Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:16]([OH:19])(=O)=[O:17])=[O:6].P(Cl)(Cl)([Cl:22])=O>CO>[CH3:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:16]([Cl:22])(=[O:19])=[O:17])=[O:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 17.3 g (0.27 mol) of potassium hydroxide (88% strength) and 100 ml of methanol is added carefully with vigorous stirring to a solution of 70.9 g (0.27 mol) of 2-methoxycarbonyl-5-nitrobenzenesulfonic acid in 300 ml of methanol. The mixture is cooled to 0° C. and the salt which is precipitated is filtered off, dried and then suspended in 150 ml of sulfolane, 150 ml of acetonitrile and 10 ml of dimethylformamide. After the dropwise addition of 100 ml (1.07 mol) of phosphorus oxychloride, the mixture is heated at boiling for 2.5 h. The reaction mixture is then poured into ice-water. The 2-methoxycarbonyl-5-nitrobenzenesulfonyl chloride (60.1 g, 70% of theory) which has precipitated is filtered off with suction through a Buchner funnel and freed from traces of solvent under reduced pressure. Melting point: 86°-88° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.Cl.O1CCOCC1>C(O)(C)C>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(O[C@H]2CC[C@H](N3CCCC3)CC2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1c(O[C@H]2CC[C@H](N3CCCC3)CC2)ccc2[nH]ncc12

Procedure:
A mixture of 4-methyl-5-[(trans-4-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole (62.1 mg, 0.162 mmol), a 4N-hydrochloric acid/dioxane solution (2.0 ml) and isopropanol (2.0 ml) was stirred at room temperature for 4 hours. The solvent was distilled off and a 1N-aqueous sodium hydroxide solution (20 ml) was added to the residue, followed by extraction with ethyl acetate (20 ml) (twice). The extract solution was dried over magnesium sulfate and then concentrated to dryness, and the residue oil was purified by elution by a silica gel column chromatography (hexane/ethyl acetate/triethylamine=20:40:3) to obtain 4-methyl-5-[(trans-4-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazole (28.3 mg, 58%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][C:17]=2[N:18]=1.[F:29][C:30]([F:47])([F:46])[C:31](=[O:45])[CH2:32][C:33]([C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[O:43][CH3:44])([CH3:35])[CH3:34]>C1COCC1>[F:47][C:30]([F:29])([F:46])[C:31]([CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][C:17]=2[N:18]=1)([OH:45])[CH2:32][C:33]([C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[O:43][CH3:44])([CH3:35])[CH3:34]
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: Cc1nc2cc(-c3ccccc3)ccc2o1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1nc2cc(-c3ccccc3)ccc2o1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
n-Butyl lithium (0.246 mL, 1.6 M in hexanes) was added to a solution of diisopropyl amine (0.055 mL, 0.45 mmol) in anhydrous THF (5 mL) at 0° C. The reaction mixture was cooled to −78° C. and stirred for 15 minutes. 2-Methyl-5-phenyl benzoxazole (75 mg, 0.4 mmol) dissolved in anhydrous THF (2 mL) was added to this mixture dropwise. After the addition, the reaction mixture was stirred for 15 to 30 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (100 mg, 0.4 mmol) was added as a solution in anhydrous THF (2 mL) in one portion, the cold bath was removed and the reaction was stirred at room temperature for 12 hours. THF was evaporated under reduced pressure. Water (2 mL) was added to the residue and the mixture was extracted with three 5 mL portions of EtOAc. The extract was dried over magnesium sulfate. After evaporation, the residue was chromatographed on a silica gel column to provide 150 mg of the title compound as white crystals, m.p. 103° C.-104° C.
Reaction SMILES: C[NH:2][C:3](=[NH:5])S.OS(O)(=O)=O.[OH-].[K+].[C:13]([CH2:21][C:22]([O:24]CC)=O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[NH2:5][C:3]1[O:20][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:21][C:22](=[O:24])[N:2]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CNC(=N)S
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(=O)cc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
To 9.45 g (0.034 M) of methylthiopseudourea H2SO4 is added 40.0 ml of H2O+8.0 g (0.142 M) of KOH. With vigorous stirring, 12.0 g (0.0625 M) of ethyl benzoylacetate (Aldrich) is also added and the heterogenous mixture allowed to stir at ambient temperature for 18 hours. The resulting solids are filtered and washed very well with H2O followed by ether. The solids are dried at 60° C. in a vacuum oven to yield 7.20 g (61.3 percent) of 2-amino-6-phenyl-1,3-oxazine-4-one. An analytical sample is recrystallized from 95 percent EtOH:DMF to yield 2-amino-6-phenyl-1,3-oxazine-4-one (m.p. 244-246 d).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(C[AlH]CC(C)C)C.Cl[Si:18]1([CH3:22])[CH2:21][CH2:20][CH2:19]1.O>CCCCCC>[CH3:22][Si:18]1([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:21][CH2:20][CH2:19]1
Reactant: C[Si]1(Cl)CCC1
Reactant: C#CCCCCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: O
Product: CCCCCC#C[Si]1(C)CCC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 4 %

