Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:13]C(=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cscn2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2cscn2)c(F)c1
Yield: 81.1 %

Procedure:
A solution of tert-butyl 3-fluoro-4-(thiazol-4-yl)phenylcarbamate (270 mg, 0.92 mmol) in CH2Cl2 (2 mL) and TFA (4 mL) was stirred at room temperature for 60 min. It was then concentrated in vacuo. The residue was dissolved in CH2Cl2 (20 mL), which was washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 3-fluoro-4-(thiazol-4-yl)benzenamine (145 mg) as free base. MS195.2 (M+H)
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH2:19](O)[CH3:20]>S(=O)(=O)(O)O>[CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[C:3]([O:5][CH2:19][CH3:20])=[O:4]
Reactant: CC(C(=O)O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(-c2ccc(O)cc2)cc1
Yield: 73.5 %

Procedure:
A mixture of α-methyl-4'-(hydroxy)[1,1'-biphenyl]-4-acetic acid (22.0 g, 90.8 mmol) in ethanol (500 mL) and concentrated sulfuric acid (5.0 mL) is refluxed for 30 hours. The solution is concentrated under reduced pressure, is diluted with water (300 mL) and is extracted with ethyl acetate (3×300 mL). The combined ethyl acetate extract is washed with water (400 mL) and brine (400 mL), dried over MgSO4 and is concentrated under reduced pressure to give 20 g of crude product. Purification of this material by column chromatography (25% ethyl acetate in hexane) followed by crystallization from ethyl acetate and hexane gives 18.0 g (73.5%) of crystalline product, m.p. 124°-125° C., MS(CI+ m/z): 271[M+H]+.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][OH:23])[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:24]C(SCC(COC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)OCC)CCCCCCCCCCCCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:1]([S:17][CH2:18][CH:19]([CH2:22][OH:23])[O:20][CH2:21][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCC(C)SCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC
Reactant: CCCCCCCCCCCCCCCCSCC(CO)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCSCC(CO)OCC
Yield: 95 %

Procedure:
This compound was prepared in an analogous manner to that of (±)-1-S-hexadecyl-2-O-methylthioglycerol from 10.0 grams (0.02 mole) of (±)-1-2-hexadecyl-2-O-ethyl-3-O-tritylthioglycerol and 0.2 gram of p-toluenesulfonic acid. Silica gel chromatography (CHCl3 eluent) provided 5.8 grams (95%) of a semi-waxy solid. 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 31H, (CH2)14, CH3 --CH2 --O--], 2.58 (m, 2H, S--CH2), 2.62 (m, 2H, CH--CH2 --S), 3.40-3.50 (m, 3H, CH, CH3 --CH2 --O), 3.75(m, 2H, CH2 --OH).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-])=O.C1COCC1.CCO>C(O)C>[F:11][C:10]([F:12])([F:13])[C:8]1[CH:7]=[CH:6][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([NH2:1])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-c1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)ccc1-c1ccccc1

Procedure:
The product from Example 218a was reacted as described in Example 212c substituting 3:1 THF/EtOH (4 mL) for ethanol to give the title amine in quantitative yield.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.[N:51]1([CH2:57][CH2:58]O)[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:58][CH2:57][N:51]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: OCCN1CCOCC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)OCCN4CCOCC4)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 3c from 80 mg (0.12 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 17 μL (0.14 mmol) 2-morpholin-4-yl-ethanol. After purification by HPLC the product obtained was dissolved in 10 mL DCM and stirred with 5 mL of 5% NaHCO3 solution. The organic phase was separated off and dried on Na2SO4. After the elimination of the desiccant and solvent the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:37]1[C:33](=[O:43])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36]1=[O:38])=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CCl)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2ccc(F)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 87.1 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-4-(4-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.15 g, 7 mmol) and potassium phthalimide (1.94 g, 10.5 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give 2-[[6-benzyloxy-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (3.42 g, 87.2%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](O)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:24][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(Cl)nc1C(C)C
Temperature: 80 °C
Yield: 75.5 %

Procedure:
In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.00 g (3.43 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 0.5 mL (3.9 mmol.) of thionyl chloride, 3.44 mL of toluene, and 0.11 ml, of N,N-dimethylformamide. The mixture was heated to 80° C. for 3 hours, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, and poured into an ice/water mixture. The resulting aqueous mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution. The neutralized aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure, to obtain 0.80 g of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product. The yield was 76% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21]1([C:31](Cl)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>ClCCl>[C:21]1([C:31]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=3)[CH2:6][CH2:5]2)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc2ccccc12)N1CCN(c2ccc(O)cc2)CC1
Reaction time: 3 h

