Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[CH:7][CH:6]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.[C:43]([CH2:45][C:46](O)=[O:47])#[N:44]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:46](=[O:47])[CH2:45][C:43]#[N:44])[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3F)cc1)nn2C[C@H]1CCCN1
Reactant: N#CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[4-(2-fluorophenoxy)phenyl]-1-((2R)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (10 mL), 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (80 mg, 0.49 mmol, 1.25 equiv), and 2-cyanoacetic acid (50 mg, 0.59 mmol, 3.80 equiv). The resulting solution was stirred for 1 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane/methanol (100:1; 50:1) to give 0.05 g (43%) of 3-[(2R)-2-([4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as alight yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:16]3[NH:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[C:4]2[N:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(CC)CC>O1CCOCC1>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[C:16]4[NH:20][C:19](=[O:21])[NH:18][C:17]4=[O:22])=[C:4]3[N:3]=[C:2]([N:32]3[CH2:33][CH2:34][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:30][CH2:31]3)[CH:7]=2)[CH2:11][CH2:10]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)N1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(N4CCN(c5ccccn5)CC4)nc23)N1
Temperature: 120 °C
Yield: 27.4 %

Procedure:
To 5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (30 mg, 0.09 mmol) in 1,4-dioxane was added 1-(pyridin-2-yl)piperazine (58 μL, 4.10 mmol) and Et3N (13 μL, 0.09 mmol). Reaction was then heated 120° C. for 35 minutes in microwave. Solvent was removed under reduced pressure, and mixture was dissolved in methanol. Solid was isolated by filtration, then air dried to yield 11 mg (26% yield) 5-((7-(cyclopropylamino)-5-(4-(pyridin-2-yl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=446)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:9]1[O:10][CH2:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH:13]=[C:8]1[CH:7]=[C:6]2[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1.[F:49][C:50]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:51]=1[C:52](O)=[O:53].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:9]1[O:10][CH2:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[CH:13]=[C:8]1[CH:7]=[C:6]2[C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([O:48][C:52](=[O:53])[C:51]3[CH:55]=[CH:56][C:57]([F:59])=[CH:58][C:50]=3[F:49])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: COc1cc2c(cc1OC)C1OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C1C=C2c1ccc(-c2ccc(O)cc2)cc1
Reactant: O=C(O)c1ccc(F)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C1OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C1C=C2c1ccc(-c2ccc(OC(=O)c3ccc(F)cc3F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A solution of 8,9-dimethoxy-6-[4′-hydroxybiphen-4-yl]-3-phenyl-3-(4-pyrrolidinophenyl)-3H-naphtho[1,2-b]pyran (0.95 g, 0.5 mmol) and 2,4-difluorobenzoic acid (0.09 g, 0.5 mmol) in DCM (40 mL) containing 4-dimethylaminopyridine (0.01 g) and N,N′-dicyclohexylcarbodiimide (0.11 g, 1.6 mmol) under N2 was stirred at room temperature for 2 h. The resulting mixture was filtered through a short plug of silica using DCM as eluent. The solvent was removed under reduced pressure and the residue chromatographed on silica using EtOAc (0-20% gradient in toluene) as eluent. The solvent was removed under reduced pressure and the residue washed with acetone to give the title compound (0.29 g, 70%) as a pale violet powder, mp 249-250° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25](=O)[C:26](OC)=[O:27].