Procedure:
To a solution of 1-heptyne (2.62 mL, 1.91 g, d=0.7328, 20.0 mmol) in n-hexane (7 mL) was added a solution of DIBAL-H (20 mL, 1.0 M in n-hexane, 20.0 mmol 1.0 equiv) at −78° C. The reaction mixture was heated at 50° C. for 2 h, then was cooled to 0° C. 1-Chloro-1-methylsilacyclobutane (2.41 g, 20.0 mmol, 1.0 equiv) was added dropwise with syringe to the reaction mixture at 0° C., which was stirred for 48 h at 50° C. Cold water (1.28 mL, 71 mmol, 3.5 equiv) was added to the action solution carefully at 0° C. The resulting white suspension was filtered through Celite and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (SiO2, pentane) and distillation to afford 2.96 g (81%) of (E)-1 as a colorless oil. 1-Methyl-(1-heptynyl)silacyclobutane (145 mg, 8%) was also isolated after column chromatography.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[C:17]([O:21][C:22]([N:24]1[CH2:31][CH:30]2[O:32][CH:26]([CH2:27][NH:28][CH2:29]2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH:26]2[O:32][CH:30]([CH2:29][N:28]([CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=3)(=[O:8])=[O:7])[CH2:27]2)[CH2:31]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: N#Cc1ccc(S(=O)(=O)NCCCBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCCNS(=O)(=O)c3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A suspension of N-(3-Bromo-propyl)-4-cyano-benzenesulfonamide (6.39 g, 0.021 mol; see step (i) above), 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4.32 g, 0.0189 mol see WO 01/28992) and dry K2CO3 (10.16 g, 0.0735 mol) in dry acetonitrile (70 ml) was stirred at 60° C. overnight under N2 atmosphere. The reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 50% ethyl acetate in petroleum ether, as eluent to give the sub-title compound (4.29 g) as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[C:4]#[N:5].C(Cl)(Cl)(Cl)[Cl:19].ClN1C(=O)CCC1=O.O>CCOCC>[CH3:1][CH:2]([CH3:17])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][C:8]=1[Cl:19])[C:4]#[N:5]
Reactant: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1Cl
Reaction time: 48 h

Procedure:
To a solution of 484 mg (2 mmol) of 3-methyl-2-(4-trifluoromethylphenylamino)butyronitrile (III; R is hydrogen) in 5 ml. of carbon tetrachloride is added 267 mg. (2 mmol) of N-chlorosuccinimide. The mixture is heated at 65°. After about 48 hours, the mixture is poured into water and ether. The organic fraction is separated, washed with water, and brine, dried over sodium sulfate, and solvent removed to give 3-methyl-2-(2-chloro-4-trifluoromethylphenylamino)butyronitrile (III; R is chloro).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:19])[C:16]([OH:18])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[C:20]([NH:24][C:16](=[O:18])[C:15]([NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:13][CH:12]=[N:11][CH:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:19])([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1cc(NC(=O)C(=O)O)ccc1-c1cnco1
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)C(=O)NC(C)(C)C)ccc1-c1cnco1
Yield: 34.7 %

