Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.F[C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([CH:39]=1)[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.CCOC(C)=O.O>[CH:1]1([C:4]2[C:5]([N:24]([C:30]3[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([CH:39]=3)[C:35]([O:37][CH3:38])=[O:36])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 91.8 %

Procedure:
A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.0 g, 2.49 mmol), methyl 5-fluoro-2-nitrobenzoate (0.99 g, 4.97 mmol), and potassium carbonate (1.03 g, 7.45 mmol) in HMPA (6.2 mL) was stirred at 60° C. for 3 days. The solution was diluted with EtOAc and water and the organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-80% EtOAc/hexanes) to afford the title compound (1.33 g, 92%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.99 (d, J=9.09 Hz, 1H), 7.85-7.92 (m, 2H), 7.56 (s, 1H), 7.53 (s, 1H), 7.50 (dd, J=9.09, 2.64 Hz, 1H), 7.43 (d, J=2.64 Hz, 1H), 7.19-7.26 (m, 2H), 5.80 (d, J=4.59 Hz, 1H), 3.90 (s, 3H), 3.34 (s, 3H), 3.02 (d, J=4.98 Hz, 3H), 1.91 (tt, J=8.37, 5.31 Hz, 1H), 1.01 (br. s., 1H), 0.89 (br. s., 1H), 0.73-0.85 (m, 1H), 0.58 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:12]=1[C:13]([OH:15])=[O:14]>>[Cl:23][C:16]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Product: COc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To 74 g (0.60 mol) of p-anisidine stirred mechanically at 75° C. was added 35.4 g (0.15 mol) of 2,6-dichloro-3-nitrobenzoic acid [Lehmstedt and Schrader, Berichte 70B, 1526 (1937)] in small portions over one-half hour. The mixture was heated at 75° C. for 24 hours with stirring during the first two hours. The reaction mixture was cooled and the resulting solid mass was triturated in a mechanical blender with 300 ml of 2.4N hydrochloric acid. The solid was collected, washed with 3N hydrochloric acid, stirred in 400 ml of 0.5N sodium carbonate, and filtered. The filtrate, diluted with 250 ml of water, was gradually acidified with 4N hydrochloric acid. The precipitate was collected, washed with water, and dried to provide 38.5 g (79%) of the red title compound, mp 205°-213° C. A purified sample, from toluene, melts at 212°-215° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:6]=1.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1>>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:13]3[C:12](=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)[NH:11][C:8](=[O:10])[C:7]=2[C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[CH:26][CH:25]=1)[CH3:28]
Reactant: CCc1ccc(C(=O)c2cc(C#N)ccc2N)cc1
Reactant: Cc1nc(CC(=O)O)cs1
Product: CCc1ccc(-c2c(-c3csc(C)n3)c(=O)[nH]c3ccc(C#N)cc23)cc1
Yield: 27 %

Procedure:
Synthesized from (2-methyl-thiazol-4-yl)-acetic acid and 4-Amino-3-(4-ethyl-benzoyl)-benzonitrile according to general procedure 2. Yield 27%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[C:3]=1[I:11]>C(Cl)Cl.[O-2].[Mn+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([F:10])[C:3]=1[I:11]
Reactant: OCc1ccc(Cl)c(I)c1F
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(Cl)c(I)c1F