Procedure:
To a stirring mixture of 4-(1-piperazinyl)phenol (5.54 g) and triethylamine (10.83 ml) in dichloromethane (140 ml) was added dropwise, 1-naphthalenecarbonyl chloride (9.83 ml). The resulting reaction mixture was stirred under a nitrogen atmosphere for 3 h. The mixture was partitioned between dichloromethane and water and the organic phase was washed with saturated brine, dried (MgSO4) and evaporated to dryness. The residue was suspended in 6:4 tetrahydrofuran-methanol (370 ml) and treated with a saturated solution of potassium carbonate in methanol (45 ml). The mixture was stirred at room temperature under a nitrogen atmosphere for 20 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic phase was washed with saturated brine, dried (MgSO4) and evaporated to give an oil (15.5 g), part of which (14.5 g) was purified by chromatography on a silica SPE bond elut cartridge eluting with 10% -80% ethyl acetate-cyclohexane gradient to give the title compound (8.9 g). LCMS RT=2.97 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])=[O:9])[CH:2]=[CH2:3].Cl.[CH3:23]O>>[CH3:23][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[C:8](=[O:9])[C:7]1[CH:19]=[CH:20][CH:21]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:6]=1
Reactant: C=CCOc1cccc(C(=O)c2ccccc2C(=O)O)c1
Reactant: CO
Agent: Cl
Product: C=CCOc1cccc(C(=O)c2ccccc2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 2-[3-(allyloxy)benzoyl]benzoic acid (9.00 g, 31.9 mmol) in methanol (100 mL) was saturated with hydrogen chloride gas. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and diluted with diethyl ether. The resulting solution was washed sequentially with a saturated sodium bicarbonate solution, water, and a saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting pale yellow oil solidified upon standing to provide 9.45 g (100%) of the desired title product as a white solid: mp 50-52° C.; NMR (CDCl3) 8.05 (d, J=7.8 Hz, 1H), 7.65 (t, J=8 Hz, 1H), 7.56 (t, J=8 Hz, 1H), 7.40 (m, 2H), 7.32 (t, J=8 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 6.08 (m, 1H), 5.40 (d, J=16 Hz, 1H), 5.30 (d, J=11 Hz, 1H), 4.78 (d, J=4 Hz, 2H), 3.62 (s, 3H); MS-FD m/e 297 (p+1, 40), 296 (p, 100); IR.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][C@@H:11]([NH:14][CH3:15])[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH:22]([N:29]=[C:30]=[O:31])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH:22]([NH:29][C:30](=[O:31])[N:14]([C@@H:11]1[CH2:12][CH2:13][N:9]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10]1)[CH3:15])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: CN[C@@H]1CCN(C(=O)c2ccccc2)C1
Solvent: ClCCl
Product: CN(C(=O)NC(c1ccccc1)c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of (R)-(1-benzoyl-pyrrolidin-3-yl)-methyl-amine(0.32 g, 1.68 mmol) in dry CH2Cl2 (5 ml) was added diphenylmethyl isocyanate(0.32 ml, 1.68 mmol) dropwise under nitrogen. The resulting mixture was stirred at room temperature overnight. Removal of solvent under reduced pressure followed by column chromatography using CH2Cl2:CH3OH(15:1) gives 0.65 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]=1[CH3:34]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][C:25]([F:24])=[C:26]([CH3:34])[CH:27]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccc(F)c(C)c4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-4-fluoro-3-methyl-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 4-fluoro-3-methylbenzoyl chloride (125 μl, 0.89 mmol). The title compound was obtained as yellow powder (220 mg, 61%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([C:10]1[O:14][N:13]=[C:12]([NH2:15])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:6]([C:10]1[O:14][N:13]=[C:12]([NH:15][C:3](=[O:4])[CH2:2][Cl:1])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)CCl)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 132.4 %

