Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.C([O-])(=O)C.[Na+].[C:13]([C:15]1[CH:16]=C([CH:21]=[CH:22][CH:23]=1)C(N)=O)#[N:14].[N]=O.[N+]([O-])=O>C(O)(=O)C>[C:13]([C:15]1[CH:16]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:5]([OH:4])=[O:7])#[N:14]
Reactant: N#Cc1cccc(C(N)=O)c1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=[N+][O-]
Agent: [N]=O
Solvent: CC(=O)O
Product: N#Cc1cccc(C(=O)O)c1
Reaction time: 4 h
Yield: 94 %

Procedure:
Acetic acid (30 ml), acetic anhydride (70 ml), sodium acetate (6.2 g), and m-cyanobenzamide (5.0 g) were mixed with stirring under cooling with ice, to thereby obtain a mixture. The mixture was allowed to react while the mixed gas of nitrogen monoxide and nitrogen dioxide (volume ratio 1:1) was introduced thereto at 286 N ml/minute for four hours. The residual solvent was removed through distillation in vacuum, and water was added to the residue, to thereby form crystals. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 4.78 g of m-cyanobenzoic acid (yield 94%, based on m-cyanobenzamide). The m-cyanobenzoic acid obtained had a purity of 98%.
Reaction SMILES: [O:1]=[C:2]1[N:13]([CH:14]2[CH:21]3[CH2:22][C:17]4([C:24](O)=[O:25])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3]1.Cl.[NH2:28][CH2:29][C:30]#[N:31].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(OCC)(=O)C>[C:29]([CH2:30][NH:31][C:24]([C:17]12[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:23][CH:15]([CH:14]3[N:13]3[C:5]4=[C:6]5[CH:12]=[CH:11][NH:10][C:7]5=[N:8][CH:9]=[C:4]4[NH:3][C:2]3=[O:1])[CH2:16]1)[CH2:18]2)=[O:25])#[N:28]
Reactant: N#CCN
Reactant: O=C(O)C12CC3CC(C1)C(n1c(=O)[nH]c4cnc5[nH]ccc5c41)C(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCNC(=O)C12CC3CC(C1)C(n1c(=O)[nH]c4cnc5[nH]ccc5c41)C(C3)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
4-(2-Oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)adamantan-1-carboxylic acid (50 mg) was suspended in N,N-dimethyl formamide (1 ml). To the suspension were added aminoacetonitrile hydrochloride (17 mg), 1-hydroxybenzotriazole (28 mg), diisopropylethylamine (62 μl), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (41 mg) successively, and the mixture was stirred overnight at ambient temperature. To the reaction solution were added ethyl acetate and water, and the organic layer was extracted. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain N-(cyanomethyl)-4-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)adamantan-1-carboxamide (23 mg).
Reaction SMILES: CC([O-])(C)C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:50]1[C:55]([NH:56][C:57](=[O:63])OC(C)(C)C)=[C:54]([CH3:64])[CH:53]=[CH:52][N:51]=1.[CH3:65][Si:66]([CH3:89])([CH3:88])[CH2:67][CH2:68][O:69][CH2:70][N:71]1[C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][C:74]=2[N:73]=[C:72]1[O:80][C:81]1[CH:87]=[CH:86][C:84]([NH2:85])=[CH:83][CH:82]=1>C1(C)C=CC=CC=1.CC(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:64][C:54]1[CH:53]=[CH:52][N:51]=[C:50]2[N:85]([C:84]3[CH:83]=[CH:82][C:81]([O:80][C:72]4[N:71]([CH2:70][O:69][CH2:68][CH2:67][Si:66]([CH3:88])([CH3:89])[CH3:65])[C:75]5[CH:76]=[CH:77][CH:78]=[CH:79][C:74]=5[N:73]=4)=[CH:87][CH:86]=3)[C:57](=[O:63])[NH:56][C:55]=12
Reactant: Cc1ccnc(Cl)c1NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOCn1c(Oc2ccc(N)cc2)nc2ccccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(Oc2nc3ccccc3n2COCC[Si](C)(C)C)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
The mixture of sodium 2-methylpropan-2-olate (0.16 g), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.054 g), tert-butyl (2-chloro-4-methylpyridin-3-yl)carbamate (0.28 g), 4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]aniline (0.41 g) and Pd2(dba)3 (0.043 g) in toluene (40 mL) and 2-propanol (10 mL) was stirred at 100° C. under N2 overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.21 g) as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]([CH2:15][CH:16]=[CH2:17])[CH3:14].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:11][N:12]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:13]([CH2:15]/[CH:16]=[CH:17]/[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1)[CH3:14]
Reactant: Brc1ccc2c(c1)OCO2