Procedure:
To a solution of (4-chloro-2-fluoro-3-iodophenyl)methanol (4.00 g, 14.0 mmol) in DCM (50 mL) was added manganese oxide (18.2 g, 209 mmol). The reaction mixture was refluxed for 10 h, then filtered through Celite® pad. The filtrate was concentrated under reduced pressure. Flash chromatography on silica gel (dichloromethane:hexane=20:80) gave 4-chloro-2-fluoro-3-iodobenzaldehyde as a white solid. MS (ESI, pos.ion) n/z: 286.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](N)[C:3]=1[S:9][CH3:10].N([O-])=[O:12].[Na+].O>Cl.[O-]S([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:12])[C:3]=1[S:9][CH3:10]
Reactant: CSc1c(Cl)ccnc1N
Reactant: O=N[O-]
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CSc1c(Cl)ccnc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution 4-chloro-3-(methylthio)pyridin-2-amine (40 mg, 0.23 mmol), NaNO2 (17 mg, 0.25 mmol) in HCl aq (6M, 0.5 mL) was added CuSO4 (37 mg, 0.23 mmol). The resulting mixture was allowed to stir at 0° C. for 0.5 h. To the solution was added water (1 mL), extracted with EtOAc (2×5 mL), dried over Na2SO4, filtered and concentrated to afford the title compound as a yellow solid. LC/MS m/z=176.1 [M+H]+
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]([CH2:14][CH3:15])=[C:12]([O:16][CH2:17][O:18][CH3:19])[CH:11]=[C:10]([O:20][CH2:21][O:22][CH3:23])[C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=[O:2].[C:24](OC(=O)C)(=O)C.O.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:14]([C:13]1[C:5]([CH2:4][C:1]([O:3][CH3:24])=[O:2])=[C:6]([C:10]([O:20][CH2:21][O:22][CH3:23])=[CH:11][C:12]=1[O:16][CH2:17][O:18][CH3:19])[C:7]([OH:9])=[O:8])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1c(OCOC)cc(OCOC)c(C(=O)O)c1CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1c(OCOC)cc(OCOC)c(C(=O)O)c1CC(=O)OC
Temperature: 100 °C
Reaction time: 4 h
Yield: 126.6 %

Procedure:
The above-obtained 2-(carboxymethyl)-3-ethyl-4,6-bis(methoxymethoxy)benzoic acid (0.38 g, 1.2 mmol) was dissolved in toluene (20 mL) and the obtained solution was added with acetic anhydride (0.20 mL, 2.1 mmol), followed by stirring at 100° C. for 4 hours. The reaction mixture was added with water and then extracted with diethylether 3 times. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure and the obtained residue was dissolved in methanol (20 mL). The obtained solution was added with sodium methoxide (0.22 g, 4.2 mmol) and stirred at a room temperature for 7 hours. After adding water, the reaction mixture was extracted with ethyl acetate 3 times. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure to obtain 3-ethyl-2-(methoxycarbonylmethyl)-4,6-bis(methoxymethoxy)benzoic acid (0.52 g, 100%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12](I)[CH:11]=1>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:12]=2[CH:11]=1
Reactant: C#Cc1ccccc1
Reactant: Oc1ccc(Br)cc1I
Product: Brc1ccc2oc(-c3ccccc3)cc2c1

