Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@H]1CCN(C2C=CN=C(NCC(C)C)N=2)C1.[C:18]([O:22][C:23](=[O:41])[NH:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][N:33]=[C:32](NCC(C)C)[N:31]=2)[CH2:26]1)([CH3:21])([CH3:20])[CH3:19].[ClH:42]>CO>[C:18]([O:22][C:23](=[O:41])[NH:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:42])[N:31]=2)[CH2:26]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)CNc1nccc(N2CC[C@@H](NC(=O)OC(C)(C)C)C2)n1
Reactant: Cl
Agent: CC(C)CNc1nccc(N2CC[C@@H](N)C2)n1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a slurry of 2,4-dichloropyrimidine (2.05 g, 13.7 mmol) and N,N-diisopropylethylamine (3.60 mL, 20.6 mmol) in i-PrOH (12 mL) was added (R)-3-N-Boc-amino pyrrolidine (2.69 g. 14.4 mmol). The mixture was heated at 160° C. in a microwave for 2 h. The reaction was cooled to rt and concentrated, and the crude residue was purified by FCC (0 to 50% EtOAc/hexanes) to yield a white solid (2.10 g, 51%). MS (ESI): mass calcd. for C13H19ClN4O2, 298.1; m/z found, 299.1 [M+H]+. 1H NMR (CDCl3): 8.02 (d, J=6.0, 1H), 6.19 (d, J=6.0, 1H), 4.85-4.47 (m, 1H), 4.40-4.16 (m, 1H), 3.94-3.08 (m, 4H), 2.46-2.17 (m, 1H), 2.12-1.78 (m, 1H), 1.45 (s, 9H). [(3R)-1-(2-Isobutylamino-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. To a slurry of [(3R)-1-(2-chloro-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (103 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.52 mmol) in i-PrOH (1.5 mL) was added isobutylamine (30 mg. 0.41 mmol). The mixture was heated to 140° C. in a microwave for 6 h. The reaction was cooled to room temperature and concentrated. The crude residue was purified by FCC (0 to 10% MeOH/CH2Cl2) to yield the desired product (93 mg, 80%). MS (ESI): mass calcd. for C17H29N5O2, 335.2; m/z found, 336.3 [M+H]+. 1H NMR (CDCl3): 7.83 (d, J=5.9, 1H), 5.64 (d, J=5.9, 1H), 4.98-4.80 (m, 1H), 4.78-4.61 (m, 1H), 4.38-4.20 (m, 1H), 3.79-3.26 (m, 4H), 3.23-3.11 (m, 2H), 2.32-2.09 (m, 1H), 1.99-1.77 (m, 2H), 1.45 (s, 9H), 0.95 (d, J=6.7, 6H). 4-[(3R)-3-Aminopyrrolidin-1-yl]-N-(2-methylpropyl)pyrimidin-2-amine. To a solution of [(3R)-1-(2-isobutylamino-pyrimidin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (93 mg, 0.28 mmol) in MeOH (0.5 mL) was added HCl (4.0 M in 1,4-dioxane; 1.0 mL). The reaction was stirred at rt for 2 h, concentrated, and the crude residue was purified by FCC (0 to 20% 2 M NH3 in MeOH/CH2Cl2) to yield the desired product (65 mg, 100%). MS (ESI): mass calcd. for C12H21N5, 235.2; m/z found, 236.2 [M+H]+. 1H NMR (CDCl3): 7.82 (d, J=5.9, 1H), 5.65 (d, J=5.9, 1H), 4.87 (s, 1H), 3.75-3.51 (m, 3H), 3.48-3.38 (m, 1H), 3.20 (dd, J=6.7, 6.1, 3H), 2.16 (d, J=6.3, 1H), 1.87 (dt, J=13.4, 6.7, 1H), 1.81-1.71 (m, 1H), 1.47 (s, 2H), 0.95 (d, J=6.7, 6H). The compounds in Example 24 through Example 30 were prepared using methods analogous to those described for Example 23.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:21][OH:22].[OH-].[Na+].CO>O>[F:1][C:2]1[CH:3]=[C:4]([C:8](=[N:21][OH:22])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: ON=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(F)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A reaction vessel was charged with 1-(3-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone (2 g, 7 mmol), hydroxylamine (2.2 g, 32 mmol), 10% NaOH aqueous solution (11 ml, 27 mmol) and methanol (24 ml). The reaction mixture was heated to 70° C. and stirred at 70° C. for 3 hrs. It was then cooled to room temperature and water (12 ml) was added. The mixture was stirred at 0° C. for 1 hr. The solids were collected on a filter, washed with water, and dried under vacuum at 50° C. overnight to provide 1.9 g (91%) of the title compound as a solid with purity 99% AUC by HPLC (Phenomenex Luna 3μ cyano, 100 mm×4.6 mm. Flow rate: 1 ml/min. UV detection: 220 nm. Eluent: 75% A, 25% B. A: 80/20/0.05 water/acetonitrile/TFA. B: 20/80/0.05 water/acetonitrile/TFA).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I-:16].O>C(#N)C.[Ag+].FC(F)(F)C([O-])=O>[I:16][C:7]1[CH:6]=[CH:5][C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])=[CH:3][C:2]=1[F:1]
Reactant: [I-]
Reactant: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
In 300 ml of acetonitrile was dissolved 30 g of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 2, and 46 g of trifluoroacetic acid silver salt (CF3COOAg) and 43 g of iodide were added to the solution. After being stirred for one day at room temperature, the solution was added with water and was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine and dehydrated. And then the residue was filtered, concentrated in vacuo and dried thereby to form the title compound 44 g. Yield 94%.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][CH:7]=1.[CH3:15]O>C(Cl)(Cl)Cl>[Cl:5][C:6]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1cccc(Cl)n1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(Cl)n1
Yield: 100 %

