCNCC2)CC1
Reactant: CCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCN(c2ccccc2C2CCC(CC)(CC)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a solution of 1-[2-(4,4-diethylcyclohexyl)phenyl]piperazine (30 mg, 0.10 mmol) produced in Example (83a) in tetrahydrofuran (1 mL) was added triethylamine (15 mg, 0.15 mmol), followed by stirring at an external temperature of 0° C. Butyryl chloride (0.015 mL, 0.14 mmol) was added to the reaction mixture while stirring, and the stirring was continued for 9 hours and 30 minutes at an external temperature of 0° C. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and filtered through Celite, and the filtrate was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 27 mg of the title compound as a yellow solid.
Reaction SMILES: C(CN[CH2:7][CH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(OC)=O.C(=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O.O>[C:10]1([CH:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:8][CH3:7])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CNCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCC(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
To a solution of (2S)-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(N-(carbomethoxy)methylamino-3,3-diphenylpropane (7.6 g, prepared as an intermediate in Example 57) in dimethylformamide (80 ml) was added potassium carbonate (10 g) and methyl iodide (4.5 ml) and the solution stirred in an enclosed atmosphere for 16 hours. Ethyl acetate (200 ml) and water were added and the organic phase washed with water, brine and dried (MgSO4). Purification by silica gel chromatography gave (2S)-1-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-((N-(carbomethoxy)methyl)-N-methyl)amino)-3,3-diphenylpropane.
Reaction SMILES: NC1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[C:4]([CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)C=1C(OCC)=O.[Si](OCCC=O)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C1C(=O)N(Cl)C(=O)C1.C(OC(=O)CC#N)C.CC[O-].[Na+].N(Cl)Cl>CN(C=O)C.CCO>[Si:17]([O:16][CH2:15][CH2:14]/[CH:4]=[N:5]/[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1c(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nn(-c2cccc(Cl)c2)c1N
Agent: CC(C)(C)[Si](OCCC=O)(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: ClNCl
Solvent: CN(C)C=O
Solvent: CCOC(=O)CC#N
Solvent: CCO
Product: CC(C)(C)[Si](OCC/C=N/Nc1cccc(Cl)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 5-amino-3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1-(3-chlorophenyl)-1H-pyrazole-4-carboxylate: To a solution of Intermediate 9A (1.34 g, 3.1 mmol) in DMF (5 mL) was added NCS (0.455, 3.41 mmol) and stirred at rt. After 4 h, the reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (2×). The organic layers were dried (MgSO4) and evaporated to a reddish oil. Separately ethylcyanoacetate (0.351 g, 3.10 mmol) was dissolved in EtOH (5 mL) and to this solution was added NaOEt (21%) (1.16 mL, 3.10 mmol) and the reaction was stirred at rt for 0.5 h followed by the introduction of the iminochloride crude mixture. The above mixture was then stirred at rt. After 2 h, the reaction was quenched with H2O and extracted with EtOAc (2×). The organic layers were dried (MgSO4) and evaporated to yield orange-red oil. The crude product was then purified using silica gel chromatography. Two peaks were isolated—one is the desired product and the other is the chlorinated pyrazoline compound and the two products were taken to the next step as a crude mixture. MS(ESI) m/z: 548.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:20][CH3:21])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:6]([NH:8][NH2:9])=[O:7].[C:22]1([CH:28]=[C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]2=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH3:21][O:20][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:6]([NH:8][N:9]=[C:30]1[CH2:31][CH2:32][CH2:33][CH2:34][C:29]1=[CH:28][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:7]
Reactant: CCCCCCOc1c(OC)cc(C(=O)NN)cc1OC
Reactant: O=C1CCCCC1=Cc1ccccc1
Solvent: CCO
Product: CCCCCCOc1c(OC)cc(C(=O)NN=C2CCCCC2=Cc2ccccc2)cc1OC
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 29.6 g (0.1 mole) of 3,5-dimethoxy-4-hexyloxybenzoic acid hydrazide in 110 cm3 of anhydrous ethanol a solution of 18.6 g (0.1 mole) of 2-phenylmethylenecyclohexan-1-one in 50 cm3 of ethanol is added. The reaction mixture is boiled for one hour, cooled and filtered. 36.35 g (78.2%) of the named compound are obtained. M.p.: 158°-160° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][C:34](=[O:38])[CH:35]([OH:37])[CH3:36])[NH:29][C:28](=[O:39])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][C:34](=[O:38])[C@@H:35]([OH:37])[CH3:36])[NH:29][C:28](=[O:39])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: CC(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)[C@H](C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 62.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide 8b obtained from step 2 of Example 8 as starting materials to obtain (S,Z)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide 38 (49 mg, yield 62.5%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.CCN(C(C)C)C(C)C.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:31]([O:15][CH2:14][C:13]1[CH:12]=[C:11]2[C:6](=[N:5][C:4]=1[CH:3]([O:2][CH3:1])[O:16][CH3:17])[NH:7][CH2:8][CH2:9][CH2:10]2)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(OC)c1nc2c(cc1CO)CCCN2
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methanol (intermediate 40, 6.5 g, 27.3 mmol) in DCM (100 ml) and DMF (25 ml) at 0° C. were added DIPEA (7.15 ml, 40.9 mmol), tert-butylchlorodimethylsilane (4.93 g, 32.7 mmol) and DMAP (0.067 g, 0.546 mmol). The reaction mixture was then stirred for 1 h at room temperature, then poured into sat. aq. NaHCO3 and extracted twice with DCM. The combined organic phases were dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (120 g silica gel cartridge, heptanes/EtOAc 95:5 to 0:100) to give the title compound as a light yellow oil which solidified upon standing to give an off-white powder. (UPLC-MS 3) tR 1.10 min; ESI-MS 353.3 [M+H]+.
