Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 (100 mg, 0.34 mmol) and piperidinomethyl polystyrene resin (100 mg) in 1 mL of dry CH2Cl2 was added propionyl chloride (30 μL, 1 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) propionamide 18 (85 mg, 71%). LRMS 248 (M-100)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH2:24][CH2:25][CH2:26][CH:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:22]3[CH3:21])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1NCCCC1c1ccccc1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1C(c2ccccc2)CCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2-methyl-3-phenylpiperidine (70769-67-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=442.5 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23]([O:25]CC)=[O:24])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].[ClH:34]>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:30])([F:31])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23]([OH:25])=[O:24])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[C:7]=1[Cl:34]
Reactant: Cl
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccn12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2cccn12
Yield: 65 %

Procedure:
A solution of ethyl 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylate (130 mg, 0.26 mmol) and NaOH (52 mg, 1.29 mmol) in H2O-MeOH (1:1, 20 mL) was stirred at rt for 3 h. The mixture was acidified with 2 N HCl and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to give 8-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylic acid (80 mg; yield 65%) as a yellow solid. MS: m/z=477.0 (M+1, ESI+).
Reaction SMILES: Br[CH:2]1[CH:12](Br)[CH2:11][CH:5]2[O:6][C:7]([CH3:10])([CH3:9])[O:8][CH:4]2[CH2:3]1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH3:9][C:7]1([CH3:10])[O:6][CH:5]2[CH:11]=[CH:12][CH:2]=[CH:3][CH:4]2[O:8]1
Reactant: CC1(C)OC2CC(Br)C(Br)CC2O1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC1(C)OC2C=CC=CC2O1

Procedure:
The compound obtained in Step (11) was placed in a reaction vessel, and air in the vessel was replaced with nitrogen. After that, the compound was dissolved in dehydrated toluene (116 ml). Distilled DBU (6.0 ml, 40.1 mmol) was added to the solution, and the mixture was refluxed for 6 hours. After the reaction product had been filtrated, sodium hydrogen carbonate was added to the filtrate, and the organic layer was dried over magnesium sulfate, whereby 2,2-dimethyl-3a,7a-dihydrobenzo[1.3]dioxol was obtained. The compound was used in the next reaction without being further purified.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)cc1

Procedure:
4-Fluorobenzoic acid, 14.0 g (0.1 mole) is refluxed for 30 minutes in 50 ml of thionyl chloride (SOCl2) and 1 drop of dimethylformamide (DMF). The thionyl chloride is removed under vacuum and azeotroped with 50 ml of benzene to give 4-fluorobenzoyl chloride as an oil.
Reaction SMILES: [CH2:1]([Si:3]([CH2:15][CH3:16])([CH2:13][CH3:14])[O:4][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6]#[CH:7])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:29]([SnH:33]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32]>>[CH2:38]([Sn:33]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:34][CH2:35][CH2:36][CH3:37])/[CH:7]=[CH:6]/[CH:5]([O:4][Si:3]([CH2:13][CH3:14])([CH2:1][CH3:2])[CH2:15][CH3:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:39][CH2:40][CH3:41]
Reactant: C#CC(CCCCC)O[Si](CC)(CC)CC
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCCC(/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](CC)(CC)CC
Temperature: 25 °C