Procedure:
Add thionyl chloride (3.7 mL, 50.8 mmol) to a solution of 6-chloropicolinic acid (4.0 g, 25.4 mmol) in methanol (85 mL) at 0° C. Stir the resultant solution for 15 minutes at 0° C., 0.5 hours at room temperature, and 6 hours at 50° C. Concentrate the reaction in vacuo and dilute with CHCl3 (150 mL). Wash the organic solution with saturated aqueous sodium bicarbonate (3×100 mL), and brine (1×100 mL) and dry with sodium sulfate. Filtration and concentration afford methyl 6-chloropicolinate 4.38 g (100%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH:26]([F:28])[F:27])=[CH:13][CH:12]=1)=[O:10].[C:30](Cl)(=[O:32])[CH3:31].N1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:30](=[O:32])[CH3:31])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH:26]([F:27])[F:28])=[CH:13][CH:12]=1)=[O:10]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (70 mg, 0.159 mmol) (intermediate 2) was treated with acetyl chloride (22 mg, 0.299 mmol) in THF (10 ml) containing pyridine (0.5 ml) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 2.0 h. THF was evaporated and the residue was washed with saturated sodium bicarbonate solution 5% HCl and water. The solid obtained was purified by silica gel column chromatography using 10% acetone-chloroform as eluent to obtain 25 mg of N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 234° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH:16]=[CH2:17])=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Br)nc1C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1nc(C(F)(F)F)c(C(=O)OCC)s1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 76.4 %

Procedure:
To a solution of thiazole IV (17.4 g, 57.3 mmol) in toluene (150 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.32 g, 1.14 mmol), tributyl(vinyl)tin (18.4 mL, 63.0 mmol), and 2,6-di-t-butyl-4-methyl phenol (catalytic). This mixture was stirred at 120° C. in a sealed tube for 25 min. The mixture was then allowed to come to 25° C. Ethyl acetate (250 mL) was added and the mixture was washed with 1 N aqueous NaOH (2×150 mL), saturated aqueous NaCl (1×150 mL), dried over MgSO4 and concentrated in vacuo to give a brown oil. Purification by flash chromatography (silica, 0-10% ethyl acetate/hexane) gave the 2-vinyl thiazole III (11.0 g, 76%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ 6.88 (dd, J=11.0, 17.6 Hz, 1H), 6.20 (d, J=17.6 Hz, 1H), 5.74 (d, J=11.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1=O.[CH:15]([C:17]([CH3:19])=[O:18])=[CH2:16].Cl>O.CO>[CH3:3][C:4]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH2:6][C:5]1=[CH:19][C:17](=[O:18])[CH2:15][CH2:16]2
Reactant: CC1C(=O)CCc2ccccc21
Reactant: C=CC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC12CCC(=O)C=C1CCc1ccccc12
Temperature: -15 °C
Reaction time: 6 h
Yield: 90.3 %

Procedure:
Potassium hydroxide in the amount of 2.25 g (40 mmol) was dissolved in 4.5 g of water in 100-ml three-necked flask, and the obtained solution was then cooled with ice under agitation in a stream of nitrogen gas. A methanol solution (8 ml) containing 4.8 g (30 mmol) of 1-methyl-2-tetralone was added dropwisely to the above obtained solution. The reaction vessel was cooled to -15° C., then, 2.1 g (30 mmol) of methyl vinyl ketone was added dropwisely to the reaction vessel and 2 ml of methanol was further added thereto. The resulted mixture was agitated under cooling with ice for 1 hour and then at room temperature for 6 hours in a stream of nitrogen-gas. Then, the mixture had been allowed to react at 70° C. for 6 hours. The reaction mixture was then poured into iced water, made acidic with hydrochloric acid and extracted with ether. The ether layer was removed and washed with water, and then dried with sodium sulfate. The ether was distilled off to obtain 5.75 g of oily yellowish orange residue. A part of this residue was crystallized and resulted crystals were recrystallized twice from cyclohexane to obtain 2.8 g of colorless plate-like crystals. The oily portion was further allowed to crystallize to obtain 1.9 g of crystals. The total yield was 4.7 g.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)[C:18]1[CH:23]=[CH:22]C=[CH:20][CH:19]=1>C(O)C>[O:1]=[C:2]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1)=[O:5]
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Reactant: OCc1ccccc1
Solvent: CCO
Product: O=C(CCc1ccccc1)CC(=O)OCc1ccccc1