Procedure:
A solution of 26 mg (0.1 mmol) of N-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamic acid, 15 mg (0.2 mmol) of tertiary butylamine, 28 mg (0.15 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 15 mg (0.11 mmol) of 1-hydroxy-7-azabenzotriazole in 1 ml of dimethylformamide was stirred at room temperature for 4 hours then diluted with ethyl acetate and washed with 2M hydrochloric acid, saturated sodium bicarbonate and water. The resulting solution was dried over magnesium sulphate and evaporated to dryness. The residue was triturated with diethyl ether/petrol (1:1) and collected by filtration to give 11 mg of N-tert-butyl-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a white solid. MS: m/e 318.0 [M+H]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:7](O)[CH2:8][OH:9].S(=O)(=O)(O)O>ClCCl>[C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: OCCO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)C(=O)OCCO
Temperature: 80 °C

Procedure:
To a suspension of isobutyric acid (5 g, 0.056 mol) and ethylene glycol (15.8 g, 0.283 mol.) was added dropwise Sulfuric acid (cat. 0.4 mL). The resulting mixture was heated at 80° C. for 4 hrs. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was then cooled down to rt, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give 2-hydroxyethyl isobutyrate isolated as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C@H:7]([CH2:12][OH:13])[CH2:8][CH2:9][CH2:10]Cl)=[N+:2]=[N-:3].[CH3:22]OS(OC)(=O)=O>CN(C=O)C>[N:1]([CH2:4][C@@H:5]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C@H:7]1[CH2:8][CH2:9][CH2:10][O:13][CH2:12]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@H](CO)CCCCl
Reactant: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
The tert-butyl (2S,4R)-1-azido-7-chloro-4-(hydroxymethyl)heptan-2-ylcarbamate (1.59 g, 4.97 mmol, 1.0 equiv) was dissolved in 15 mL of DMF and the solution cooled to 0° C. A solution of NaNTMS2 (1.0 M, 14.9 mmol, 3.0 equiv) was added via syringe at such a rate that the internal reaction temperature remains below 5° C. After stirring for 2 h LC/MS analysis showed formation of the cyclised product. Dimethylsulfate (940 mg, 0.71 mL, 7.5 mmol, 1.5 equiv) was added and the reaction mixture stirred overnight with concomitant warming to ambient temperature. LC/MS analysis showed formation of the desired methylated carbamate. The reaction was quenched by addition of 10% K2CO3 solution (˜30 mL) and the mixture stirred for 0.5 h. The volatile materials were removed in vacuo and the residue partitioned between EtOAc/water. The layers were separated and the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. The product was purified by flash chromatography on silica (40 g), eluting with 0-7% EtOAc in hexanes. This afforded 1.21 g (82% yield) of the desired tert-butyl (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate as a colorless liquid.
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[C:23]([OH:30])=[CH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])([CH3:4])([CH3:3])[CH3:2].[Br:33]N1C(=O)CCC1=O.O>ClCCl>[Br:33][CH:24]([C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C:23]([C:8]1[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:12][C:7]=1[O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:32])[CH3:31])=[O:30]
Reactant: COc1ccc(COc2ccc(C(O)=CC(=O)C(C)C)c(O[Si](C)(C)C(C)(C)C)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C(=O)C(Br)C(=O)C(C)C)c(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[2-(tert-Butyl-dimethyl-silanyloxy)-4-(4-methoxy-benzyloxy)-phenyl]-1-hydroxy-4-methyl-pent-1-en-3-one (5.81 g, 12.72 mmol) is dissolved in dry dichloromethane (100 ml) at room temperature. N-bromosuccinimide (2.38 g, 13.36 mmol) is added portionwise. The reaction mixture is stirred at room temperature for 30 minutes, poured into water (200 ml) and extracted with dichloromethane (3×75 ml). The dichloromethane extracts are combined, washed with saturated brine (100 ml), dried (MgSO4), filtered and evaporated to give a pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[C:9]1(N)[C:14]([F:15])=[C:13](F)[C:12](F)=[C:11]([NH2:18])[C:10]=1F.Cl.Cl>>[F:15][C:14]1[CH:9]=[CH:10][C:11]2[NH:18][C:3]3[CH2:8][CH2:7][N:6]([CH2:2][CH2:1][C:3]4[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=4)[CH2:5][C:4]=3[C:12]=2[CH:13]=1
Reactant: C=Cc1ccncc1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: Fc1ccc2[nH]c3c(c2c1)CN(CCc1ccncc1)CC3

