Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]([C:12]([CH2:14][CH3:15])=O)[CH3:11].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:10]([CH:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1)[CH2:14][CH3:15])[CH3:11]
Reactant: Cc1ccc(N)cc1C
Reactant: CCC(=O)CC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC(CC)Nc1ccc(C)c(C)c1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
A solution of 3,4-xylidine (1.2 g., 0.01 mole) and diethyl ketone (5 ml.) in methanol (20 ml.) is stirred at room temperature in the presence of sodium cyanoborohydride (1.1 g.) and 3A molecular sieves (3.0 g.). The pH is monitored each half hour and maintained at 6 by adding acetic acid in 5 drop portions as required. After 7 hours, the sieves are removed by filtration and the filtrate is diluted with water (100 ml.) and then acidified with hydrochloric acid. The solution is then basified with solid potassium carbonate and extracted with ethyl ether. The ether solution is dried and then evaporated leaving the desired product as a residual oil in 97.5% yield and in 93% purity as determined by gas-liquid chromatography. The compound had a boiling point of 80° C. at a pressure of 0.1 mm. Its elemental analysis is as follows:
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH-].[Ca+2].[OH-].C([O-])(=O)C.[Ca+2].C([O-])(=O)C>O>[OH:1][CH2:2][C:3]([C@@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO
Agent: CC(=O)[O-]
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=C(CO)[C@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 2 h
Yield: 44 %

Procedure:
To a 25 ml Erlenmeyer flask, equipped with a magnetic stirrer, was added 0.5 g L-galactose, 5 ml water, 0.2 g calcium hydroxide, and 22 mg calcium acetate. The mixture was stirred. After 2 hours, the solution was filtered to collect the calcium hydroxide-L-tagatose complex that had formed. The sticky complex was resuspended in 5 mL of H2O, and CO2 was bubbled through the slurry until the pH was below 7. The solution, after filtering off the calcium carbonate, was deionized as in Example 1 and concentrated in vacuo to a syrup which, after seeding with a few L-tagatose crystals, provided 0.22 of pure L-tagatose, a 44% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:33])[C@@H:18]([NH:19][C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])[C@H:15]3[S@@:14](=O)[C:13]2([CH3:36])[CH3:35])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(Cl)(Cl)C[N:42]=[C:43]=[O:44].[O:47]1CCOCC1>>[N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:33])[C@@H:18]([NH:19][C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])[C@H:15]3[S:14][C@:13]2([CH2:36][O:47][C:43](=[O:44])[NH2:42])[CH3:35])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C=NCC(Cl)(Cl)Cl
Reactant: CC1(C)[C@H](C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2[S@]1=O
Reactant: C1COCCO1
Product: C[C@@]1(COC(N)=O)S[C@@H]2[C@H](NC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A mixture of (1S,3S,5R,6R) 6-(4-nitrobenzyloxycarbonyl)amino-2,2-dimethylpenam-3-carboxylic acid-oxide p-nitrobenzyl ester (8.19 g, 15.0 mmol), trichloroethyl isocyanate (5.0 ml, 7.9 g, 42 mmol) and dioxane (75 ml) was refluxed under nitrogen for 3.5 hours and concentrated in vacuo to a light brown oil. The oil was stirred with warm methanol (150 ml) for 0.5 hour and the solution was decanted from a small amount of dark residue. The methanol solution was adjusted to pH 7.4 with 5% sodium bicarbonate and held at pH 7.4-7.5 with 3% sulfuric acid during a 2.0 hour stirring period. The mixture was then distributed between methylene chloride (250 ml) and water (100 ml). The organic layer was washed with water (100 ml), combined with a CH2Cl2 back-extract (100 ml), dried (4A molecular sieve), polish filtered, and concentrated in vacuo to a light brown oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[CH2:10][CH2:9][NH:8][CH:7]=[C:6]1[C:11]([O:13][CH3:14])=[O:12].O1CCCC1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([N:5]1[CH2:10][CH2:9][NH:8][CH:7]=[C:6]1[C:11]([O:13][CH3:14])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COC(=O)C1=CNCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1=CNCCN1C(C)=O
Temperature: 25 °C
Yield: 68.8 %