Procedure:
A solution of 20 g of 3-triethylsilyloxy-1-octyne, 150 mg of azobisisobutyronitrile, and 30 ml of tri-n-butyltin hydride is magnetically stirred un er an argon atmosphere at 140° C. for 2 hours, (EXOTHERMIC), then cooled to ambient temperature. The excess tin hydride is removed by distillation (~70°/1.0 mm). The residue is purified by distillation to provide 36.5 g of the oil (bp 165° C. at 0.05 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.O[CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25].S(=O)(=O)(O)O.N>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]3[C:17]=2[CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[O:25])=[CH:6][CH:7]=1
Reactant: O=C1CCCN1CO
Reactant: Cc1ccc2nc(-c3ccc(Cl)cc3)cn2c1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2nc(-c3ccc(Cl)cc3)c(CN3CCCC3=O)n2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
An intimate mixture is prepared of 4.8 g (0.02 mol) of 2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridine and 2.53 g (0.022 mol) of N-hydroxymethyl-2-pyrrolidinone, and this is then introduced into 20 ml of concentrated sulphuric acid. The solution is stirred for one day at room temperature, then poured into 800 ml of water, and 55 ml of ammonia solution are added. The lactam is extracted with methylene chloride, the organic phase is washed, dried and evaporated, and the residue is purified by chromatography, eluting with a 70:30 ethyl acetate, toluene mixture. The white solid obtained melts at 186°-187.5° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.[F:8][C:9]1[C:37]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:36][C:12]2[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][C:11]=2[CH:10]=1>ClCCl>[CH:1]1([CH2:4][C:5]([N:41]2[CH2:42][CH2:43][N:38]([C:37]3[C:9]([F:8])=[CH:10][C:11]4[N:15]=[C:14]([CH2:16][O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:13]([CH2:24][C:25]5[CH:26]=[CH:27][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=5)[C:12]=4[CH:36]=3)[CH2:39][CH2:40]2)=[O:7])[CH2:2][CH2:3]1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Reactant: O=C(O)CC1CC1
Solvent: ClCCl
Product: O=C(CC1CC1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
0.020 ml of cyclopropyl-acetic acid (0.2 mmol) and 40 mg of 1′1-carbonyldiimidazole (0.24 mmol) were refluxed in 4 ml dichloromethane under nitrogen for 40 minutes. 100 mg 5-Fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.2 mmol) were added and the resulting mixture refluxed for additional 26 h. The reaction mixture was then diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 129 mg yellow solid. This residue was purified by column chromatography (24 g silicagel, dichloromethane/methanol 24:1) leading to 77 mg light yellow solid (63%). MS (ISP) 583.3 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O.[CH:32]([C:35]1[CH:41]=[CH:40][CH:39]=[C:38]([CH:42]([CH3:44])[CH3:43])[C:36]=1[NH2:37])([CH3:34])[CH3:33]>CN(C=O)C>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:37][C:36]1[C:38]([CH:42]([CH3:43])[CH3:44])=[CH:39][CH:40]=[CH:41][C:35]=1[CH:32]([CH3:34])[CH3:33])=[O:31]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CCCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.1 %

Procedure:
2 N Jones' reagent (20 ml) was gradually and dropwise added to an acetone (20 ml) solution of 7-bromoheptanol (1.95 g, 10 mmols) with cooing with ice, and then stirred at room temperature for 10 minutes. The reaction mixture was extracted three times with ether (80 ml). The organic layer was washed with water, and then extracted three times with an aqueous saturated solution of sodium hydrogencarbonate (120 ml). The aqueous layers were combined, then made acidic (pH=1) with 5% sulfuric acid added thereto, and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. 1.45 g (70%) of 7-bromoheptanoic acid was obtained as colorless needle-like crystals. WSC (891 mg, 4.7 mmols) and HOBt (628 mg, 4.1 mmols) were added to a DMF (20 ml) solution of the resulting carboxylic acid (1.06 g, 5 mmols) and 2,6-diisopropylaniline (738 mg, 4.2 mmols), and stirred at room temperature for 12 hour. The reaction mixture was extracted with ether. The organic layer was washed with water, 1N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated Then, the residue was purified through silica gel colt chromatography (developer:hexane/acetone=5/1), and the resulting crystals ware recrystallized from ether-hexane to obtain 466 mg (yield: 30%) of 7-bromo-N-(2, 6-diisopropylphenyl) heptanamide as colorless needle-like crystals.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.S(Cl)([Cl:12])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH:1]1([C:7]([Cl:12])=[O:9])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CC=CCC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)C1CC=CCC1
Yield: 84.4 %

Procedure:
An acid chloride was prepared as follows: anhydrous 3-cyclohexenecarboxylic acid (50 g, 0.4 mol) was placed in a 500 mL round-bottom flask and a few drops of N,N-dimethylformamide was added as a catalyst. To this was added dropwise thionyl chloride (58.4 mL, 0.8 mol), diluted with anhydrous toluene (50 mL), at room temperature and the reaction mixture was refluxed for 4 hours. The final product was fractionally distilled to yield 48.8 grams of 3-cyclohexenecarboxylic acid chloride at a yield of 85%.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]([F:20])([F:19])[CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>CC(C)=O>[Br:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]([F:19])([F:20])[CH:9]2[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)=[CH:5][CH:4]=1
Reactant: FC(F)(Oc1ccc(Br)cc1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(C(F)(F)Oc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4 N HCl (4.23 mL, 16.9 mmoles) was added to a solution of 8-((4-bromophenoxy)difluoromethyl)-1,4-dioxaspiro[4.5]decane (1230 mg, 3.387 mmoles) in acetone (11.3 mL, 0.3M) and was allowed to stir overnight at room temperature. The reaction mixture was concentrated onto silica gel and purified via chromatography (9:1 heptane:ethyl acetate to 3:7 heptane:EtOAc over 40 minutes followed by 100% EtOAc for 10 minutes) afforded the desired material (1081 mg, 97.13%). 1H NMR (400 MHz, METHANOL-d4) 6 ppm 1.27 (br. s., 2H) 1.39-1.51 (m, 2H) 1.96-2.10 (m, 5H) 3.32-3.38 (m, 0H) 3.47-3.55 (m, 1H) 7.05-7.13 (m, 2H) 7.45-7.53 (m, 2H)
Reaction SMILES: [O:1]1[CH2:7][CH2:6][C:5]([C:8](O)=[O:9])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.S(Cl)([Cl:17])=O>O1CCCC1>[O:1]1[CH2:7][CH2:6][C:5]([C:8]([Cl:17])=[O:9])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: O=C(O)C1=Cc2ccccc2OCC1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)C1=Cc2ccccc2OCC1
Reaction time: 2 h