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]1[C:26](=[O:27])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(C)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc2[nH]cc(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c2c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (260 mg, 1.4 mmol) and methyl 2-(5-methyl-1H-indol-3-yl)oxoacetate (300 mg, 1.4 mmol) in DMF (5.4 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.4 mL, 1.4 mmol) at 4° C. under N2. The reaction was stirred for 20 min, and additional potassium tert-butoxide (1.0 M, 2.8 mL, 2.8 mmol) was added. The resulting dark purple solution was heated to 50° C. and stirred over night. The mixture was cooled to 4° C. and quenched with 1.0 N hydrochloric acid (9 mL), and extracted with EtOAc (300 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (150 mL), brine (150 mL), and dried (MgSO4). The mixture was filtered, and concentrated to a red solid. Flash chromatography (SiO2, 40% EtOAc/hexanes) gave the title compound (320 mg, 65%) as a red solid, mp 174–176° C. 1H NMR (DMSO-d6) δ 8.02 (s, 1H), 7.61 (m, 1H), 7.24 (s, 1H), 7.16 (m, 1H), 6.95 (m, 1H), 6.85 (m, 1H), 6.75 (m, 1H), 6.46 (s, 1H), 5.71 (s, 1H) 3.62 (s, 3H), 1.71 (s, 3H). MS (ESI): m/z=356 [C22H17N3O2+H]+
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:7]=2[CH:24]=1.[CH2:27]=[O:28]>C1(C)C(C)=CC=CC=1>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][CH2:27][OH:28])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:7]=2[CH:24]=1
Reactant: C=O
Reactant: Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 8-trifluoromethyl-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine in xylene is heated with excess paraformaldehyde in a sealed, glass-lined vessel at 155°-160° C. to give 8-trifluoromethyl-1-(2-hydroxyethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]([CH3:47])[CH2:43][CH2:44][NH:45][CH3:46])(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl.O>[F:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([N:42]([CH3:47])[CH2:43][CH2:44][N:45]([CH3:46])[C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([NH:14][C:8]3[C:7]4[C:12](=[CH:13][C:4]([C:3]([F:25])([F:24])[F:2])=[CH:5][CH:6]=4)[N:11]=[CH:10][CH:9]=3)=[CH:16][CH:17]=2)(=[O:40])=[O:41])=[CH:37][CH:38]=1
Reactant: CNCCN(C)S(=O)(=O)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(CCN(C)S(=O)(=O)c1ccc(F)cc1)C(=O)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
4-(7-Trifluoromethyl-4-quinolinylamino)benzoyl chloride hydrochloride (2.0 g) was added portionwise to a well-stirred mixture of sodium carbonate (8.0 g) and 4-fluoro-N-methyl-N-[2-(methylamino)ethyl]benzenesulphonamide (1.48 g) in chloroform (60 ml) and water (70 ml) at about 10° C. The mixture was warmed to room temperature and, after 1 hour, the chloroform layer was separated, dried (MgSO4) and evaporated under reduced pressure to give an oil, which crystallised on standing. Recrystallisation from ethanol/water gave a white solid, which was further purified by recrystallisation from ethanol, giving the pure title compound (1.4 g), m.p. 191°-3° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:7]=1
Reactant: Oc1ccc(Br)cn1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2cc(Br)ccc2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a solution of 5-bromopyridin-2-ol (0.250 g, 1.437 mmol) in DMF (1.50 mL) at 0° C., was added NaH (60% in mineral oil, 0.075 g, 1.868 mmol) portion-wise over a period of 10 min. The mixture was warmed to room temperature and stirred for 30 min. To the mixture was added methyl 3-(bromomethyl)benzoate (0.395 g, 1.724 mmol) in one portion. The reaction was stirred at room temperature for 16 h and partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (0.274 g, 59% yield) as clear pale-yellow oil. LCMS, [M+H]+=322.0. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=7.7 Hz, 1H), 7.95 (s, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.37 (d, J=2.7 Hz, 1H), 7.33 (dd, J=9.7, 2.7 Hz, 1H), 6.52 (d, J=9.7 Hz, 1H), 5.11 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1N.N([O-])=[O:14].[Na+].O>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[OH:14]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C)c1O
Temperature: 0 °C

