Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:16])([O-:15])([O:3][C@H:4]1[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6])=[O:2].[K+].[Br-].CC1(C)N([O])C(C)(C)CCC1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:35].C(OO)(=O)C.[OH-].[K+]>O>[P:1]([O:3][C@H:4]1[O:12][C@H:11]([C:13]([OH:35])=[O:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6])([OH:16])([OH:15])=[O:2]
Reactant: O=P([O-])([O-])O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: CC(=O)OO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Solvent: O
Product: O=C(O)[C@H]1O[C@H](OP(=O)(O)O)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 16 h

Procedure:
1.97 g of α-Glc-1-P (2K+.C6H11O9P2−.2H2O, 5.5 mmol) was dissolved in 60 ml of water at room temperature. To this solution was added 210 mg KBr (1.76 mmol), 20 mg TEMPO (0.13 mmol), 10 mg EDTA, and 2.5 g KHCO3. Peracetic acid (10 ml, 1.69 mmol/ml) was added at a rate of 200 μl per 10 minutes. The pH was maintained at 8 by addition of 2M KOH using a pH-stat. After 16 h the reaction was complete. The product crystallized from the mixture after addition of MeOH to obtain α-D-glucopyranuronic acid 1-phosphate (3K+.C6H8O10P3−.5H2O, 1.90 g, 4.0 mmol, 73%), NMR (500 Mhz, D2O, in ppm): 1H δ 3,32 (dd, H-4J3,4=9.5 Hz, J4,5=9.9 Hz), 3.35 (m, H-2, JP,H2=1.8 Hz, J1,2=3.4 Hz, J2,3=9.5 Hz), 3.62 (dd, H-3, J2,3=9,5 Hz, J3,4 =9.5 Hz)), 3.99 (d, H-5, J4,5=9.9 Hz,), 5.30 (dd, H-1, JP,H1=7.3 Hz, J1,2=3.4 Hz), 13C δ71.4 (C-2), 71.5 (C-3,C-4), 72.4 (C-5), 93.0 (C-1), 176.6 (C-6).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[H-].[Na+].I[CH3:14]>CN(C=O)C>[CH3:14][O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of sesamol (10.0 g, 0.072 mol) in DMF (50 ml) was added sodium hydride (2.08 g, 0.087 mol) at room temperature under argon. After stirring for 1 h, the mixture was treated with iodomethane (13.5 ml, 0.216 mol) and stirred for another 18 h. Upon the removal of the solvent the residue was extracted with ethyl acetate and washed with water, dried (Na2SO4) and concentrated to afford the title compound as a dark brown oil (10.5 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([CH3:21])([CH3:20])[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.[Na].O>C(O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:11]([CH3:21])([CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:10][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:4][CH:3]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CCCO
Solvent: O
Product: CC(C)(Cc1ccc(Cl)cc1)C(O)(Cn1ccnc1)c1ccc(Cl)cc1
Yield: 30.2 %