Procedure:
2,3-Dihydro-benzo[b]oxepine-4-carboxylicacid (2.3 mmol) was dissolved in 15 ml tetrahydrofuran. 0.7 ml of thionylchloride were added dropwise and the solution was stirred for two hours. The reaction was quenched by methanol. Methanol and thionylchloride were removed in vacuo yielding 340 mg of 2,3-Dihydro-benzo[b]oxepine-4-carbonylchloride. This was used for step E without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=CC=2F)=[CH:10][C:9]=1[NH:22][C:23](=[O:38])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[CH:27]=1)(C)(C)C.[C:40](O)([C:42]([F:45])(F)F)=O>C(Cl)Cl>[F:45][C:42]1[CH:40]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[N:33]4)[CH:27]=3)[CH2:24][C:23](=[O:38])[NH:22][C:9]=2[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(-c3cc(F)ccc3F)cc2N1

Procedure:
Prepared from {2′,5′-difluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K93) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (67 mg).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:23])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH3:22])=[N:8]1.[Br:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>O1CCCC1>[Br:24][C:25]1[CH:26]=[C:27]([CH2:28][CH2:22][C:13]2[CH:14]=[C:15]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:17][C:12]=2[C:9]2[O:10][CH2:11][C:7]([CH3:23])([CH3:6])[N:8]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: BrCc1cccc(Br)c1
Reactant: Cc1cc(C(F)(F)F)ccc1C1=NC(C)(C)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(C(F)(F)F)cc2CCc2cccc(Br)c2)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
n-Butyllithium (1.6 ml of a 2.5M solution in hexanes) was added to the product of step (ii) (0.59 g) in tetrahydrofuran (15 ml) at -65° C. After 1.5 hours 3-bromobenzyl bromide (1.0 g) in tetrahydrofuran (6 ml) was added. The reaction was stirred at room temperature for 2 hours, partitioned between brine and ethyl acetate, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 10% ethyl acetate in isohexane. Yield 0.44 g.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C@@H:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[N:47]([CH3:51])[N:46]=[C:45]2[C:52]1[N:53]=[C:54]2[C:60]([C:61](O)=[O:62])=[CH:59][N:58]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:55]2=[N:56][CH:57]=1>CN(C=O)C>[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[N:47]([CH3:51])[N:46]=[C:45]2[C:52]1[N:53]=[C:54]2[C:60]([C:61]([NH:25][C@@H:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:62])=[CH:59][N:58]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:69])([CH3:71])[CH3:70])[C:55]2=[N:56][CH:57]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)O)cn3COCC[Si](C)(C)C)nn2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)N[C@@H]1CCOC[C@@H]1NC(=O)OC(C)(C)C)cn3COCC[Si](C)(C)C)nn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (80.5 mg, 212 μmol.20) and tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (prepared as described in WO2010/97248 A1, 2010; 38.1 mg, 176 μmol) then 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 176 mmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (60 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to yield tert-butyl (3R,4R)-4-(2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)tetrahydro-2H-pyran-3-ylcarbamate (115 mg, 176 μmol, 100%) as a very light yellow solid. MS (M+Na)+=674 (>90% purity); 1H NMR (CDCl3) δ: 9.29 (s, 1H), 8.51 (d, J=9.1 Hz, 1H), 8.37 (s, 2H), 7.48 (d, J=9.1 Hz, 1H), 7.31 (dd, J=9.1, 3.0 Hz, 1H), 6.27 (d, J=10.2 Hz, 1H), 5.75 (s, 2H), 4.59-4.81 (m, 1H), 4.18-4.36 (m, 4H), 3.91-4.16 (m, 5H), 3.54-3.81 (m, 4H), 2.33 (qd, J=12.7, 4.9 Hz, 1H), 1.89 (d, J=13.2 Hz, 1H), 0.93-1.12 (m, 2H), 0.82 (s, 9H), 0.00 (s, 9H).
Reaction SMILES: N1C2C(=NC=CC=2)N([N:10]2[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:13]([CH3:27])[C:12]([C:28]([O-])=[O:29])=[C:11]2[CH3:31])N=1.CCN(C(C)C)C(C)C.[NH2:41][C@H:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]1[OH:48]>CN(C=O)C>[OH:48][C@H:43]1[CH2:44][CH2:45][CH2:46][CH2:47][C@@H:42]1[NH:41][C:28]([C:12]1[C:13]([CH3:27])=[C:14](/[CH:15]=[C:16]2\[C:17](=[O:26])[NH:18][C:19]3[C:24]\2=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[NH:10][C:11]=1[CH3:31])=[O:29]