Procedure:
2,6-Dimethyl-3-nitrobenzenamine (10.4 g, 62.6 mmol) was dissolved in 75% sulfuric acid (200 ml). Mixture cooled to 0° C. and treated with a solution of sodium nitrite (4.53 g, 65.7 mmol) in concentrated sulfuric acid (25.0 ml). After the mixture had been stirred for 1 hour at this temperature, water (200 ml) was added and the mixture warmed to 60° C. until the evolution of gas ceased. The mixture was allowed to cool to room temperature and then filtered to afford 2,6-dimethyl-3-nitrophenol. MS m/z=168 (M+H)+. Calc'd for C8H9NO3: 169.18.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][CH2:10][C:11](O)=[O:12])=[C:4]([N+:14]([O-])=O)[CH:3]=1.BrC1C=C([N+]([O-])=O)C(F)=CC=1NCC(O)=O.O.O.[Sn](Cl)Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:9][CH2:10][C:11](=[O:12])[NH:14]2)=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CNc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C(O)CNc1cc(F)c([N+](=O)[O-])cc1Br
Solvent: O
Solvent: CCO
Product: O=C1CNc2cc(F)c(Br)cc2N1
Temperature: 25 °C
Yield: 24 %

Procedure:
A solution of mixture of N-(4-bromo-5-fluoro-2-nitrophenyl)glycine and N-(2-bromo-5-fluoro-4-nitrophenyl)glycine (0.150 g, 0.512 mmol, as prepared above) and tin (II) chloride dihydrate (0.346 g, 1.53 mmol, Aldrich, used as received) in ethanol (3.0 mL) was refluxed for 30 min. It was then cooled to r.t. and the solvent was removed under vacuum. The residue was diluted with water (10 mL) and basified with saturated NaHCO3 (3.0 mL) to pH ~8. The resulting white suspension was extracted with ethyl acetate (30 mL). The extract was dried over Na2SO4 and evaporated to yield 0.050 g of crude product which was purified by precipitation from ethanol: water (1:1) to give 30 mg (24%) of pure title compound as a light yellow powder; m.p. 172° C. (decomposed); 1H NMR (DMSO-d6) 3.73 (s, 2H), 6.37 (s, 1H), 6.551 (d, 1H, J=10.2 Hz), 6.825 (d, 1H, J=6.6 Hz), 10.303 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:17]
Reactant: Cc1cccc(Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cccc(Cl)[n+]1[O-]
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of 2-chloro-6-methylpyridine (24.6 g, 193 mmol) in dichloromethane (100 mL), a solution of m-chloro-per-benzoic acid (46.2 g, 268 mmol; purified) in dichloromethane (480 mL) was added over a period of 30 min. The reaction mixture was stirred at room temp. overnight, and concentrated to about 100 mL. The slurry was filtered, and the solid washed with ice-cold dichloromethane. The combined filtrate was washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under vacuum to provide 2-chloro-6-methylpyridine N-oxide as clear colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 435 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:18][C:17]([O:19][C@H:20]3[CH2:25][O:24][C@H:23]([CH2:26][OH:27])[C@@H:22]([OH:28])[CH2:21]3)=[N:16][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1.Br[C:30]1[N:31]=[N:32][N:33]([CH3:35])[N:34]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.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.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:18][C:17]([O:19][C@H:20]3[CH2:25][O:24][C@H:23]([CH2:26][OH:27])[C@@H:22]([OH:28])[CH2:21]3)=[N:16][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[CH:10][CH:9]=1
Reactant: Cn1nnc(Br)n1
Reactant: C#Cc1ccc(-c2nc3nc(O[C@H]4CO[C@H](CO)[C@@H](O)C4)[nH]c3cc2Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(C#Cc2ccc(-c3nc4nc(O[C@H]5CO[C@H](CO)[C@@H](O)C5)[nH]c4cc3Cl)cc2)n1

Procedure:
A mixture of (2R,3 S,5R)-5-((6-chloro-5-(4-ethynylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl)-oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol (60 mg, 0.150 mmol), Pd(Ph3P)4(17.34 mg, 0.015 mmol), copper(I) iodide (2.85 mg, 0.015 mmol), 5-bromo-2-methyl-2H-tetrazole (48.9 mg, 0.300 mmol) and diisopropylethylamine (0.210 ml, 0.450 mmol) in dioxane (2 ml) was charged in a reaction tube. The tube was sealed and N2 was bubbled through for 5 min. The reaction was heated at 80 C for 18 h, and then concentrated. The resulting residue was purified on reverse phase HPLC eluting with 10-70% CH3CN/H2O with TFA as an additive to give the title compound. LC-MS: m/e: 481.97.53 (M+H)+ (Rt 1.70/4 min); 1H NMR δ (ppm) (CD3OD): 7.84-7.75 (m, 4H), 5.11 (septet, 1H, J=5 Hz)), 4.38-4.31 (m, 1H), 4.24 (s, 3H), 3.89 (dd, 1H, J=12, 2 Hz), 3.69-3.59 (m, 2H), 3.37 (t, 1H, J=11 Hz), 3.20-3.15 (m, 1H), 2.79-2.72 (m, 1H), 1.70 (dd, 1H, J=23, 12 Hz),
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][CH2:52]O>O1CCCC1>[CH3:11][C:5]1[CH:6]=[C:7]([O:10][CH2:52][CH2:51][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=2)[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: OCCc1ccccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCc2ccccn2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-nitro-m-cresol (3.0 g, 0.020 mmol) and triphenylphosphine (7.7 g, 0.029 mmol) in tetrahydrofuran (50 mL) cooled with ice bath, diisopropyl azodicarboxylate (5.8 mL, 0.030 mmol) was added dropwise. The mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled with ice bath, and a solution of 2-pyridineethanol (2.6 mL, 0.024 mmol) in tetrahydrofuran (5.0 mL) was added dropwise to the reaction mixture then the mixture was stirred at ambient temperature for further 16 h. The solvent was removed under reduced pressure, then the residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 2-methyl-4-[2-(2-pyridinyl)ethoxy]-1-nitrobenzene as solid (2.0 g, y. 40%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([F:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:24][CH2:23]1.C(O)C.Cl>O>[F:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:7][C:2]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([N:25]3[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]3)[CH:29]=2)=[N:3][CH:4]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1F
Temperature: 95 °C