Procedure:
30 g (0.935 mol) of 2-(4-chlorophenyl)-2-(4-chlorophenyl-tert.-butyl)-oxirane in 40 ml of n-propanol are added dropwise to a solution of 7.7 g (0.108 mol) of sodium imidazole in 60 ml of n-propanol at the reflux temperature. The reaction mixture is subsequently stirred under reflux for 48 hours and cooled, water is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. The oily residue is stirred into diisopropyl ether. The resulting crystalline precipitate is filtered off with suction and dried. 12.7 g (35% of theory) of 2,4-bis-(4-chlorophenyl)-3,3-dimethyl-1-(imidazol-1-yl)-2-butanol of melting point 174° C. are obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][C@H:3]1[C:6]([O:8][CH3:9])=[O:7].[C:10]1([CH2:16][S:17](Cl)(=[O:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:9][O:8][C:6]([C@@H:3]1[CH2:4][CH2:5][N:2]1[S:17]([CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:19])=[O:18])=[O:7]
Reactant: COC(=O)[C@@H]1CCN1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCN1S(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
(2S)-Methyl azetidine-2-carboxylate hydrochloride from Reference Example 1 (361.4 mg, 2.26 mmol, 1.0 eq) was dissolved in dry dichloromethane (10.0 mL) and treated with α-toluenesulfonyl chloride (458.1 mg, 2.40 mmol, 1.1 eq). After cooling to about 0° C. under argon atmosphere, diisopropylethylamine (420 μL, 2.41 mmol, 1.1 eq) was added and the reaction mixture was stirred at about room temperature overnight. The solvent was evaporated and the residue was subjected to flash chromatography (in dichloromethane) to give 431.2 mg (71 % yield) of the product as a colorless oil. 1H NMR (CDCl3) δ 2.29-2.51 (m, 2H); 3.21-3.29 (m,1H); 3.81 (s, 3H); 4.02 (q,1H, J=8.6); 4.32 (d, 1H, J=9.4, 6.9); 4.46 (d, 1H, J=14.6); 4.86 (dd, 1H, J=9.4, 6.9); 7.34-7.43 (m, 3H); 7.46-7.54 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=[C:6]([Cl:14])[C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:5][CH2:4][C:3]1[C:6]([Cl:14])=[CH:7][CH:8]=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:2]=1[Cl:1])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(Cl)c(CO)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Temperature: 5 °C
Yield: 94.2 %

Procedure:
To a mixture of 2,6-dichloro-3-isopropoxybenzyl alcohol (1.65 g) and triethylamine (808 mg) in dichloromethane was added methanesulfonyl chloride (884 mg) in a few minutes at 5° C. After stirring for half an hour at 5° C., the mixture was washed with diluted hydrochloric acid and then with aqueous sodium bicarbonate solution, dried, and concentrated in vacuo. The residue was crystallized from n-hexane to give 2,6-dichloro-3-isopropoxybenzyl methanesulfonate (2.07 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:18]1[O:21][CH:19]1C.C(O)CCO.C(O)(=O)CCCCC(O)=O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1.[CH2:19]1[O:21][CH2:18]1
Reactant: CC1CO1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C(O)CCCCC(=O)O
Solvent: OCCCO
Product: C1CO1

Procedure:
An adduct of bisphenol A with 2 mols of propylene oxide, 1,3-propylene glycol, terephtaric acid, and adipic acid were placed in a reaction container equipped with a thermocouple, a stirrer, a dewatering tube, and a nitrogen-introducing tube in such a manner that the molar ratio ([OH]/[COOH]) of a hydroxy group to a carboxylic group was 1.4. Diol was formed of 90% by mol of bisphenol A with 2 mols of ethylene oxide and 10% by mol of 1,3-propylene glycol. Dicarboxylic acid was formed of 80% by mol of terephtaric acid and 20% by mol of adipic acid. 500 ppm of titanium tetraisopropoxide was added to all of the monomers. Next, reaction was conducted at 230° C. for eight hours and continued with a reduced pressure of from 10 mmHg to 15 mmHG for four hours. Furthermore, trilmellitic anhydride was added to be 1% by mol to the total of monomers followed by three hour reaction at 180° C. to obtain [Linear non-crystalline polyester E-2]. [Linear non-crystalline polyester E-2] had a weight average molecular weight of 5,600 and a glass transition temperature of 61° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a light yellow solid (299 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[I:22]Cl>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([I:22])=[C:11]([CH:10]=1)[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: ClI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: OCc1cc(OCc2ccccc2)ccc1I
Reaction time: 1 h
Yield: 71 %

Procedure:
To a well stirred solution of 3-benzyloxybenzyl alcohol (5.5 g, 25.7 mmol) in methanol (100 mL) and sodium hydrogencarbonate (8.4 g, 100 mmol) was added a 1.0 M solution of iodine monochloride in dichloromathane (30 mL) at 0° C. The reaction mixture was brought to room temperature and stirring continued for additional 1 h. The reaction mixture was concentrated and then diluted with dicholomethane (150 mL), washed with 10% aqueous sodium thiosulfate and dried (Na2SO4). The desired compound was purified by flash chromatography (silica) using 20% ethyl acetate in hexane to give 5-benzyloxy-2-iodobenzyl alcohol (6.2 g, 71% yield). The alcohol (4.2 g, 12.4 mmol) was dissolved in dichloromethane (100 mL) added acetic anhydride (2.52 g, 24.7 mmol) and catalytic amount of 4-dimethylaminopyridine. The reaction mixture was then stirred for 12 h, washed with aqueous sodium hydrogencarbonate and then dried (Na2SO4) to give acetic acid 5-benzyloxy-2-iodo-benzyl ester in quantitative yield. MS (ESI) 405 (M+Na); Rf=2.27.
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)C.CC(C)=O.Cl>O>[F:17][C:12]([F:18])([C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1)[C:13]([F:14])([F:16])[F:15]
Reactant: CCOCOc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Oc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 50 °C

