Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Br)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-bromobenzenesulfonyl chloride according to METHOD A, giving 0.14 g (31%) of a pink solid after recrystallization from acetone/ether/petroleum ether: mp 183° C.; MS (Ionspray, [M+H]+) m/z 405; Anal. Calcd (found) for C13H13BrN2O4S2: C, 38.5 (38.5)%, H, 3.2 (3.0)%, N, 6.9 (6.6)%
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:14]2[C:19]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)=[CH:18][C:17]3[C:5]([CH3:10])([CH3:6])[C:17]4[C:16](=[CH:15][C:14]([C:8]5[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=5)=[C:19]([C:8]5[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=5)[CH:18]=4)[C:1]([CH3:3])([CH3:2])[C:16]=3[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccccc1
Reactant: CC(C)(C)c1ccc(B(O)O)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: [K+]
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2cc3c(cc2-c2ccc(C(C)(C)C)cc2)C(C)(C)c2cc(-c4ccc(C(C)(C)C)cc4)c(-c4ccc(C(C)(C)C)cc4)cc2C3(C)C)cc1
Temperature: 80 °C

Procedure:
10 mmol of product in Example 2, 40 mmol of 4-tert-butylphenylboronic acid, and 0.2 mmol of Pd(PPh3)4 were charged in a reaction vessel under nitrogen. The mixture was added deoxygen benzene (50 mL), ethanol (4 mL), and 2M potassium carbonate solution (10 mL) to be dissolved, and then heated to 80° C. and reacted for 24 hours. The reaction result was extracted by 50 mL of ethyl acetate to obtain an organic layer. The organic layer was filtered through diatomite and dried by anhydrous magnesium sulphate. Most of the solvent of the dried organic layer was removed to obtain a solid. The solid was subsequently washed by distillation water, methanol, ethyl ether to obtain 2,3,6,7-Tetrakis-(4-tert-butyl-phenyl)-9,9,10,10-tetramethyl-9,10-dihydro-anthracene (hereinafter TTA-tBu). The Suzuki coupling was shown in Formula 7, and the product had spectra as below. 1H NMR (400 M Hz, CDCl3): δ 1.31 (s, 36 H), 1.79 (s, 12 H), 7.12 (d, 8 H, J=8.4 Hz), 7.24 (d, 8 H, J=8.4 Hz), 7.55 (s, 4 H). 13C NMR (100 M Hz, CDCl3): δ 31.4 (CH3), 34.4(C), 35.1 (CH3), 37.1 (C), 124.6 (CH), 128.9 (CH), 129.5 (CH), 138.3 (C), 138.8 (C), 141.0 (C), 149.1 (C). HRMS (FAB, m/z): calcd for C58H68 764.5321, found 765.5397 (M+H+). Anal. Calcd. for C58H68: C, 91.04; H, 8.96%. Found: C, 91.07; H, 8.90%. FIG. 4 shows UV-VIS absorption and photo luminescent spectra of the TTA-tBu in a dichloromethane solution and thin film type, and solid phosphorescence emission spectra at 77K of the TTA-tBu.
Reaction SMILES: C1(C)C(C=[O:8])=CC=CC=1.[CH3:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][CH2:15][C:16]2=[O:21].[Se](=O)=O>>[CH3:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][CH2:15][C:16]2=[O:21].[CH3:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15](=[O:8])[C:16]2=[O:21]
Reactant: Cc1ccccc1C=O
Agent: Cc1cccc2c1CCCC2=O
Agent: O=[Se]=O
Product: Cc1cccc2c1C=CC(=O)C2=O

Procedure:
5-Methyl-1-tetralone was prepared from o-tolualdehyde according to the literature (J. Med Chem 1997, 40, 3014–3024). Treatment of 5-methyl-1-tetralone with selenium dioxide as described in Reference Example 1A yielded 5-methyl-[1,2]naphthoquinone. This was reacted with 2,3-diamino-benzoic acid, diacetate salt, as described in Reference Example 1A to yield the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25]>CN(C)C=O.CCOCC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=2[CH3:17])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cccc(O)c1C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1C
Temperature: 100 °C
Yield: 100.5 %