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C/C=C/c1ccc2c(c1)OCO2)N(C)C(=O)OC(C)(C)C
Temperature: 82.5 °C
Yield: 111.7 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4-bromo-1,2-(methylenedioxy)benzene (1.20 g, 5.97 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.19 g, 5.97 mmol), palladium(II) acetate (13.5 mg, 0.06 mmol), tri-o-tolylphosphine (73.1 mg, 0.24 mmol), triethylamine (1.7 mL, 11.9 mmol) and anhydrous acetonitrile (3.4 mL) was stirred and heated under reflux at 80-85° C. (oil bath temperature) for 22 h. The resulting mixture, containing brown solids, was cooled to ambient temperature, diluted with water (25 mL), and extracted with CHCl3 (3×25 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation and dried under high vacuum to produce an orange-yellow oil (2.13 g). The crude product was purified by column chromatography on silica gel (100 g), eluting with ethyl acetate-hexane (15:85, v/v). Selected fractions containing the product (Rf 0.33) were combined, concentrated by rotary evaporation and the residue was vacuum dried to give 1.08 g (56.6%) of a light-yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]C#N)=[CH:5][C:4]=1[CH:15]([CH3:17])[CH3:16].SC1C=CC=CC=1O.[OH-].[Na+].Br[CH:30]([CH2:34][CH2:35][CH2:36][CH3:37])[C:31]([OH:33])=[O:32].Cl>>[CH3:18][N:2]([CH3:1])[C:3]1[C:4]([CH:15]([CH3:17])[CH3:16])=[CH:5][C:6]([S:12][CH:30]([CH2:34][CH2:35][CH2:36][CH3:37])[C:31]([OH:33])=[O:32])=[CH:7][C:8]=1[CH:9]([CH3:11])[CH3:10]
Reactant: CCCCC(Br)C(=O)O
Reactant: CC(C)c1cc(SC#N)cc(C(C)C)c1N(C)C
Agent: Cl
Agent: Oc1ccccc1S
Agent: [Na+]
Product: CCCCC(Sc1cc(C(C)C)c(N(C)C)c(C(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the toluene solution containing the mercaptophenol prepared above 200 ml. of 20% sodium hydroxide and 7.4 grams of 2-bromo-hexanoic acid were added. The reaction mass was stirred at room temperature for about one hour. The mixture was then treated with 100 ml. of 1 N hydrochloric acid. The resulting layers were separated and the toluene was washed twice or until neutral. The organic layers were dried over Na2SO4 and evaporated to leave a light yellow oil weighing 13.4 grams which crystallized on standing. The crystals of 2-((4-(dimethylamino)-3,5-bis(1-methylethyl)phenyl)thio)-hexanoic acid were washed with cold pentane and sucked dry on a suction filter to give 3.14 grams of product. The melting point was found to be 66°-68° C. Infrared and NMR analysis confirmed the structure.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](O)=[CH:5]1)(=O)C.[N+:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(O)(=O)C>[N+:14]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)n1cc(O)c2ccccc21
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Nc2c[nH]c3ccccc23)cc1
Temperature: 25 °C

Procedure:
More in particular, to a mixture of N-acetyl-3-hydroxyindole (a) (0.114 mol, 20 g) in acetic acid (150 ml), was added 4-nitroaniline (1.5 equiv., 0.171 mol, 23.65 g). The mixture was heated at reflux for 5 hours and cooled to room temperature. An orange precipitate was filtered off and washed with isopropanol and diisopropyl ether, affording intermediate b.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([S:25]([NH2:28])(=[O:27])=[O:26])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][O:22][CH2:23][CH3:24].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][C:2]([CH3:29])([S:25]([NH2:28])(=[O:27])=[O:26])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][O:22][CH2:23][CH3:24]
Reactant: OB(O)c1ccccc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCC(C)(C)S(N)(=O)=O
Product: CCOCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)(C)S(N)(=O)=O
Yield: 20.8 %

Procedure:
Dimethyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.66 g, 1.4 mmol) and phenyl boronic acid (0.20 g, 1.6 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 14 hours, and the work-up procedure used in Part F of Examples 125-135 was followed. The crude product was recrystallized from methanol and then purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 90:10). The solid was then purified by HPFC to provide 0.14 g of dimethyl 4-[4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as Off-white needles, mp 207-208° C.