Procedure:
7.39 g of 1-ethoxymethoxy-4-pentafluoroethyl benzene, 30 ml of acetone and 30 ml of 6 M hydrochloric acid were stirred while heating at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and then poured into water, followed by extraction with ethyl acetate. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 4-(pentafluoroethyl)phenol.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[CH:3][CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[CH:3][CH:2]=1
Reactant: COc1cccc2c1cc(C)n2Cc1ccc(-c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1ccc(-c2ccccc2)cc1
Yield: 77.4 %

Procedure:
By the method used in Example 1, Part D, 1.3 g (4.0 mmol) of 1-([1,1′-biphenyl]-4-ylmethyl)-4-methoxy-2-methyl-1H-indole was O-demethylated by treating it with 16 mL of 1M BBr3/CH2Cl2 to give 970 mg (77% yield) of crude 1-([1,1′-biphenyl]-4-ylmethyl)-4-hydroxy-2-methyl-1H-indole.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][S:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]([OH:6])=[O:5].O.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)([OH:23])(=[O:22])=[O:21].[CH2:25]([O:5][C:4](=[O:6])[CH:3]([NH2:2])[CH2:7][S:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)SCC(N)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Product: CC(C)(C)SCC(N)C(=O)OCc1ccccc1
Yield: 78.9 %

Procedure:
A mixture of 14 (23.4 g, 109.5 mmol), p-toluenesulfonic acid monohydrate (62.5 g, 328.5 mmol), and benzyl alcohol (56.7 mL, 547.4 mmol) in CHC13 (320 mL) was refluxed for 4 h by using a Soxhlet apparatus containing dry silica gel. After cooling, CHC13 was evaporated and an equal volume of diethyl ether was added to the residue. The resulting ppt was collected by filtration, washed with ether, and air-dried to provide 15 as a white solid (38.0 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 8.58 (br s, 3H), 7.45 (m, 7H), 7.11 (d, 2H), 5.24 (AB, 2H), 4.38 (t, 1H), 3.00 (d, 2H), 2.29 (s, 3H), 1.26 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][CH:11]([CH3:16])[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)NCCC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(NCCC(=O)OC(C)(C)C)C(=O)O
Reaction time: 12 h
Yield: 73.6 %

Procedure:
Methyl 2-(tert-butoxycarbonylethylamino)propionate (1.27 g; 5.5 mmol) is dissolved in 5 ml of methanol, and potassium hydroxide (1.2 eq.; 6.6 mmol; 0.37 g) dissolved in 1.6 ml of water is then added. The reaction medium is left at room temperature for 12 hours and then evaporated to dryness, taken up in water and washed with ether. The aqueous phase is acidified by adding 1N hydrochloric acid and extracted three times with ether. The organic phases are combined, dried over sodium sulfate and evaporated to dryness to give 0.88 g of a white solid.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[H-].[Na+].[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)[CH3:27]
Reactant: CCI
Reactant: Oc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 1.2 g (2.7 mmoles) of 2-(4-hydroxyphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo-[1,2-a]imidazole dihydrobromide of Example 10 in 25 ml of dry dimethylformamide cooled in an ice bath was treated with 360 mg (9.0 mmoles) of 60% sodium hydride dispersion and allowed to warm to room temperature. A solution of 420 mg (2.7 mmoles) of ethyl iodide in 2 ml of dimethylformamide was added dropwise, and after 2 hours an additional 105 mg (0.67 mmole) of ethyl iodide was added followed by another 90 mg (2.25 mmoles) of 60% sodium hydride suspension. After stirring overnight, the mixture was poured into 10 volumes of ice water and extracted three times with ethyl acetate. The organic phase was washed with water, dried over anhydrous potassium carbonate and concentrated in vacuo. The residue was flash chromatographed on silica and the fractions eluting with 4 to 6% methanol in chloroform were combined, concentrated in vacuo, and recrystallized from ethyl acetate to afford the titled compound, mp 133°-135° C. Anal. Calcd. for C19H19N3O: C, 74.73, H, 6.27; N, 13.76. Found: C, 74.23; H, 6.01; N, 13.74.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32](=[O:36])[CH2:33][C:34]#[N:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:42][CH2:41][CH2:40][CH2:39]C1>CO.C1(C=O)CC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[C:32]([C:33](=[CH:39][CH:40]3[CH2:42][CH2:41]3)[C:34]#[N:35])=[O:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2)c2c(N)ncnc21
Reactant: C1CCNCC1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 25 %