Procedure:
The general procedure was used to convert phenylacetylene and 4-bromo-2-iodophenol to the title product. Purification by flash chromatography (20% CH2Cl2 in hexanes as the eluent) gave the analytically pure product as a white solid (468 mg, 86% yield). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=6.97, 2H), 7.69-7.67 (m, 1H), 7.46-7.35 (m, 5H), 6.91 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 157.18, 153.56, 131.17, 129.85, 128.97, 128.82, 127.04, 125.02, 123.43, 115.95, 112.56, 100.58. Anal. Calcd. for C14H9BrO: C, 61.57; H, 3.32; Br, 29.26. Found C, 61.46; H, 3.26; Br, 29.50. m.p.: 157° C. (lit.,9, 158-159° C.).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[CH3:18][O:17][CH2:16][CH2:15][N:4]1[C:3](=[O:19])[C:2]([NH:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13]
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCOCC1
Product: COCCN1C(=O)C(NC2CCOCC2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and tetrahydro-2H-pyran-4-amine in a similar manner as described for Example 1. 1H NMR (400 MHz, CD3CN): δ 7.58-7.50 (m, 5H), 5.70 (d, 1H), 3.84 (t, 2H), 3.74-3.66 (m, 4H), 3.35 (s, 3H), 3.21-3.10 (m, 1H), 2.86-2.78 (m, 2H), 1.61-1.54 (m, 2H), 1.48-1.36 (m, 2H); Mass Spectrum: M+H+ 367.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[Li]CCCC.CN(C)CCN(C)C.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[O:31]>CCOCC>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[CH:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=1)[OH:31]
Reactant: O=Cc1ccccn1
Reactant: COc1cccc(CO)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cccc(CO)c1C(O)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a solution of 3-methoxybenzylalcohol (50.0 g, 0.36 mol) in ether (1.1 L) at -20° C. was added n-BuLi (76.0 mL, 0.756 mol) at such a rate that the internal temperature of the reaction was maintained at less than -10° C. When the addition of n-BuLl was complete, the mixture was warmed to room temperature and stirred for 2 hours. The mixture was cooled to 0° C. and tetramethylethylene diamine (42.0 g, 0.36 reel) was added. The reaction mixture was cooled to -30° C. and 2-pyridinecarboxaldehyde (58.0 g, 0.36 mol) was added over 5 minutes. The reaction was warmed to 0° C. over a 30 minute period and was then quenched with water (500 mL). The mixture was chilled for 24 hours, and the product was collected by filtration and washed with ether. The product was recrystallized from ethanol to afford 30.0 g (34%) of α-[2-(hydroxymethyl)-6-methoxyphenyl]-2-pyridinemethanol (Formula XV: R2 =6-OCH3 ; R3 =R4 =H) . The mother liquor from the recrystallization step was concentrated, diluted with ether and refrigerated for 16 hours. A solid precipitated, which was collected by filtration to afford an additional 13.1 g of the desired product for a total of 43.1 g (49%).
Reaction SMILES: [Cr:1]([O:24][Si:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:4][Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])=[O:2].C=C.C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)O)C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6].C1([Si](O[Si](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:110]>C(O)(=O)C.C(#N)C.C(C#N)CC>[C:6]1([Si:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[Cl:110])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cr:1]([O:24][Si:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([O:4][Si:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])=[O:2]
Reactant: ClC(Cl)(Cl)Cl
Agent: O=[Cr](=O)(O[Si](c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cr+6]
Agent: C=C
Solvent: CCCC#N
Solvent: CC(=O)O
Solvent: CC#N
Product: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Bistriphenylsilyl chromate is usually used as the catalyst of unsaturated hydrocarbon compound polymerization such as ethylene polymerization. With respect to its synthesis process, early in 1958, U.S. Pat. 7,863,891 disclosed a process wherein bistriphenylsilyl chromate can be obtained with a yield of 85% by reacting triphenylsilanol and chromium trioxide in glacial acetic acid at 50° C. for 10 minutes. L. M. Bakert et al disclosed a process wherein bistriphenylsilyl chromate can be obtained with a yield of about 60% by reacting triphenylsilanol and chromium trioxide in carbon tetrachloride at room temperature for 24 hours [J. Org. Chem., Vol. 85, No. 8, pp. 774-776, March 1970]. The former Czechoslovakia Patent CS 175856 disclosed a process wherein bistriphenylsilyl chromate can be obtained with a yield of 43-71% by reacting triphenylsilanol or triphenylsilyl ether and chromium trioxide in acetonitrile or propyl cyanide. However, the starting material triphenylsilanol used in the above processes is obtained by the hydrolysis of triphenylchlorosilane, so the process for the preparation of bistriphenylsilyl chromate is relatively complicated and the yield thereof is relatively low. The former Soviet Union Patent SU 689192 .disclosed a process wherein bistriphenylsilyl chromate can be obtained with a yield of 94% by reacting triphenylchlorosilane and potassium dichromate in glacial acetic acid at 40°-50° C. for 1.5 hours. The reaction equation thereof is as follows: ##STR1##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH:20]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21]1>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:24]([CH:20]2[CH2:23][CH2:22][CH2:21]2)=[O:25])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(N)c1
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)C2CCC2)c1