Reaction SMILES: [CH:1](/[CH:5]1[CH2:10][O:9][CH:8]([CH2:11][CH2:12][CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])[O:7][CH2:6]1)=[CH:2]\[CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH:1](/[CH:5]1[CH2:6][O:7][CH:8]([CH2:11][CH2:12][CH:13]([CH2:14][OH:15])[CH2:19][OH:20])[O:9][CH2:10]1)=[CH:2]\[CH2:3][CH3:4]
Reactant: CC/C=C/C1COC(CCC(C(=O)OCC)C(=O)OCC)OC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC/C=C/C1COC(CCC(CO)CO)OC1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
A solution of 16.75 g of diethyl (E)-[2-(5-but-1-enyl-1,3-dioxan-2-yl)-ethyl]-malonate in 25 ml of tetrahydrofuran was added dropwise at 5°-8° C. under a protective gas to a suspension of 3.87 g of lithium aluminium hydride in 100 ml of tetrahydrofuran. The reaction mixture was stirred at 5° C. for a further 15 minutes, then at room temperature for 2 hours and finally at the boiling temperature for 1.2 hours. After cooling 3N sodium hydroxide solution was cautiously added dropwise until a solid white clump formed. The solution was decanted and the residue was washed twice with diethyl ether. The organic phases were combined, washed in succession with 25 ml of concentrated sodium bicarbonate solution and twice with 25 ml of concentrated sodium chloride solution each time, dried over sodium sulfate, filtered and the filtrate was concentrated. 12.20 g of crude (E)-2-[2-(5-but-1-enyl-1,3-dioxan-2-yl)-ethyl]-1,3-propanediol were obtained as a sticky-solid crude product, m.p. up to 87.1° C. (GC purity 86%, trans/cis ratio 7:3), which was used in the final step without further purification.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[NH:9].Br/[C:16](=[C:20](/[Br:23])\[CH:21]=O)/[C:17]([OH:19])=[O:18]>C(O)C>[Br:23][C:20]1[C:16]([C:17]([OH:19])=[O:18])=[N:9][C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[F:5])=[N:10][CH:21]=1
Reactant: N=C(N)c1ccccc1F
Reactant: O=C/C(Br)=C(\Br)C(=O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1nc(-c2ccccc2F)ncc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium ethoxide (21 mass % in ethanol; 8.69 mL, 23.268 mmol) was added to an ice-bath cooled mixture of 2-fluorobenzamidine (2.71 g, 15.512 mmol) in ethanol (100 mL). The resulting mixture was allowed to warm to room temperature and stirred at rt (room temperature) under nitrogen for 30 min. To the reaction mixture was added a solution of (E)-2,3-dibromo-4-oxo-but-2-enoic acid (2.00 g, 7.7561 mmol) in ethanol (20 ml). The mixture was heated at 50° C. for 3 h. After cooling to RT, the reaction was concentrated in vacuo. Water and 1M NaOH (˜50 ml) were added and the aqueous mixture was extracted with EtOAc. The aqueous phase was acidified to pH4 with 1N HCl (about 30 ml), then extracted with EtOAc 3×. Combined organic extracts were dried over sodium sulfate, filtered and concentrated to gave 5-bromo-2-(2-fluorophenyl)pyrimidine-4-carboxylic acid, 770 mg.