Procedure:
Ethyl 2-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]benzoate (1.0 g, 3.4 mmol), 3-(4-methyl-1-piperazinyl)aniline (0.65 g, 3.4 mmol), ethanol (45 mL) and 6N HCl (1.5 mL, 8.8 mmol) were heated with stirring in a reaction vessel, which was sealed and heated at 95° C. for 24 h. The reaction mixture was cooled to room temperature, poured into water, extracted with ethyl acetate and neutralized to pH 7 by the slow addition of 6N NaOH. The resulting precipitate was collected on a sintered glass funnel and washed with water and ethyl ether to afford the title compound as a tan solid; yield 1.0 g (65%). MS: M(C24H27FN6O2)=450.52 (M+H)+=451.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=O.[K+].[Br-]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]1[NH:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[N:10]=1
Reactant: COc1ccccc1C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1nc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 76 %

Procedure:
Prepared from 4-nitrophenylenediamine and 2-methoxybenzoic acid, in a manner similar to that of Example 9b. Yield: 76%; Rf (6/4 toluene/ethyl acetate): 0.43; IR (KBr): 3005, 1515, 1335, 750 cm−1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].[CH2:19]([O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)[CH3:20]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:19][CH3:20])=[CH:30][CH:29]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CCOc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2N)c1
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)cc1

Procedure:
Using a procedure similar to 1B except starting with N1-(3-cyanobenzoyl)-1,2-benzenediamine, 4-ethoxybenzoyl chloride and triethylamine as base, the title compound was obtained as a white solid (39%); mp: 168-9° C.; IR(KBr): 1645, 1672, 2231, 3377 cm−1; MS(FD): 385(M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1nccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nccc2ccccc12

Procedure:
The title compound (0.76 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1.6 ml) and 1-chloroisoquinoline (0.8 g) according to the method used for the preparation of the compound of D8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[NH:5][CH:6]=1.O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][N:11]2[C:15](=[O:16])[CH2:14][CH2:13][C:12]2=[O:17])=[O:8])[NH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1cc(Cl)c[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(ON1C(=O)CCC1=O)c1cc(Cl)c[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-chloro-1H-pyrrole-2-carboxylic acid (1 eq), N-hydroxysuccinimide (1 eq) and DCC (1.05 eq) in dry THF was stirred at RT for 12 h. The solid urea was filtered off and washed with THF. The filtrate was evaporated under reduced pressure and the resulting crude was purified by on silica gel eluting with petrol ether/EtOAc to obtain the title compound as a white-off powder. 1H NMR (400 MHz, DMSO-d6) δ: 12.87 (1H, br. S), 7.50-7.45 (1H, m), 7.16-7.12 (1H, m), 2.87 (4H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)C.Br([O-])(=O)=O.[Na+].BrBr>O>[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=2)=[CH:14][CH:13]=1)=[O:16]
Reactant: OCc1ccc(-c2ccc(CO)cc2)cc1
Agent: BrBr
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 75 °C
Yield: 101.1 %

Procedure:
In a 50 ml three-necked flask equipped with a magnetic stirrer, a reflux condenser and a thermometer, 4.28 g (20 mmols) of 4,4′-bishydroxymethylbiphenyl and 10 ml of (166 mmols) of acetic acid were charged, followed by heating to 75° C. An aqueous solution prepared by dissolving 2.04 g (13.5 mmols) of sodium bromate in 10 ml of water was added dropwise, and then the mixture was stirred at 75° C. until a color of bromine disappears. To the system, 50 ml of water was added and, after filtration, the resulting substance was dried to obtain 4.25 g of 4,4′-bisformylbiphenyl as a white crystal. Yield: 99.9%. It was confirmed by GS-MS that a molecular ion peak is 209.