Procedure:
The title compound was prepared following the procedure of Example 2 with the exception 4-vinylpyridine was used instead of 2-vinylpyridine. The product was converted to the dihydrochloride salt; mp. 233°-235° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12](/[C:17](/[C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:18]/[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:13][C:14]=1[O:15][CH3:16]>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12](/[C:17](/[C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[CH:18]/[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:13][C:14]=1[O:15][CH3:16]
Reactant: COc1nc(/C(=C/C2CCCC2)c2ccc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1nc(/C(=C/C2CCCC2)c2ccc(S(=O)(=O)N3CCNCC3)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (0.2 mL) was added to a solution of tert-butyl 4-({4-[(E)-1-(5-chloro-6-methoxypyridin-2-yl)-2-cyclopentylethenyl]phenyl}sulfonyl)piperazine-1-carboxylate (178 mg) in chloroform (3 mL), and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure to give 1-({4-[(E)-1-(5-chloro-6-methoxypyridin-2-yl)-2-cyclopentylethenyl]phenyl}sulfonyl)piperazine as a crude product.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26](O)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:31][CH2:32][C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]3[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]3)[CH:40]=2)[CH:36]=[CH:37][CH:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]6[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)NCc2cccc(-c3cccc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acid (100 mg, 0.241 mmol), 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperidinecarboxylate (70.9 mg, 0.241 mmol), HBTU (110 mg, 0.289 mmol) and Et3N (0.101 mL, 0.722 mmol) in DCM (3 mL) was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were dried under GeneVac and then combined to give the intermediate 1,1-dimethylethyl 4-[(3′-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperidinecarboxylate. It was then dissolved in 2 mL of 25% TFA in DCM and stirred at room temperature for 3 h. The crude products were purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and washed with 1 N NaOH and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-{[3′-(4-piperidinylmethyl)-3-biphenylyl]methyl}-1,1-cyclopropanedicarboxamide as a solid (32 mg, 19.6%). LC-MS m/z 678 (M+H)+, 0.79 min (ret time).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[C:12]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=2[F:35])=[C:13]([F:26])[C:14]2[N:15]([C:17]([C:20]#[C:21][Si](C)(C)C)=[CH:18][N:19]=2)[CH:16]=1)=[O:10]>CO.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C:12]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=2[F:35])=[C:13]([F:26])[C:14]2[N:15]([C:17]([C:20]#[CH:21])=[CH:18][N:19]=2)[CH:16]=1)=[O:10]
Reactant: COC(=O)c1cn2c(C#C[Si](C)(C)C)cnc2c(F)c1Nc1ccc(C)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cnc2c(F)c(Nc3ccc(C)cc3F)c(C(=O)OC)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Potassium carbonate (70 mg, 0.51 mmol) was added to a solution of 8-fluoro-7-(2-fluoro-4-methyl-phenylamino)-3-trimethylsilanylethynylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester in MeOH (5 mL) and stirred at room temperature for two hours. The mixture was diluted with ethyl acetate, washed with brine (2×), dried over Na2SO4 and concentrated to a brown residue. Flash column chromatography (dichloromethane to 80:1 dichloromethane/MeOH) provided the desired product (16 mg, 65%) as a yellow liquid. MS APCI (+) m/z 342 (M+1) detected.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:15])([F:14])[CH:11]1[O:13][CH2:12]1>>[C:2]1([CH2:1][N:8]([CH2:12][CH:11]([OH:13])[C:10]([F:15])([F:14])[F:9])[CH2:12][CH:11]([OH:13])[C:10]([F:15])([F:14])[F:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: FC(F)(F)C1CO1
Product: OC(CN(Cc1ccccc1)CC(O)C(F)(F)F)C(F)(F)F
Temperature: 80 °C
Yield: 57.8 %