Reaction SMILES: [Li+].[AlH4-].C([O:6][C@H:7]1[CH2:11][CH2:10][C@@H:9]([CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH2:13]2)[C@:8]1([CH3:28])[CH2:24][C:25](O)=[O:26])(=O)C.[OH-].[Na+].ClCCl>CCOCC.C1COCC1>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([C@H:9]1[C@:8]([CH3:28])([CH2:24][CH2:25][OH:26])[C@@H:7]([OH:6])[CH2:11][CH2:10]1)[CH2:21][CH2:20]2
Reactant: COc1ccc2c(c1)CCC([C@@H]1CC[C@H](OC(C)=O)[C@@]1(C)CC(=O)O)C2
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC([C@@H]1CC[C@H](O)[C@@]1(C)CCO)C2

Procedure:
To a slurry of 0.420 g of lithium tetrahydro-aluminate(1-) in 400 ml of ether is slowly added, with stirring, a solution of 0.780 g of (1S,2S,5S)-2-acetoxy-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-1-methylcyclopentaneacetic acid in a mixture of 10 ml of diethyl ether and 5 ml of THF. When the addition is complete, stirring is continued at room temperature for 18 hours, whereupon 1.7 ml of aqueous 5% sodium hydroxide followed by 40 ml of dichloromethane is introduced. The resultant mixture is filtered. Solvent is stripped from the filtrate by vacuum distillation, leaving a white solid residue which, crystallized from a mixture of benzene and hexane, affords (1S,2S,5S)-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-2-hydroxy-1-methylcyclopentaneethanol melting at 151°-153° further characterized by a specific rotation of +62°.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[SH2:23]>N1C=CC=CC=1>[C:1]1([CH:7]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:8]([NH2:9])=[S:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S
Reactant: N#CC(c1ccccc1)c1cccnn1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)C(c1ccccc1)c1cccnn1
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A 1.0 g quantity (0.005 mols) of 2-phenyl-2-(3-pyridazinyl)acetonitrile was dissolved in 50 ml of dry pyridine in a sealed tube, and 4 ml of triethylamine was added. After allowing the resulting solution to stand for 1.5 hours, dry hydrogen sulfide was passed through the solution in a steady stream at room temperature for 15 minutes. The sealed mixture was then left to stand at room temperature for 24 hours. The reaction mixture was concentrated in a vacuum to give a yellow solid cake. Recrystallization of the concentrate from ethanol afforded 1.1 g (94% yield) of 2-phenyl-2-(3-pyridazinyl)thioacetamide in the form of pale yellow plates, m.p. 161° to 163° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[F:10])(=[O:3])[NH2:2].NC1C=C(C(F)=CC=1[F:36])C(N)=O.COC1C=C(B(O)O)C=CC=1OC.O.C(O)(=O)C=O>>[C:1]([C:4]1[C:9]([F:10])=[CH:8][C:7]([F:36])=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(C(Nc2ccc(F)c(C(N)=O)c2)C(=O)O)cc1OC
Reactant: NC(=O)c1cc(N)c(F)cc1F
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: COc1ccc(C(Nc2cc(C(N)=O)c(F)cc2F)C(=O)O)cc1OC
Yield: 80 %

Procedure:
23A was prepared in a procedure similar to that of 13A using 3-amino-4,6-difluorobenzamide, 3,4-dimethoxyphenylboronic acid and glyoxylic acid monohydrate. Yield: 80%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.73-3.87 (m, 6H) 5.07 (s, 1H) 6.92 (t, J=7.69 Hz, 1H) 6.96-7.13 (m, 4H), LCMS: 367 (M+1).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[F:7][CH2:8][C:9]1([CH2:23][F:24])[CH2:14][C:13](=O)[C:12]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=2[O:10]1.C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>[I-].[Zn+2].