Procedure:
Into a 50 mL, round-bottom flask, was placed a solution of 3-[(2R)-2-([4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (109 mg, 0.22 mmol, 1.00 equiv) in methanol (10 mL), cyclopropanecarbaldehyde (1 mL), and piperidine (1 mL). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The resulting solution was diluted with ethyl acetate and the resulting mixture was washed with water and brine. The organics were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 32 mg (25%) of the title compound as a white solid. LC-MS: (ES, m/z): 542 [M+H]+. 1H-NMR: (300 MHz, CDCl3, ppm): δ 8.38 (s, 1H), 7.74 (d, 2H), 7.18 (d, 2H), 7.08 (m, 2H), 6.92 (m, 1H), 6.81 (d, 1H), 5.54 (s, 2H), 4.82 (m, 1H), 4.68 (m, 2H), 3.65 (m, 1H), 3.51 (m, 1H), 2.02 (m, 3H), 1.20 (m, 3H), 0.88 (m, 3H).
Reaction SMILES: C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[Br:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([OH:41])=O)=[N:37][CH:38]=1.Cl.[N:43]1([CH2:49][CH:50]([N:54]2[CH:58]=[C:57]([C:59]3[C:60]4[CH:67]=[CH:66][N:65](COCC[Si](C)(C)C)[C:61]=4[N:62]=[CH:63][N:64]=3)[CH:56]=[N:55]2)[CH2:51][C:52]#[N:53])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C1COCC1>[Br:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([N:46]2[CH2:45][CH2:44][N:43]([CH2:49][CH:50]([N:54]3[CH:58]=[C:57]([C:59]4[C:60]5[CH:67]=[CH:66][NH:65][C:61]=5[N:62]=[CH:63][N:64]=4)[CH:56]=[N:55]3)[CH2:51][C:52]#[N:53])[CH2:48][CH2:47]2)=[O:41])=[N:37][CH:38]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCC(CN1CCN(C(=O)c2ccc(Br)cn2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.25 h

Procedure:
Triethylamine (72 uL, 0.52 mol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (39 mg, 0.103 mmol) were added to a solution of 5-bromopyridine-2-carboxylic acid (26 mg, 0.13 mmol) in THF (0.95 mL). After 15 minutes, 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (51 mg, 0.086 mmol; from Example 12, Step 2) was added and the reaction was stirred for two hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1 N NaOH and brine, dried over sodium sulfate and concentrated. The residue was dissolved and stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, then stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (20 mg, 44%). 1H NMR (400 MHz, d6-dmso): δ 12.10 (br s, 1H), 8.81 (s, 1H), 8.70 (dd, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 8.16 (dd, 1H), 7.60 (d, 1H), 7.52 (dd, 1H), 6.97 (d, 1H), 4.98 (tt, 1H), 3.61-3.54 (m, 2H), 3.37-3.28 (m, 2H), 3.24-3.19 (m, 2H), 2.86 (dd, 1H), 2.81 (dd, 1H), 2.63-2.54 (m, 1H), 2.52-2.40 (m, 2H), 2.39-2.31 (m, 1H); LCMS (M+H)+: 520.2/522.2.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16](=[O:19])[NH:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.Cl[CH2:23][C:24]1[O:28][N:27]=[C:26]([CH3:29])[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:29][C:26]1[N:25]=[C:24]([CH2:23][N:17]2[C:16](=[O:19])[N:14]3[CH:15]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=4)[CH:11]=[CH:12][C:13]3=[N:18]2)[O:28][N:27]=1
Reactant: Cc1noc(CCl)n1
Reactant: O=c1[nH]nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1noc(Cn2nc3ccc(-c4ccc(OC(F)(F)F)cc4)cn3c2=O)n1
Temperature: 110 °C