Procedure:
Ethyl 3-oxo-5-phenylpentanoate (64.2 g, 0.29 mole) was heated between 190° and 210° C. under nitrogen with benzyl alcohol (28.9 ml, 0.28 mole) for 6 hours, the ethanol formed being distilled out of the reaction mixture. The resulting pale yellow oil was essentially pure product, slightly contaminated by starting materials, n.m.r. δ (CCl4) 7.23 (5H, s), 7.06 (5H, s), 5.03 (2H, s), 3.23 (2H, s) and 2.73 (4H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:14])[C:5](=[O:15])[C:4]=1[C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].[C:29](OC(=O)C)(=[O:31])[CH3:30].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:14][C:29](=[O:31])[CH3:30])[C:5](=[O:15])[C:4]=1[C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cc(C)cc(OC)c1C1=C(OC)C(=O)c2c(O)cccc2C1=O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)cc(OC)c1C1=C(OC)C(=O)c2c(OC(C)=O)cccc2C1=O
Reaction time: 8 h

Procedure:
In pyridine (3 ml) was dissolved methyl 2-(3-methoxy-5-hydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoate (20 mg) as obtained in Example 3, followed by addition of acetic anhydride (3 ml). The mixture was allowed to stand at room temperature overnight. After addition of water, the mixture was extracted with ethyl acetate. The solvent layer was washed with dilute HCl, water and dilute aqueous sodium hydrogen carbonate in that order, and dried over magnesium sulfate. The solvent was then distilled off and the residue was crystallized by addition of methanol. The above procedure gave methyl 2-(3-methoxy-5-acetoxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoate (13 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH:7]([CH2:9][C:10]([NH2:12])=[O:11])[CH3:8].C(=O)(O)[O-].[Na+].Cl>C1C=CC=CC=1.O>[Cl:1][CH2:2][C:3]([N:7]([CH2:9][C:10]([NH2:12])=[O:11])[CH3:8])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNCC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CN(CC(N)=O)C(=O)CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
A solution of chloroacetyl chloride (0.1 mole, 11.3 g) in benzene (40 ml) was added over 30 min to a mixture of sarcosinamide hydrochloride (0.1 mole, 12.45 g) and sodium bicarbonate (0.25 mole, 20.0 g) in 40 ml of water. The mixture was vigorously stirred for 3 h at room temperature. The aqueous phase was acidified with 5M hydrochloric acid to pH 5 and extracted with ethyl acetate (3×400 ml). The combined extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The solid residue obtained was recrystallized from ethanol-ether to give 8.5 g (52%) of the title compound. Mp 85°-86° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7](C=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH:12](OC)([O:15][CH3:16])[O:13][CH3:14].Cl>CO>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:7]1[CH:10]=[CH:11][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: COC(OC)OC
Reactant: CCCc1ccc(C=O)cc1
Agent: Cl
Solvent: CO
Product: CCCc1ccc(C(OC)OC)cc1
Temperature: -5 °C