Procedure:
In a microwave vial 1-fluoro-4-nitrobenzene (500 mg, 3.54 mmol) was dissolved in N,N-Dimethylformamide (10 mL) to give a pale yellow solution. Potassium carbonate (1469 mg, 10.63 mmol) and 2,3-dimethylphenol (433 mg, 3.54 mmol) were added. The reaction vessel was sealed and heated in Biotage Initiator at 100° C. for 1 hour. After cooling the reaction was diluted with 25 mL of Et2O. The organic phase was washed with 3 times 25 mL of water, 10 mL of saturated brine, dried over sodium sulphate, filtered and evaporated under vacuum to afford the title compound as a yellow solid (865.1 mg).
Reaction SMILES: C(O[SiH](OCC)OCC)C.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].C1COCC1.[OH-].[Na+]>[Ti+4].CC(C)[O-].O.CCOCC>[CH3:12][CH:11]([OH:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CCO[SiH](OCC)OCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccccc1
Temperature: 48 °C
Yield: 96.1 %

Procedure:
A dry Schlenk tube under argon was charged with triethoxysilane (1.1 ml, 6.0 mmol) and acetophenone (580 μL, 5 mmol) and heated to 48° C. Titanium (IV), isopropoxide (75 μL, 0.25 mmol) was then added. After stirring at 48° C. for an hour the color changed to deep blue. After 6 hours the reaction mixture was cooled to room temperature. After 12 hours it was added to THF (5 mL). Aqueous NaOH (1 N, 15 mL) was then added to the solution. After vigorous stirring at room temperature for 1 hour, the reaction mixture was added to a water/ether mixture (100 mL each), shaken vigorously, and the organic layer was separated. The aqueous layer was washed with an additional 100 mL of ether, and the combined ether extracts were dried over MgSO4. Concentration in vacuo afforded 587 mg (97% yield, greater than 95% pure by NMR and GC) of sec-phenethyl alcohol as a slightly yellowish oil.
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=O)[CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[C:23]([OH:29])=[N:24][CH:25]=[CH:26][C:27]=1[OH:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:29][C:23]1[C:22]([NH:21][C:18]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:10]=2[N:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:17]=[CH:16]3)=[O:20])=[C:27]([OH:28])[CH:26]=[CH:25][N:24]=1
Reactant: O=C(O)c1cccc2ccc(Oc3ccccc3)nc12
Reactant: Nc1c(O)ccnc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1c(O)ccnc1O)c1cccc2ccc(Oc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-phenoxyquinoline-8-carboxylic acid (178c 217 mg, 0.818 mmol), 3-aminopyridine-2,4-diol (155 mg, 1.227 mmol), HATU (622 mg, 1.636 mmol), and DIPEA (438 μl, 2.454 mmol) in DMF (1636 μl) was stirred at RT for 1 h. Purification by silica gel (100% DCM to 5% MeOH/DCM) provided N-(2,4-dihydroxypyridin-3-yl)-2-phenoxyquinoline-8-carboxamide (179c) as a yellow solid. MS (ESI, pos. ion) m/z: 374.2 (M+1).
Reaction SMILES: NN1CCCC1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:17]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23]3[N:32]=[C:31]([N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH2:18]2)=[O:16])=[CH:10][CH:9]=1.[ClH:46]>CO.C(OCC)(=O)C>[ClH:7].[ClH:46].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([N:17]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23]3[N:32]=[C:31]([N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH2:18]2)=[O:16])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccc(Cl)cc4)C3)nc3ccccc23)CC1
Agent: Cl
Agent: NN1CCCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(Cl)cc1)N1CC[C@H](Nc2nc(N3CCNCC3)c3ccccc3n2)C1
Reaction time: 8 h