Procedure:
15.10 g (192.5 mmol) of acetyl chloride was added dropwise over 25 minutes to 25.00 g (175.9 mmol) of methyl 1,4,5,6-tetrahydropyrazine-2-carboxylate, 250 ml of tetrahydrofuran and 21.30 g (210.5 mmol) of triethylamine at 0° C. The mixture was then heated to room temperature and, after 1 hour, 200 ml of ethyl acetate were added. The aqueous phase was washed a further 3 to 4 times with a total of 500 ml of ethyl acetate and the combined organic extracts were dried over magnesium sulfate. After the solvent had been stripped off, 22.30 g (69%) of the title compound were obtained as a yellow oil. Recrystallization from ethyl acetate gave methyl 1-acetyl-1,4,5,6-tetrahydropyrazine-2-carboxylate in the form of a light yellow, crystalline solid. The melting point of the title compound was: 136° to 139° C. Other data concerning the title compound was:
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[CH2:5][C:4](=[O:16])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[ClH:14].[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:15])[C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:16])[CH2:5]1
Reactant: NC1=CC(=O)CC(c2c(Cl)cccc2Cl)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1C(=O)CC(c1c(Cl)cccc1Cl)C2
Product: Cl
Temperature: 115 °C
Yield: 89.7 %

Procedure:
In a mixture of ethanol (23 ml) and toluene (70 ml) was dissolved 1-amino-5-(2,6-dichlorophenyl)cyclohexen-3-one (1.25 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (1.84 g) and granulated potassium hydroxide (303 mg). The mixture was stirred at 115° C. (bath temperature), and to the mixture was added granulated potassium hydroxide (62 mg), 30 minutes later; 1 hour later; and 1.5 hours, respectively. The reaction solution was stirred at the same temperature for 1 hour, cooled and concentrated under reduced pressure, and to the residue were added ethyl acetate (50 ml) and water (15 ml). The mixture was separated and the separated upper layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) and eluted with ethyl acetate/hexane, which was concentrated under reduced pressure. The residue was dissolved in a mixture of ether (4 ml) and ethanol (2 ml), and to the solution was added concentrated hydrochloric acid (0.25 ml). Precipitated crystals were filtered, washed with the same mixed solvent and dried to give 7-(2,6-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (0.75 g) as colorless crystals.
Reaction SMILES: [C:1]([C:8]([O:10]CC)=O)#[C:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:25]=[C:24]([NH2:26])[NH:23][N:22]=2)=[CH:17][CH:16]=1.C(OCC)(=O)C>C(O)(=O)C>[OH:10][C:8]1[N:23]2[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[CH:25]=[C:24]2[N:26]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:1]=1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: COc1ccc(-c2cc(N)[nH]n2)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(O)n2nc(-c3ccc(OC)cc3)cc2n1
Reaction time: 3 h

Procedure:
Diethyl acetylenedicarboxylate (883 μL, 5.6 mmol) was added to a solution of 3-(4-methoxyphenyl)-1H-pyrazol-5-amine (1.1 g, 5.6 mmol) in acetic acid (5 mL). The very thick mixture was allowed to stand at room temperature with occasional stirring for 3 h. Ethyl acetate (5 mL) and hexanes (15 mL) were added and the precipitate was filtered, and dried under high vacuum. Yield: 1.26 g (76%); LCMS m/z 314.1 (M+H)+, ret. time=2.25 min.
Reaction SMILES: [NH:1]([C:3](=[O:9])[C:4](OCC)=[O:5])[NH2:2].[CH3:10][NH:11][CH3:12]>>[NH:1]([C:3](=[O:9])[C:4]([N:11]([CH3:12])[CH3:10])=[O:5])[NH2:2]
Reactant: CCOC(=O)C(=O)NN
Reactant: CNC
Product: CN(C)C(=O)C(=O)NN
Temperature: 70 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a round-bottom flask was added ethyl 2-hydrazinyl-2-oxoacetate (compound 134.1, 2.00 g, 13.6 mmol, 1.00 equiv, 90%). Dimethylamine (10 mL) was added to the reaction, and then the reaction was stirred overnight at 70° C. in an oil bath. The mixture was cooled to room temperature and concentrated in vacuo to yield 1.50 g (76%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH:26]2[CH:24]([O:25]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].FC(F)(F)S([O-])(=O)=O.[Ca+2].FC(F)(F)S([O-])(=O)=O>C(#N)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][C@@H:24]([OH:25])[C@H:26]([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1ccc(N2CCCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ca+2]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2CCCN(c3ccc(Cl)cc3)CC2)C1
Temperature: 80 °C
Reaction time: 17 h
Yield: 43.1 %