Procedure:
Benzylamine (1.5 eq, 2.88 g, 2.94 mL, 26.8 mmol) was combined with 3,3,3-trifluoro-1,2-epoxypropane (2.0 g, 17.86 mmol) in a sealed glass tube and heated at 80° C. for 18 h. Upon cooling to room temperature, the reaction mixture formed a slushy white solid. The solid was collected by filtration and washed with diethyl ether. The mother liquor was concentrated in vacuo to give 1.71 g (43%) of the desired 1,1′-[(phenyl-methyl)imino]bis[3,3,3-trifluoro-2-propanol] product as a colorless oil. FABMS m/z=332 [M+H]+. 1H NMR (CDCl3) δ 2.85-2.96 (m, 4H), 3.94 (s, 2H), 3.94-3.97 (m, 2H), 7.24-7.37 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:19]=3)[N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=1)[CH2:5]2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:28])=[O:29])=[CH:25][CH:26]=4)[N:19]=3)[NH:14][CH:13]=1)[CH2:5]2
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cc(Br)ccc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(N4Cc5cc(Br)ccc5C4=O)c3n2)cc1
Reaction time: 8 h
Yield: 50.1 %

Procedure:
5-bromo-2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]isoindolin-1-one (50 mg, 0.06634 mmol) suspended in DCM (2 mL) under N2 and triethylsilane (53 μL, 0.3317 mmol) then TFA (300 μL, 3.894 mmol) added. RM stirred overnight then concentrated. Residue partitioned between DCM and saturated NaHCO3 solution. Organic phase washed with brine then dried and concentrated to a yellow solid. Dried at 60° C. in a vacuum oven to give title compound as a pale yellow solid (17 mg, 49%); 1H NMR (400 MHz, DMSO) δ1.22 (6H, d), 3.50 (1H, sep), 5.54 (2H, s), 7.77 (2H, s), 7.99 (2H, d), 8.08 (1H, s), 8.51-8.55 (3H, m), 9.11 (1H, s), 12.36 (1H, brs) ppm; MS (ES+) 512.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][N:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([Cl:34])[CH:28]=1>>[Cl:34][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][NH:24][C:2]2[N:7]=[C:6]([C:8]3[CH:23]=[CH:22][CH:21]=[C:10]([CH2:11][NH:12][CH2:13][CH2:14][C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:32]=[CH:31][C:30]=1[OH:33]
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: Clc1nccc(-c2cccc(CNCCc3cccnc3)c2)n1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CNCCc4cccnc4)c3)n2)cc1Cl

Procedure:
Intermediate 172 from above was coupled with 4-(2-aminoethyl)2-chlorophenol following procedure F. LC-MS showed the product had the expected M+H+ of 460 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.50-8.43 (m, 2H) 8.29 (d, 1H) 8.21 (s, 1H), 8.1 (d, 1H), 7.7 (d, 1H) 7.63-7.55 (m, 2H), 7.42-7.38 (m, 1H), 7.19 (d, 1H) 7.09 (d, 1H), 6.99 (d, 1H), 6.8 (d, 1H), 4.2 (s, 2H), 3.6 (t, 2H), 3.3 (t, 2H), 3.0 (t, 2H), 2.8 (t, 2H).