Procedure:
Chloroacetic acid chloride (0.93 ml; II.42 mmol) is dropped slowly into a stirred solution of 5-t-Butyl-3-amino isoxazole (1.5 g; 7.67 mmol) in pyridine (1.09 ml; 13.49 mmol) and dichloromethane (20 ml), cooled to 0° C. Stirring is continued for 2 h at room temperature. The reaction mixture is diluted with dichloromethane, washed twice with 1N aqueous hydrochloric acid, twice with an aqueous solution of NaHCO3 and with water. The reaction mixture is then dried over Na2SO4, filtered and evaporated to yield 2.2 g (98%) brownish solid of 10.
Reaction SMILES: [OH-].[Na+].C([O:11][CH:12]1[CH2:16][CH:15]([C:17]2[N:21]3[C:22]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:23]=4[N:24]=[CH:25][C:20]3=[N:19][N:18]=2)[CH:14]([CH2:37][CH3:38])[CH2:13]1)(=O)C1C=CC=CC=1>CO>[CH2:37]([CH:14]1[CH:15]([C:17]2[N:21]3[C:22]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][C:20]3=[N:19][N:18]=2)[CH2:16][CH:12]([OH:11])[CH2:13]1)[CH3:38]
Reactant: CCC1CC(OC(=O)c2ccccc2)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC1CC(O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a solution of NaOH (0.088 g, 2.20 mmol) in MeOH (8 mL) was added a solution of 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl benzoate (0.158 g, 0.312 mmol, prepared using KK from Preparation #20.2) in MeOH (2 mL). The reaction mixture was stirred at ambient temperature for about 3 h. The solvent was removed under reduced pressure and DCM (150 mL) was added. The organic layer was washed with water (5 mL), saturated aqueous NaHCO3 (15 mL), brine (15 mL), and dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.123 g, 98%) as clear oil: LC/MS (Table 1, Method b) Rt=2.34 min; MS m/z: 402 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:3]#[C:4][C:5]([CH3:18])([NH:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:6].C([Mg]Br)C.Cl[C:31]([O:33][CH3:34])=[O:32].O>C1COCC1>[CH3:34][O:33][C:31]([O:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:3]#[C:4][C:5]([CH3:6])([NH:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:18])=[O:32]
Reactant: CCCCCCCC(O)C#CC(C)(C)NS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)Cl
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCC(C#CC(C)(C)NS(=O)(=O)c1ccc(C)cc1)OC(=O)OC
Reaction time: 0.67 h
Yield: 86 %

Procedure:
In 10 ml of THF was dissolved 1.37 g (3.76 mmole) of the 5-hydroxy-2-methyl-2-tosylamino-3-dodecyne obtained in Reference Example 1, and a THF solution of ethylmagnesium bromide (8.27 mmole) was added thereto, followed by stirring for 40 minutes. To the mixture was added dropwise 0.668 ml (8.65 mmole) of methyl chloroformate, and stirring was further continued for 50 minutes. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed successively with a hydrochloric acid aqueous solution, a sodium hydrogencarbonate aqueous solution, and water, and then dried. The solvent was removed by distillation, and the residual oily substance was purified by column chromatography to obtain 1.37 g (percent yield: 86%) of 5-methoxycarbonyloxy-2-methyl-2-tosylamino-3-dodecyne.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[O:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[OH-].[Na+].Cl>CO.O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:23])=[O:2])=[C:7]([O:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH:8]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)cc1OC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(C=CC(=O)O)c(OC2CCOCC2)c1
Reaction time: 12 h
Yield: 99.9 %

Procedure:
3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)phenyl]acrylic acid methyl ester (31.5 mg, 0.099 mmol, 1 eq) and sodium hydroxide (19.8 mg, 0.4955 mmole) were added in methanol and H2O. The reaction mixture was stirred for 12 hrs. The reaction mixture was acidified with 5% HCl. The mixture was concentrated in vacuo to yield 3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)-phenyl]acrylic acid (30.1 mg, 100%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41][S:53]([CH3:52])(=[O:55])=[O:54])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (0.77 g) in dichloromethane (5 mL) were added triethylamine (0.26 mL) and methanesulfonylchloride (0.12 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]phenyl}methyl)-1H-pyrazole (0.85 g). The obtained 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[(3-(methanesulfonyloxy)propoxy]phenyl}-methyl)-1H-pyrazole (0.2 g) was dissolved in a mixed solvent of acetonitrile (1.5 mL) and ethanol (1.5 mL). To the solution were added 2-[2-amino-2-(methyl)propionylamino]ethanol (0.25 g) and a catalytic amount of sodium iodide, and the mixture was stirred at 60° C. for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-(3-[1-(2-hydroxyethylcarbamoyl)-1-(methyl)ethylamino]propoxy)phenyl)methyl]-5-isopropyl-1H-pyrazole (0.13 g). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.05 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (93 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH3:11])=[N:8][C:7]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:6]=2[C:5]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[C:24]([O:31][CH3:32])(=[O:30])[CH2:25][CH2:26][C:27]([O-])=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:15]([N:12]1[C:7]2=[N:8][C:9]([CH2:10][CH3:11])=[C:4]([CH2:3][NH:2][C:27](=[O:28])[CH2:26][CH2:25][C:24]([O:31][CH3:32])=[O:30])[C:5]([NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:6]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)CCC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)OC
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (400 mg, 1.18 mmol), mono-methyl succinate (156 mg, 1.18 mmol), HBTU (536 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (8 mL) was stirred at room temperature over the weekend. It was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layer was dried over sodium sulfate, filtered, concentrated and purified with CombiFlash eluting with 70% ethyl acetate in hexane. The product fractions were combined and concentrated to give methyl 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoate as an oil (520 mg, 105%). LC-MS m/z 418 (M+H)+.