Procedure:
A reaction flask was charged with 4-propyl benzaldehyde (1.064 Kg, commercially available from Mitsubishi Gas Chemical Company, Inc.), methanol (500 mL), and trimethyl orthoformate (TMOF) (1.144 Kg, commercially available from Sigma-Aldrich, Inc.). The reaction mass was cooled to −10 to 0° C. and hydrochloric acid (37%, 1 g) was added in one portion. The reaction was instantaneous and the temperature was allowed to rise to 25° C. for over 30 minutes. The reaction mass was then quenched with sodium acetate (20 g) and the solvent was removed by evaporation. The crude intermediate product 1-dimethoxymethyl-4-propyl-benzene (1.388 Kg) was obtained and charged to a second reaction flask at 25° C. Boron trifluride etherate (1 g, commercially available from Sigma-Aldrich, Inc.) was added. Ethyl vinyl ether (684 g, commercially available from Sigma-Aldrich, Inc.) was then fed for over 4 hours with the temperature maintained at 25-30° C. The reaction mass was quenched with saturated sodium carbonate (500 mL). The crude intermediate products methoxy ethoxy acetals were obtained, which were contained in the organic layer and confirmed by NMR analysis. Crude methoxy ethoxy acetals were hydrolyzed in the presence of water (500 mL) containing hydrochloric acid (37%, 50 g) at 90° C. for 5 hours and further catalytically hydrogenated in 2-propanol (200 mL) using palladium on carbon (5%, 1 g) and hydrogen in a 1 L zipper autoclave to provide the product 3-(4-propyl-phenyl)-propionaldehyde (1.008 Kg), which had a boiling point of 115° C. at a pressure of 6 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH:13](OC)OC)[C:5]([O:7][CH3:8])=[O:6].O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([N:1]2[C:2]3[C:11](=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=3)[CH:12]=[CH:13]2)[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(CC(OC)OC)c(N)c1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
44.3 g of methyl 3-amino-4-(2,2-dimethoxyethyl)benzoate synthesized according to the publication (Tetrahedron Letters, Vol. 37, No. 34, pp. 6045-6048) and 64.9 g of benzyl 4-oxo-1-piperidinecarboxylate were dissolved in 485 ml of acetic acid, followed by stirring at room temperature. Approximately 20 minutes later, 58.9 g of sodium triacetoxyborohydride was added to the reaction solution. Then, the reaction solution was further stirred for 2 hours. Thereafter, 485 ml of water was added to the reaction solution, and the obtained mixture was heated to a temperature between 100° C. and 115° C. Approximately 3 hours later, the reaction solution was cooled, and then concentrated under a reduced pressure. Thereafter, water and ethyl acetate were added thereto, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by NH silica gel column chromatography (hexane/ethyl acetate). The obtained solid was suspended in a mixed solvent consisting of hexane and t-butylmethyl ether, followed by filtration, so as to obtain 64.6 g of the subject compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([NH:17][CH2:11][C:10]3[CH:13]=[CH:14][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:15][CH3:16])[CH2:1][CH3:2])=[CH:8][CH:9]=3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: CCN(CC)CCOc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN(CC)CCOc1ccc(CNc2ccc3ncccc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.3 %

Procedure:
To a stirred solution of 1.0 gram (0.0045 mole) of 4-(2-(diethylamino)ethoxy)benzaldehyde and 0.65 gram (0.0045 mole) of 6-aminoquinoline (available from Aldrich Chemical Company) in 25 mL of 1,2-dichloroethane (DCE, available from Aldrich Chemical Company) was added 0.3 mL (0.0045 mole) of glacial acetic acid (available from J. T. Baker Inc.) followed by 1.4 grams (0.0068 mole) of sodium triacetoxyborohydride (available from Aldrich Chemical Company). Upon completion of addition, the reaction mixture was stirred at ambient temperature for three hours. At the conclusion of this period, 50 mL of 10% aqueous sodium hydroxide was added dropwise. The resulting solution was extracted with three 25 mL portions of diethyl ether. The extracts were combined, washed with one 25 mL portion of an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.25 grams of a dark brown paste. The dark brown paste was purified by column chromatography on silica gel, yielding 0.13 gram of Compound 15. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@@H:21]([OH:23])[CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].S(OC)(O[CH3:47])(=O)=O.[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@@H:21]([O:23][CH3:47])[CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:8])=[O:9]
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@@H](OC)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 52.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (114 mg, 0.185 mmol) prepared in Example 120c, dimethyl sulfate (17.9 μL, 0.189 mmol), sodium hydride (63%; 10.5 mg, 0.276 mmol) and THF (2.0 mL), to yield the title compound (60.0 mg, 51%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]4[CH:28]=[N:29][N:30]([CH2:32][CH:33]5[CH2:37][O:36]C(C)(C)[O:34]5)[CH:31]=4)[N:21]=3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>ClC(Cl)C.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]4[CH:28]=[N:29][N:30]([CH2:32][CH:33]([OH:34])[CH2:37][OH:36])[CH:31]=4)[N:21]=3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(Cn2cc(Nc3ncnc(N4CCN(c5ncc(Cc6ccccc6)cn5)CC4)n3)cn2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: OCC(O)Cn1cc(Nc2ncnc(N3CCN(c4ncc(Cc5ccccc5)cn4)CC3)n2)cn1
Temperature: 25 °C
Yield: 9.4 %

Procedure:
A solution of 4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine (200 mg, 0.3 mmol), and p-TSA (40 mg, 0.2 mmol) in dichloroethane (2.5 mL) was stirred at 80° C. under N2 overnight. LCMS showed the reaction was completed. The reaction mixture was cooled to RT and diluted with ethyl acetate (40 mL). The organic phase was washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to give 3-(4-(4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)propane-1,2-diol (13.8 mg, yield 7%) as a white solid. MS (ES+) C24H28N10O2 requires: 488, found: 489 [M+H]+.