Procedure:
To a solution of 1-(4-Chloro-phenyl)-[1,4]diazepane (1.00 g, 4.80 mmol) in acetonitrile (10 mL) was added 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.925 g, 5.00 mmol) and calcium(II) trifluoromethanesulfonate (0.676 g, 2.00 mmol). The solution was stirred at 80° C. for 17 hours under nitrogen atmosphere. The reaction was concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine, dried over MgSO4, and evaporated. The residue was purified by silica gel chromatography (gradient ethyl acetate to 87:10:3 ethyl acetate:methanol:triethylamine) to yield 0.819 g (41%) of the title compound. ESI-MS m/z: 396 (M+1), FAS method rt: 1.25 min
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.Cl.[O:15]1[CH2:20][CH2:19][CH:18]([NH:21][NH2:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[I:1][C:2]1[C:7]([C:8]([NH:22][NH:21][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)=[O:10])=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1
Reactant: NNC1CCOCC1
Reactant: COc1nccc(I)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc(I)c1C(=O)NNC1CCOCC1
Yield: 81.2 %

Procedure:
A solution of 4-iodo-2-methoxynicotinic acid (1.75 g) obtained in Step C of Example 6, tetrahydro-2H-pyran-4-ylhydrazine dihydrochloride (0.957 g), DIEA (2.2 mL), EDCI hydrochloride (1.44 g) and HOBt (1.02 g) in DMF (100 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (1.55 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4].[CH2:17]([OH:20])[C:18]#[CH:19].O>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:1][CH2:2][C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([C:19]#[C:18][CH2:17][OH:20])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4]
Reactant: C#CCO
Reactant: CC(C)(CO)NC(=O)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(CO)NC(=O)c1ccc(C#CCO)cc1F
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 2261.8 %

Procedure:
To a solution of N-(2-hydroxy-1,1-dimethylethyl)-4-bromo-2-fluorobenzamide (0.29 g, 1.0 mmol) in triethylamine (5 ml), dichlorobis(triphenylphosphine)palladium(II) (0.035 g, 0.05 mmol), copper(I) iodide (0.009 g, 0.05 mmol) and 2-propyn-1-ol (0.085 g, 0.05 mmol) were added and stirred at 50° C. for 3.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate and dried over Na2SO4. After the solvent was evaporated under a reduced pressure, the residue was subjected to silica gel chromatography (hexane/ethyl acetate=1/2) to give the title compound (0.30 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C(C(/N=N/C(C)(C)C#N)(C)C)#N.[Br:21]N1C(=O)CCC1=O.FC1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Br:21])[CH:3]=1
Reactant: Cc1cc(Br)ccn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)/N=N/C(C)(C)C#N
Solvent: Fc1ccccc1
Product: BrCc1cc(Br)ccn1
Temperature: 90 °C
Yield: 100 %