[I-].CCCCCC.C(Cl)Cl.N1C=CC=CC=1>[F:7][CH2:8][C:9]1([CH2:23][F:24])[CH:14]=[C:13]([C:5]#[N:6])[C:12]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=2[O:10]1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Agent: [I-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.52 ml of trimethylsilylcyanide and 0.82 g of zinc iodide were added to a mixture of 4.05 g of 2,2-bisfluoromethyl-3,4-dihydro-6-nitro-2H-1-benzopyran-4-one and 10 ml of dried benzene, and the mixture was stirred at room temperature for 12 hours. Further, 8 ml of pyridine and 4.41 ml of phosphorus oxychloride were added thereto, followed by heat-refluxing for 6 hours. Ice water was added to the reaction mixture which was then made acidic with hydrochloric acid, and the mixture was extracted with methylene chloride. After washing the organic layer with water and drying, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (an eluting solvent: methylene chloride:hexane=7:3) to obtain 0.99 g of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carbonitrile having a melting point of 136°-137° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C([O-])([O-])=O.[K+].[K+].O.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1>[CH2:19]([O:18][C:16]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 146 %

Procedure:
To a magnetically stirred solution of piperazin-2-one (2.0 g, 20.0 mmol) in THF (10 mL) at room temperature under Ar atmosphere, K2CO3 (8.25 g, 120 mmol), water (10 mL), and benzyl chloroformate (3.14 mL, 22.0 mmol) were added. The reaction mixture was stirred for 18 hours at room temperature. Water (50 mL) was added, and the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried with MgSO4, and concentrated in vacuo to the give the title compound (6.84 g, 100%). 1H NMR (400 MHz, CDCl3) δ 3.37 (bs, 2H), 3.68 (t, J=4.7 Hz, 2H), 4.13 (s, 2H), 5.14 (s, 2H), 7.34 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:24]1([C:30]([NH2:33])([CH3:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.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(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:33][C:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)([CH3:32])[CH3:31])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)c4ccccc4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), 2-phenylpropan-2-amine (0.05 g, 0.37 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), HATU (0.114 g, 0.3 mmol) and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF were stirred at room temperature overnight. The solvent was removed under reduced pressure at 70° C. The residue was triturated with 5 mL of water and then purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 60% acetonitrile/40% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(2-phenylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.017 g, 18%) as a yellow solid. MS: (M+H)+=445; 1H NMR (300 MHz, DMSO): δ 12.89 (s, 1H), 9.13 (s, 1H), 8.46-8.43 (m, 2H), 8.38-8.37 (m, 1H), 8.00 (s, 1H), 7.51-7.49 (m, 2H), 7.34-7.16 (m, 4H), 4.20 (s, 3H), 1.86 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8]C2C=CN=C(C3C=CC=CC=3)N=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.B(OC)(OC)OC.OO.[F:35][C:36]1[C:41]([F:42])=[C:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:39]=[CH:38][C:37]=1[C:48]1[N:53]=[CH:52][C:51]([OH:54])=[CH:50][N:49]=1>C1COCC1>[F:35][C:36]1[C:41]([F:42])=[C:40]([CH2:43][CH2:44][C@H:45]2[CH2:8][CH2:7][C@H:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:47][CH2:46]2)[CH:39]=[CH:38][C:37]=1[C:48]1[N:49]=[CH:50][C:51]([OH:54])=[CH:52][N:53]=1