Procedure:
To a mixture of t-butyl 4-(2-((S)-pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.30 g), p-chlorophenylacetic acid (0.13 g), and chloroform (5 mL) were added HOBt.H2O (0.18 g) and EDC.HCl (0.18 g), and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=3:2) to obtain t-butyl 4-(2-((S)-1-(2-(4-chlorophenyl)ethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.29 g). (2) To a solution of t-butyl 4-(2-((S)-1-(2-(4-chlorophenyl)ethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.28 g) in methanol (5 mL) was added a solution (1.3 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, and the residue was crystallized in diethyl ether to obtain the title compound (0.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:4]([C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6])[CH2:47][CH2:48][CH3:49]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,5-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.27-1.35 (m, 2 H) 1.67-1.76 (m, 2 H) 2.50 (s, 3 H) 4.16 (t, 2 H) 6.25 (s, 1 H) 7.46-7.53 (m, 2 H) 7.55-7.57 (m, 1 H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:8](=[O:9])[O:7][CH2:6][C:5]=1[N:10]1[CH2:14][CH2:13][C:12]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[C:11]1=[O:27])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([C:4]1[C:8](=[O:9])[O:7][CH2:6][C:5]=1[N:10]1[CH2:14][CH2:13][C:12]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:11]1=[O:27])([CH3:3])[CH3:2]
Reactant: CC(C)C1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (195 mg, 0.515 mmol) in methylene chloride was added trifluoroacetic acid at rt and the resulting solution was stirred at rt for 1 h. After removing the volatiles the residue was dissolved in methylene chloride and treated with hydrogen chloride (2 mL, 4 N in dioxane) and concentrated again to give 2-(4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one as hydrogen chloride salt. LC/MS: (M+1)+: 279.16.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][CH:30]([F:47])[C:31]1[CH:32]=[C:33]([OH:46])[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:34]=[C:33]([OH:46])[CH:32]=[C:31]([CH:30]([F:47])[F:29])[CH:36]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(O)cc(C(F)F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(C(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (65 mg, 0.15 mmol) were added 3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (91 mg, 0.15 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12 mg, 0.01 mmol) and 147 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 48 mg (64% yield) as a solid. Purity 99%.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)(=O)[CH3:6].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:3][O:2][N:4]=[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:6]
Reactant: CON
Reactant: CC(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CON=C(C)c1cccnc1

Procedure:
6.85 g of methoxylamine hydrochloride is added to 10 g of 3-acetyl pyridine in 50 cm3 of methanol and the whole is heated to reflux for 3 hours. The solvent is eliminated under reduced pressure, the residue is taken up in water, alkanlized with potassium carbonate and extracted with ethyl acetate. After evaporating, 11 g of the expected product is recovered. (b.p.: 115°-118° C. under 18 mm Hg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=[C:12]3[NH:21][CH:22]=[CH:23][C:11]=23)[CH2:4]1.N1C=CN=C1.Cl[Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32].O>CN(C)C=O.CCOC(C)=O>[CH:31]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=[C:12]3[NH:21][CH:22]=[CH:23][C:11]=23)[CH2:4]1)([CH3:33])[CH3:32]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1N[C@H]1CCC[C@@H](CO)C1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2[nH]ccc2c1N[C@H]1CCC[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 4-{[cis-3-(hydroxymethyl)cyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (125 mg) in N,N-dimethylformamide (1.25 ml) were added imidazole (40 mg) and chloro(triisopropyl)silane (125 μl). The mixture was stirred at ambient temperature for 18 hours. To the mixture were added water and EtOAc. The mixture was extracted with EtOAc and washed with saturated aqueous sodium hydrogencarbonate and brine. The extract was dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography on silica gel with chloroform:methanol=100:1-95:5 to give ethyl 4-{[cis-3-{[(triisopropylsilyl)oxy]methyl}cyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (170 mg) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][C:7](=[O:16])[C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@:27]([OH:42])([C@H:34]([S:36][CH:37]([CH2:40]O)[CH2:38][OH:39])[CH3:35])[CH2:28][N:29]1[CH:33]=[N:32][CH:31]=[N:30]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7](=[O:16])[C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[O:39][CH2:38][C@H:37]([S:36][C@H:34]([CH3:35])[C@:27]([C:21]4[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=4[F:19])([OH:42])[CH2:28][N:29]4[CH:33]=[N:32][CH:31]=[N:30]4)[CH2:40][O:15]3)=[CH:10][CH:9]=2)=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(Cl)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(3) a reaction was carried out using 4′-chloro-4-formylbenzanilide (300 mg, 1.2 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (359 mg, 1.0 mmol) and p-toluenesulfonic acid monohydrate (342 mg, 1.8 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 3(3) to give the trans isomer of the title compound (290 mg, yield 48%) as a colorless solid and the cis isomer (82 mg, yield 14%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][CH:6]([C:8]([CH3:14])([CH:10]([OH:13])[CH2:11][CH3:12])[CH3:9])[CH2:5][CH2:4][O:3]1.C[N+]1([O-])CCOCC1>C(Cl)Cl>[CH3:15][C:2]1([CH3:1])[O:7][CH:6]([C:8]([CH3:14])([C:10](=[O:13])[CH2:11][CH3:12])[CH3:9])[CH2:5][CH2:4][O:3]1
Reactant: CCC(O)C(C)(C)C1CCOC(C)(C)O1
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCC(=O)C(C)(C)C1CCOC(C)(C)O1
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
70 mg (0.32 mmol) of alcohol 46 is dissolved in 5 ml of CH2Cl2, and 6 4A molecular sieve spheres and 66 mg (0.48 mmol, 1.5 equivalents) of 4-methylmorpholine N-oxide (NMO) are added. After 10 minutes of stirring, 6 mg of tetrapropylammonium-perruthenate(VII) (TPAP) (0.016 mmol, 0.05 equivalent) is added and stirred for 4 hours at room temperature. Then, the reaction mixture is concentrated by evaporation in a rotary evaporator and directly purified by column chromatography with pentane:ether=1:1. 60 mg (0.28 mmol) of ethyl ketone 2, corresponding to a yield of 86%, is obtained.
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH3:5])C.[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([NH:26][NH2:27])=[N:24][CH:25]=1)(=[O:19])=[O:18].O>ClCCl.CO>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:26]([C:23]3[CH:22]=[CH:21][C:20]([S:17]([CH3:16])(=[O:19])=[O:18])=[CH:25][N:24]=3)[N:27]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CCOC(C)=NC(=O)c1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Br)cc2)n(-c2ccc(S(C)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
N-(1-ethoxy-ethylidene)-4-bromo-benzamide 565 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, (5-methansulfonyl-pyridine-2-yl)-hydrazine 431 mg (2.23 mmol) was added to the solution and the solution was stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 2-[5-(4-bromo-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-5-methanesulfonyl-pyridine (502 mg, yield: 61%) was obtained as a solid phase.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][CH3:8])[C:3]([CH3:6])([OH:5])[CH3:4].F[C:10]1[C:11]([C:20]#[C:21][Si](C)(C)C)=[C:12]([C:18]#[N:19])[C:13](=[CH:16][CH:17]=1)[C:14]#[N:15].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CCOC(C)=O.CN1C(=O)CCC1>[OH:5][C:3]([CH3:6])([CH:2]([N:1]1[C:10]2[C:11](=[C:12]([C:18]#[N:19])[C:13]([C:14]#[N:15])=[CH:16][CH:17]=2)[CH:20]=[CH:21]1)[CH2:7][CH3:8])[CH3:4]
Reactant: CCC(N)C(C)(C)O
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C#N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC(n1ccc2c(C#N)c(C#N)ccc21)C(C)(C)O
Temperature: 140 °C
Yield: 17.7 %