Procedure:
4-bromo-2-methyl-pyridine (5 g, 29.07 mmol), 2-[(E)-(1-cyano-1-methyl-ethyl)azo]-2-methyl-propanenitrile (954.7 mg, 5.814 mmol) and N-bromosuccinimide (7.244 g, 40.70 mmol) were added to fluorobenzene (8 mL) and the mixture heated to 90° C. for 1 hour. Reaction mixture was purified by filtering through a silica gel pad and eluting with 50% diethylether/petroleum ether. Product fractions were combined and concentrated in vacuo to give the crude sub-title product (7.294 g, assumed 100% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 4.52 (s, 2H), 7.42 (d, 1H), 7.65 (s, 1H) and 8.42 (d, 1H) ppm.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:25])[NH:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][C:28]=2[O:36][CH3:37])=[CH:7]1)=[O:5])[CH3:2].ClCCCl.[C:44]1([CH3:54])[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([NH2:53])(=[O:52])=[O:51]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([N:3]([CH2:38][CH3:39])[C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:25])[NH:16][CH2:17][CH:18]([CH3:24])[CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:53][S:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[CH3:54])(=[O:51])=[O:52])=[O:33])=[CH:29][C:28]=2[O:36][CH3:37])=[CH:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: CCN(CC)C(=O)n1cc(Cc2ccc(C(=O)O)cc2OC)c2cc(C(=O)NCC(C)CC(F)(F)F)ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CC)C(=O)n1cc(Cc2ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc2OC)c2cc(C(=O)NCC(C)CC(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
To a solution of 4-[1-diethylcarbamoyl-5-(4,4,4-trifluoro-2-methylbutylcarbamoyl)-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (0.12 grams, 0.22 mmol), 4-dimethylaminopyridine (0.040 grams, 0.33 mmol) and 1,2-dichloroethane (0.063 grams, 0.33 mmol) in methylene chloride (15 mL) was added o-tolylsulfonamide (0.038 grams, 0.22 mmol). The resulting solution was stirred, at room temperature, for 12 hours. The reaction mixture was then diluted with methylene chloride and washed with 1 M hydrochloric acid (aq). The organics were dried over magnesium sulfate and concentrated in vacuo. Recrystallization from wet ether gave the titled compound (0.115 grams, 75% yield), m.p.=153-154° C. Anal calcd. for C35H39H4O6SF3 : C, 59.92; H, 5.60; N, 7.99. Found: C, 60.18; H, 5.68; N, 8.41.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1.CI.[C:20]([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:20])=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Reaction time: 65 h
Yield: 82.5 %

Procedure:
A mixture of 2-chloro-6-((R)-3-methylmorpholin-4-yl)-9H-purine (635 mg, 2.50 mmol), methyl iodide (187 μL, 3.00 mmol) and K2CO3 (484 mg, 3.50 mmol) in THF (15 mL) were stirred at r.t. for 18 h before further methyl iodide (187 μL, 3.00 mmol) was added. The resulting mixture was allowed to stir for 65 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O, the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo affording the title compound as an off-white solid (552 mg, 83%). LCMS (method H): RT 2.76 min [M+H]+ 268.3
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[Si:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])=[CH:29][CH:28]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[Si:45]([O:52][C@@H:53]1[CH2:58][CH2:57][C@H:56]([C:59](=[O:70])[C:60]([O:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[O:61])[CH2:55][CH2:54]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>C1COCC1>[Si:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[C:59]([C@H:56]2[CH2:57][CH2:58][C@@H:53]([O:52][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:54][CH2:55]2)([OH:70])[C:60]([O:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[O:61])=[CH:29][CH:28]=1)([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C(=O)C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(C(=O)OCc2ccccc2)C(O)(C(=O)OCc2ccccc2)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M n-butyllithium solution in hexane (0.49 ml, 1.22 mmol) was added to a solution of diisopropylamine (0.18 ml, 1.29 mmol) in anhydrous THF (3.0 ml) at −78° C. under an argon stream. The mixture was brought to 0° C., and the mixture was stirred for 30 min and was again cooled to −78° C. A solution of benzyl 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)propanoate (300 mg, 0.81 mmol) in anhydrous THF (4.0 ml) was added dropwise thereto at −78° C., and the mixture was stirred for additional one hr. A solution of benzyl 2-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-oxoacetate (304 mg, 0.81 mmol) in anhydrous THF (4.0 ml) that had been cooled to −78° C. was added through a cannula to the resultant enolate solution over 10 min. The mixture was stirred at −78° C. for one hr, was quenched and adjusted to pH 4 with acetic acid and was allowed to cool to room temperature. The reaction solvent was removed by distillation under reduced pressure, and the residue was diluted with ethyl acetate, and the diluted solution was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=95:5) to give the title compound as an oil (a diastereomeric mixture; 120 mg, yield 19%).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH2:10])[C:4]=1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.[C:52]([O:56][C:57]([NH:59][C@@H:60]([CH3:64])[C:61](O)=[O:62])=[O:58])([CH3:55])([CH3:54])[CH3:53]>CN(C=O)C>[NH2:10][C:5]1[C:4]([CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:61](=[O:62])[C@@H:60]([NH:59][C:57](=[O:58])[O:56][C:52]([CH3:54])([CH3:53])[CH3:55])[CH3:64])[CH2:15][CH2:14]2)=[C:3]([Cl:2])[N:8]=[C:7]([CH3:9])[N:6]=1
Reactant: Cc1nc(N)c(CCC2CCNCC2)c(Cl)n1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC2)c(Cl)n1
Reaction time: 0.08 h
Yield: 153.2 %