Reactant: CCCCCc1ccc(-c2ncc(O)cn2)c(F)c1F
Reactant: c1ccc(-c2nccc(CCC3CCCCC3)n2)cc1
Agent: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(-c3ncc(O)cn3)c(F)c2F)CC1
Yield: 57 %

Procedure:
--Quantities bromopyrimidine 16 (3.72 g, 8.25 mmol), 1.6M butyllithium (5.7 ml, 9.1 mmol), trimethyl borate (1.9 ml, 16.5 mmol), THF (80 ml), 30% hydrogen peroxide (3.7 ml, 33 mmol). The experimental procedure was as described for compound 33. The crude product was purified by flash chromatography (10 to 30% ethyl acetate-light petroleum) to give the hydroxypyrimidine 48 (1.82 g, 57%) (from MeOH), m.p. 157.3° C.; νmax /cm-1 (KBr) 2920, 2720, 2580, 1505, 1430, 1280, 1240 and 1180 δ 0.85 (7H, m), 1.05-1.38 (10H, m), 1.50 (2H, m), 1.73 (4H, t), 2.68 (2 H, t, ArCH2), 7.01 (1H, ddd, 5'-H), 7.55 (1H, ddd, 6'-H), 8.37 (2H, s, 4- and 6-H) and 9.7 (1H, br s); m/z 388 (M+), 317 (M+ -C5H11), 235, 222 and 204.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].C([Li])(C)(C)C.CCCCC.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CCOCC>[C:19]([C:3]1[CH:4]=[C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:12])[CH3:13])[CH:8]([CH3:9])[CH3:10])[CH:17]=[CH:18][C:2]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: CC(C)[Si](Oc1ccc(Br)c(C(C)(C)C)c1)(C(C)C)C(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CCOC(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1C(C)(C)C
Temperature: 25 °C
Yield: 124.9 %

Procedure:
To a solution of (4-bromo-3-tert-butyl-phenoxy)-triisopropyl-silane (Intermediate 105, 1.00 g, 2.60 mmols) in 15 mL Et2O cooled to −78° C. was added 3.6 mL of tert-butyllithium, 1.7 M in pentane (395.0 mg, 6.2 mmols). After stirring for 30 minutes ethyl chloroformate (607.6 mg, 5.6 mmols) was added. The resulting solution was warmed to room temperature and quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the combined organic layers dried (MgSO4) concentrated under reduced pressure The residue was chromatographed (2-5% EtOAc-hexanes) to give 1.23 g (88%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:22](=[O:23])[N:16]2[CH2:17][CH:18](O)[CH2:19][CH2:20][C:15]2=[N:14]1.C(N(S(F)(F)[F:30])CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:22](=[O:23])[N:16]2[CH2:17][CH:18]([F:30])[CH2:19][CH2:20][C:15]2=[N:14]1
Reactant: C#CCOc1cc(-n2nc3n(c2=O)CC(O)CC3)c(Cl)cc1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C#CCOc1cc(-n2nc3n(c2=O)CC(F)CC3)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a solution of 169 mg (0.477 mmol) of 5,6,7,8-tetrahydro-2-[2,4-dichloro-5-(2-propynyloxy)phenyl]-6-hydroxy-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one in 5 mL of dichloromethane was added 76 μl (0.573 mmol) of diethylaminosulfur trifluoride (DAST) at 0° C. The reaction mixture was stirred at 0° C. for 1h. The mixture was then quenched with ice and extracted with dichloromethane. The organic extracts were dried (MgSO4), and then concentrated in vacuo to give a pale red solid. The crude product was purified by flash chromatography over silica gel, eluting with a 95:5 v:v mixture of dichloromethane and methanol to give 64 mg of the title product as a pale yellow foam. 19F NMR (CDCl3, 400 MHz) δ-188 ppm, 1H NMR (CDCl3, 400 MHz) δ 7.5 (s,1H), 7.1 (s,1H), 5.2 (m,1H), 4.8 (s,2H), 4.2-3.6 (m,2H), 3.2-3.0 (m,1H), 3.0-2.6 (m,1H), 2.5 (s,1H), 2.3-1.8 (m,2H).