Procedure:
An 11.4 g portion of m-aminoacetophenone, 10.9 g of diisopropylethylamine, 10.0 g of cyclobutanecarboxylic acid chloride and 200 ml of dichloromethane were reacted as described in Example 1, giving 14.68 g of N-(3-acetylphenyl)cyclobutanecarboxamide.
Reaction SMILES: CN1CCOCC1.OC1C2N=NNC=2C=CC=1.[NH2:18][C@H:19]([CH2:27][OH:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:29]([N:32]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:35]([CH2:44][C:45](O)=[O:46])[C:34](=[O:48])[CH:33]1[CH:49]([CH3:51])[CH3:50])(=[O:31])[CH3:30].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OCC)(=O)C>[C:29]([N:32]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:35]([CH2:44][C:45]([NH:18][C@@H:19]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:27][OH:28])=[O:46])[C:34](=[O:48])[CH:33]1[CH:49]([CH3:51])[CH3:50])(=[O:31])[CH3:30]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)O)C(=O)C1C(C)C
Reactant: N[C@H](CO)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@H](CO)Cc2ccccc2)C(=O)C1C(C)C
Reaction time: 72 h

Procedure:
N-Methylmorpholine (525 μl), hydroxybenzotriazole (647 mg) and L-phenylalaninol (491 mg) are added to a solution of {(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetic acid (1.01 g, Reference compound No. 51-1) in methylene chloride (25 ml). The mixture is cooled with ice, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added to the mixture, and the whole is stirred for three days. Ethyl acetate is added to the reaction mixture, and the whole is washed with a 0.1 N aqueous sodium hydroxide solution, saturated brine, 1 N hydrochloric acid and saturated brine successively. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (1.37 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.[Cl-].[Na+].O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=34)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: CC1(C)OB(c2cnn3ccccc23)OC1(C)C
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1nc(-c2cnn3ccccc23)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under Ar, (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (21.7 mg, 0.074 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (40 mg, 0.16 mmol), K3PO4 (57 mg, 0.27 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.3 mg, 0.0047 mmol) were taken up in dioxane (0.65 mL) and water (0.07 mL). The stirred mixture was heated to 100° C. for 70 min, at which time additional boronic ester (28 mg, 0.12 mmol), K3PO4 (45 mg, 0.21 mmol) and precatalyst (3.3 mg, 0.0047 mmol) were added. The mixture was stirred for an additional 15 h and was then cooled to r.t. and diluted with EtOAc (20 mL), water (10 mL) and brine (10 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated directly onto silica gel. Purification by silica gel chromatography (0% to 15% MeOH in CH2Cl2) provided (R)-4-((R)-1-(3-methyl-6-(pyrazolo[1,5-a]pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.20.
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:20]=[CH:19][N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][N:16]3[CH:21]=[CH2:22])=[CH:7][CH:6]=1)([CH3:4])=[O:3].[Cl:23][C:24]1[C:29](I)=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=1.C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:23][C:24]1[C:29](/[CH:22]=[CH:21]/[N:16]2[CH:15]=[N:14][C:13]3[C:17]2=[N:18][CH:19]=[N:20][C:12]=3[NH:11][C:8]2[CH:9]=[CH:10][C:5]([P:2]([CH3:1])([CH3:4])=[O:3])=[CH:6][CH:7]=2)=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=1
Reactant: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Reactant: Cc1ccnc(Cl)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccnc(Cl)c1/C=C/n1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Temperature: 120 °C