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Reactant: N[C@H]1CCCC[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)N[C@H]1CCCC[C@@H]1O
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To the solution of A4 (100 mg, 0.24 mmol) and DIEA (140 mg, 0.96 mmol) in 10 mL of DMF, was added (1S,2S)-2-Amino-cyclohexanol (45 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for several hours. LC/MS was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (25 mL) under sonication. The solid was collected by filtration and washed with methanol), dried under vacuum to provide to provide title compound (70 mg, 74% yield) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.62 (s, 1H), 10.88 (s, 1H), 7.71-7.77 (m, 2H), 7.36-7.39 (d, 1H), 6.81-6.95 (m, 2H), 4.58-4.60 (d, 1H), 3.48-3.60 (m, 1H), 3.30-3.35 (m, 1H), 2.41-2.44 (ds, 6H), 1.88-1.90 (t, 2H), 1.62 (S, 2h), 1.23 (s, 4H). LC/MS: 398.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([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>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:19]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1
Reactant: Fc1cnc2[nH]nc(Br)c2c1
Reactant: Clc1ccccc1C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine, 4, (0.97 g, 4.49 mmol) and K2CO3 (1.86 g, 13.47 mmol) in DMF (9.7 mL) was cooled to 0° C. Chlorodiphenylmethylbenzene (1.38 g, 4.94 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with 40 mL of ethyl acetate and washed with 30 mL of water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (40% ethyl acetate/hexanes) to afford 1.68 g of the desired product as a white solid: 1H NMR (300 MHz, d6-DMSO) δ 8.45-8.38 (m, 1H), 8.04 (dd, J=8.0, 2.7 Hz, 1H), 7.35-7.16 (m, 15H); LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, Retention Time=3.03 min, (M+H) 459.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:25])[NH:11][N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.I[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.N>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([N:11]2[C:10](=[O:25])[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:13]=[N:12]2)=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Cc2ccc(F)cc2)cc1
Reactant: Fc1ccc(I)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 62, starting with 4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and reacting with 1-iodo-4-fluorobenzene (yield: 0.0881 g, 78%). mp 175–177° C. 1H NMR (300 MHz, DMSO d6) δ 3.27–3.36 (3H, obstructed by H2O), 3.88 (bs, 2H), 6.98–7.09 (m, 4H), 7.34 (m, 2H), 7.65 (m, 2H), 7.71 (m, 2H), 8.06 (m, 3H). MS (DCI/NH3) m/z 453 (M+H)+, 470 (M+NH4)+. Anal. calc. for C24H18F2N2O3S: C, 63.71; H, 4.01; N, 6.19. Found: C, 63.61; H, 4.26; N, 6.03.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.CS(O[CH:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1)(=O)=O>CN(C=O)C.O>[Br:7][C:8]1[CH:9]=[N:10][N:11]([CH:18]2[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:12]=1
Reactant: CCOC(=O)C1CCC(OS(C)(=O)=O)CC1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(n2cc(Br)cn2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Cesium carbonate (1.96 g, 6 mmol) and 4-bromopyrazole (321 mg, 2.2 mmol) were added to a solution of ethyl 4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (0.50 g, 2 mmol) in DMF (10 mL). The mixture was stirred at 80° C. for 16 hours. Upon cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give ethyl 4-(4-bromo-1H-pyrazol-1-yl)cyclohexanecarboxylate. MS ESI calc'd. for C12H18BrN2O2 [M+H]+ 301 and 303. found 301 and 303. 1H NMR (400 MHz, CDCl3): δ 7.45 (s, 1H), 7.44 (s, 1H), 4.23 (q, J=7.2 Hz, 2H), 2.46-2.38 (m, 1H), 2.26-2.18 (m, 4H), 2.06-1.98 (m, 2H), 1.86-1.78 (m, 3H), 1.36 (t, J=7.2 Hz, 3H).