Procedure:
An oven-dried 20 mL microwave vial was charged with 3-amino-2-methylpentan-2-ol (Example 34A) (0.0705 g, 0.602 mmol), 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (Example 40C) (0.146 g, 0.602 mmol), and K2CO3 (0.100 g, 0.722 mmol). Anhyd NMP (3 mL) was added via syringe and the vial was sealed with a PTFE-faced crimp top. The mixture was subjected to microwave heating (140° C.) for 35 min. The mixture was cooled, poured into satd NaHCO3, layered with EtOAc and the whole was filtered (Whatman #2). Layers were separated and the aqueous layer was extracted with EtOAc (×2). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution). Fractions containing the desired product were decolorized with activated carbon affording 1-(2-hydroxy-2-methylpentan-3-yl)-1H-indole-4,5-dicarbonitrile (0.0285 g, 18% yield) as an amber film: 1H NMR (400 MHz, CDCl3) δ 7.75-7.61 (m, 2H), 7.53 (d, J=8.6 Hz, 1H), 6.88 (d, J=3.3 Hz, 1H), 4.16-4.07 (m, 1H), 2.20-2.01 (m, 2H), 1.37 (s, 3H), 1.08 (s, 3H), 0.65 (t, J=7.3 Hz, 3H); MS (LCMS ES+) m/z 268 ([M+H]+, 26%), 285 (100%), 309 ({[M+H]+MeCN}+, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10]C)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: COc1cc(Br)cn(C)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1cc(Br)cc(O)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.2 %

Procedure:
To a solution of 5-bromo-3-methoxy-1-methylpyridin-2-one (5.60 g, 25.7 mmol) stirred at 0° C. in DCM (100 mL) was added BBr3 (12.87 g, 51.4 mmol). The icebath was removed and the mixture was stirred at rt for 5 h. After the mixture was cooled to 0° C., it was quenched with MeOH (5 mL), concentrated to near dryness and purified by column chromatography on silica gel to give title compound (3 g, 57%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.49 (s, 1H), 6.80 (s, 1H), 3.44 (s, 3H). LCMS (M+H)+=205.