Procedure:
Into each of two round bottom flasks add 6-chloro-2-methyl-5-[2-(4-piperidyl)ethyl]pyrimidin-4-amine hydrochloride (12.50 g, 42.92 mmol), diisopropylethylamine (22.46 mL, 128.7 mmol) and DMF (100 mL). Cool the two mixtures in a cold water bath and stir for 5 min. Add to each of the mixtures [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (17.95 g, 47.21 mmol) and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (8.93 g, 47.21 mmol) in one portion. Stir the mixtures at RT for 90 min Pour the mixtures into separate separatory funnels along with water (300 mL) and EtOAc (400 mL), shake and partition. Extract the aqueous layers with EtOAc (3×300 mL), wash the respective organic layers with water (4×250 mL), saturated aqueous NaCl (200 mL) and dry over MgSO4, filter and concentrate under reduced pressure. Purify the combined materials via silica gel chromatography eluting with 70% to 100% EtOAc in hexanes. Combine and concentrate the purified fractions under reduced pressure. Dilute the residue with EtOAc (500 mL) and wash with saturated aqueous NH4Cl (100 mL), saturated aqueous NaHCO3 (100 mL), water (100 mL) and saturated aqueous NaCl (100 mL). Dry the organics over MgSO4, filter, and concentrate under reduced pressure to give the title compound as a white solid (28.00 g, 76%). LC-ES/MS m/z (35Cl/37Cl) 426.2/428.2 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>CN(C=O)C>[C:44]([N:34]1[CH2:35][CH2:36][N:29]2[CH:30]([CH2:31][O:32][CH:27]([C:19]3[N:20]4[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[C:17]([C:12]4[CH:13]=[CH:14][C:15]5[C:10]([CH:11]=4)=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:16]=5)[CH:18]=3)[CH2:28]2)[CH2:33]1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.10 mmol), triethylamine (29 μL, 0.21 mmol), in DMF (1 mL) at 0° C., acetic anhydride (11 μL, 0.11 mmol) was added. The reaction was allowed to stir for 20 minutes while warming to rt. The mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous K2CO3 solution (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 19 mg (35%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35-7.28 (m, 5H), 7.10 (dd, 1H), 6.71 (s, 1H), 5.64 (s, 2H), 5.14 (dd, 1 H), 4.33-4.21 (m, 1H), 3.91-3.84 (m, 1H), 3.79-3.68 (m, 1H), 3.39-3.27 (m, 2H), 3.06-3.00 (m, 1H), 2.76-2.64 (m, 2H), 2.41-2.37 (m, 1H), 223-2.11 (m, 1H), 2.07-1.95 (m, 1H), 1.99 (s, 3H); LC-MS [M+H]+=523, RT=2.24 min.