Procedure:
A mixture of 90 mg 6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.30 mmol), 40 mg 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole (0.30 mmol) and 23 mg potassium carbonate (0.17 mmol) in 2 mL DMA was heated at 110° C. for 2 h. The reaction mixture was then filtered and the filtrate concentrated. The residue was column purified on 12 g silica, eluting with 36 mL 5% ethyl acetate in hexanes, then 5-50% over 60 mL, and then 50% 120 mL. 2-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was isolated as a yellow solid. m/z (ESI)=392.0 [M+H]+. 1H NMR (δ, d6-DMSO, 400 MHz) 7.95 (dd, 1H) 7.54 (d, 2H), 7.40 (dd, 1H), 7.32 (d, 2H), 7.20 (dd, 1H) 5.43 (s, 2H), 2.40 (s, 3H)
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([CH3:16])[CH2:13][CH:12]([NH:17][C:18]3[C:23]([F:24])=[CH:22][N:21]=[C:20]([C:25]4[C:33]5[C:28](=[N:29][CH:30]=[C:31]([F:34])[CH:32]=5)[N:27](S(C5C=CC(C)=CC=5)(=O)=O)[CH:26]=4)[N:19]=3)[CH2:11]2)=[O:8])[CH2:3]1.C[O-].[Na+]>CO>[F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C@@H:10]2[CH2:15][C@H:14]([CH3:16])[CH2:13][C@H:12]([NH:17][C:18]3[C:23]([F:24])=[CH:22][N:21]=[C:20]([C:25]4[C:33]5[C:28](=[N:29][CH:30]=[C:31]([F:34])[CH:32]=5)[NH:27][CH:26]=4)[N:19]=3)[CH2:11]2)=[O:8])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CC(C)CC(NC(=O)N5CC[C@H](F)C5)C4)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1C[C@@H](NC(=O)N2CC[C@H](F)C2)C[C@@H](Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3S)-3-fluoro-N-(3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-1-carboxamide, 76d, (0.090 g, 0.143 mmol) in MeOH (2.5 ml) was added 25% sodium methoxide in methanol (2 ml). The reaction was stirred at room temperature for 30 minutes and quenched with aqueous saturated NH4Cl. The methanol was removed in-vacuo and the residue was extracted with EtOAc and water. The organics were dried over sodium sulfate and concentrated to dryness. The resulting crude racemate was purified by SFC separation on a chiral column. The second peak was concentrated in vacuo to afford 32 mg of enantiomerically pure (S)-3-fluoro-N-((1R,3S,5R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-1-carboxamide as a white solid: LCMS RT=1.89 (M+1) 474.2, (M−1) 472.4; SFC RT=3.2 min., 15% MeOH @ 5 mL/min on an ODH (4.6*100), 100 bar, 35 C, 220 nm; 1H NMR (300 MHz, DMSO) δ 12.26 (s, 1H), 8.41 (dd, J=9.9, 2.8 Hz, 1H), 8.32-8.18 (m, 2H), 8.14 (d, J=4.0 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 6.02 (d, J=7.9 Hz, 1H), 5.28 (d, J=53.6 Hz, 1H), 4.35-4.00 (m, 1H), 3.81-3.09 (m, 12H), 2.24-1.77 (m, J=41.2, 26.1, 10.6 Hz, 4H), 1.74-1.51 (m, 1H), 1.51-1.22 (m, 1H), 1.14-0.70 (m, 4H).