Reaction SMILES: CC1(C)[O:7][C:6](=O)[CH:5]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)C(=O)O1.[CH3:27][NH2:28]>N1C=CC=CC=1>[CH3:27][NH:28][C:6](=[O:7])[CH2:5][CH:9]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1
Reactant: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3ncccc23)C(=O)O1
Reactant: CN
Solvent: c1ccncc1
Product: CNC(=O)CC(c1ccccc1)c1c[nH]c2ncccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A sealed tube loaded with 2,2-dimethyl-5-[phenyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-[1,3]dioxane-4,6-dione (700 mg), methylamine (2M in THF, 3 ml) and pyridine (5 ml) was stirred at 120° C. for 2 hours. The reaction mixture was cooled to RT and partitioned between H2O and EtOAc. The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording N-Methyl-3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[NH:12][C:13](=[O:15])[CH3:14].[C:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=1)(=[O:18])[CH3:17]>CN(C)C=O.[Cu]>[C:13]([NH:12][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][C:2]=1[C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:21][C:22]=1[NH:26][C:27](=[O:29])[CH3:28])(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(Br)c(NC(C)=O)c1
Reactant: CC(=O)Nc1cccc(NC(C)=O)c1
Agent: [Cu]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2ccc(NC(C)=O)cc2NC(C)=O)c(NC(C)=O)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
136 g of 4-bromo-N,N'-bisacetyl-1,3-phenylenediamine, prepared by bromination of N,N'-bisacetyl-1,3-phenylenediamine, are heated, in 300 ml of dimethylformamide, to 100° C. After adding 38 g of copper powder, the reaction mixture is stirred for 4 hours at 100° C. After cooling to room temperature, the mixture is freed from copper as indicated in Example 2. 72 g (75% of theory) of 2,2',4,4'-tetrakis-(acetylamino)-biphenyl of the formula ##STR32## are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1(B(O)O)[C:22]2[C:23]3=[C:24]4[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[C:15]4[CH:14]=[CH:13][C:12]3=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[C:15]3[C:24]4=[C:23]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][CH:9]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)cc1
Yield: 80.3 %

Procedure:
Under an atmosphere of argon, 4-bromoiodobenzene (7.0 g, 25 mmole), 1-pyreneboronic acid (5.7 g, 23 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (50 ml). To the obtained solution, an aqueous solution of sodium carbonate (7.3 g, 69 mmole, 3 eq/35 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+10% dichloromethane, successively) and white needle crystals (6.6 g, 80%) were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:18]=[C:19]([NH:22][C:23](=O)OC(C)(C)C)[S:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.[H-].[Na+].BrC[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(Cl)Cl>[CH:35]1([CH2:34][CH2:23][NH:22][C:19]2[S:20][CH:21]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:18]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: Cn1nnnc1C(=NOCc1csc(NC(=O)OC(C)(C)C)n1)c1ccccc1
Reactant: BrCCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nnnc1C(=NOCc1csc(NCCC2CCCCC2)n1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A stirred solution of tert-butyl {4-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}carbamate (0.185 g, 0.445 mmol, 1 eq.) in 3 ml of dry DMF was treated with NaH (60% dispn in mineral oil, 0.019 g, 0.49 mmol, 1.1 eq.) added in one portion. After 20 mins (2-bromoethyl)cyclohexane (0.096 g, 0.49 mmol, 1.1 eq.) was added and the reaction was stirred for 1 hr. Then TFA (1.48 g, 12.98 mmol, 30 eq.) was added carefully and the reaction was heated to 60° C. for 12 h. After cooling, sat. aqueous Na2CO3 was added followed by DCM. The layers were separated and the aqueous layer was extracted with DCM. The organics were combined, washed with sat. aqueous Na2CO3, dried over MgSO4 and concentrated. The crude was purified by chromatography on silica gel to give N-(2-cyclohexylethyl)-4-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-amine (0.144 g, 76% yield) as a clear viscous oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][C:7]2[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[CH:9][C:8]=2[N:15]=1)([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([N+:34]#[C-:35])S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CCO>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:34]=[CH:35][O:14][C:13]=1[C:11]1[N:10]=[CH:9][C:8]2[N:15]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[S:6][C:7]=2[CH:12]=1
Reactant: CC(C)Nc1nc2cnc(C=O)cc2s1
Reactant: [C-]#[N+]C(c1ccccc1F)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)Nc1nc2cnc(-c3ocnc3-c3ccccc3F)cc2s1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A solution of 2-(isopropylamino)thiazolo[4,5-c]pyridine-6-carbaldehyde (presumed 0.234 mmol, 1.0 eq.), 1-fluoro-2-(isocyano(tosyl)methyl)benzene (0.079 g, 0.273 mmol, 1.2 eq.), and K2CO3 (0.0654 g, 0.473 mmol, 2.0 eq.) in EtOH (2.4 mL) was refluxed for 4.75 hr. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and the residue was taken up in EtOAc and water. After separation of the layers, the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. MeOH was added to the residue, and the mixture was subjected to autoprep. The appropriate fractions were collected, and NaHCO3 (s) was added. The solution was then concentrated in vacuo not to dryness and extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 6-(4-(2-fluorophenyl)oxazol-5-yl)-N-isopropylthiazolo[4,5-c]pyridin-2-amine as a light yellow solid (0.0243 g, 29% yield). LC/MS (MH)=355.16.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)=[O:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([CH:38]=[O:39])[CH:45]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1cccc(B(O)O)c1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4cccc(C=O)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 obtained in Example 128-(4) and 3-formylphenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-formylphenyl)-2-thienylmethyl)benzene as a colorless solid. APCI-Mass m/Z 660/662 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-formylphenyl)-2-thienylmethyl)benzene was treated in a manner similar to Example 130-(2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)benzene as colorless crystals. APCI-Mass m/Z 682/684 (M+NH4). (3) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)benzene was treated in a manner similar to Example 120-(3) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(3-difluoromethylphenyl)-2-thienylmethyl)benzene as colorless powder. APCI-Mass m/Z 514/516 (M+NH4).