Procedure:
N-(4-(Dimethylphosphoryl)phenyl)-9-vinyl-9H-purin-6-amine (Example 3, 1 mmol), 2-chloro-3-iodo-4-methylpyridine compound (1.3 mmol), diisopropylethyl amine (3 mmol), palladium acetate (0.05 mmol), tri-o-tolylphosphine (0.1 mmol) in DMF (5 mL) was thoroughly purged with argon for 10-15 min. and sealed and heated for 120° C. for 18 h. until the starting materials disappeared. The reaction mix. was passed through celite, and washed with dichloromethane containing 30% methanol. The filtrate was concentrated in vacuo. The residue was purified by Biotage-S column chromatography using 1/1 hexane ethyl acetate, ethyl acetate and 1-10% methanol containing ethyl acetate: MS [M+H]+ 439.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:16]([N:19]=[C:20]=[O:21])[CH:17]=[CH2:18]>C(OC(C)C)(C)C>[CH2:16]([NH:19][C:20]([N:10]1[CH2:9][CH:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:13][CH:12]=2)[CH2:11]1)=[O:21])[CH:17]=[CH2:18]
Reactant: C=CCN=C=O
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Solvent: CC(C)OC(C)C
Product: C=CCNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 72 h
Yield: 27.5 %

Procedure:
A solution of 8.7 g (0.04 mole) of crude 3-[4-(trifluoromethyl)phenoxy]azetidine in 75 ml of isopropyl ether was stirred under a blanket of nitrogen while 4.2 g (0.05 mole) of 2-propenyl isocyanate was added dropwise. After stirring for 3 days, no crystalline product precipitated. The reaction mixture was concentrated to a dark reddish oil. TLC (20% ethyl acetate/methylene chloride on silica gel) showed at least 6 spots, all well separated. The residue was dissolved in chloroform, chromatographed on a 350 g silica gel column and eluted with chloroform until the reddish forerun was removed. The column was then eluted with an ethyl acetate/chloroform gradient to 4% ethyl acetate. All the fractions were combined and concentrated to give 4.8 of orange oil, which crystallized on standing. Recrystallization from acetone/cyclohexane gave 3.3 g (27.5%) of beige crystals, m.p. 91°-92.5° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17](O)=[O:18])=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[Br:32].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Br:32][C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([NH:22][C:17]([C:10]3[CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:8][CH:7]=4)[CH2:14][C:13](=[O:15])[NH:12][C:11]=3[CH3:16])=[O:18])[CH:24]=2)[NH:28][N:27]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Reactant: Nc1ccc2[nH]nc(Br)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Br)c3c2)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.6 %

Procedure:
The product of Example 5, Step 2 (110 mg, 0.368 mmol, 1.00 equiv), 5-amino-3-bromoindazole (78 mg, 0.368 mmol, 1.0 equiv), and EDC (84 mg, 0.441 mmol, 1.20 equiv) were suspended in 1.0 mL DMF. Et3N (0.061 mL, 0.441 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 52 mg (29%) of the title compound as an off white solid. MS (ES+) m/e 494 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10])#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][O:20][N:45]1[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]2[C:49]1=[O:50])(=[O:11])=[O:10])#[N:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C#N)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCCCON2C(=O)c3ccccc3C2=O)cc(OS(=O)(=O)c2ccccc2C#N)c1
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of 3-[3-(2-cyanophenylsulfonyloxy)-5-methylphenoxy]propanol (1.04 g, 3.0 mmol), as prepared in the preceding step, triphenylphosphine (1.05 g, 4.0 mmol), and N-hydroxyphthalimide (490 mg, 3.0 mmol) at 0° C. in tetrahydrofuran (20 mL) was added diethyl azodicarboxylate (700 mg, 4.0 mmol). The reaction mixture was stirred overnight. Water (50 mL) was added, the reaction mixture was extracted into ethyl acetate (3×50 mL). The ethyl acetate solution was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent, the residue was purified by flash column chromatography (2:1 dichloromethane/hexane to dichloromethane) to give the title compound as a colorless foam (1.12 g, 76%). 1H-NMR (300 MHz, CDCl3) δ8.09 (m, 1H), 7.97 (m, 1H), 7.84 (m, 2H), 7.78 (m, 4H), 6.67 (s, 1H), 6.60 (s, 1H), 6.50 (s, 1H), 4.37 (t, J=6.1 Hz, 2H), 4.13 (t, J=6.1 Hz, 2H), 2.27 (s, 3H), 2.19 (m, 2H).