Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C@@H:3]([NH:11][C@@H:12]([CH2:16][S:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([OH:15])=O)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.Cl.[NH2:40][C:41]1([C:44]#[N:45])[CH2:43][CH2:42]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:44]([C:41]1([NH:40][C:13](=[O:15])[C@@H:12]([NH:11][C@@H:3]([C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=2)[C:2]([F:1])([F:37])[F:38])[CH2:16][S:17][C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:43][CH2:42]1)#[N:45]
Reactant: O=C(O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2(R)-[2,2,2-trifluoro-1-(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionic acid (21.58 g, 40 mmol; Reference D) and 1-aminocyclopropane-carbonitrile hydrochloride (OmegaChem, 6.16 g, 52 mmol) in DMF (75 mL) at rt was added DIPEA (Aldrich, 21 mL, 120 mmol) followed by solid HATU (ChemPacific, 19.77 g, 52 mmol) in one portion. This dark, homogeneous solution was allowed to stir at rt for 24 h. The reaction mixture was quenched by addition of 10% NaHCO3 (50 mL), followed by water (100 mL) and then extracted with EtOAc and the combined organics were washed with brine. Following drying over anhydrous MgSO4 and concentration in vacuo, the resulting dark oil was chromatographed on silica gel with 3/1 hex/EtOAc elution to afford a diastereomer mixture (ranging from 5.7/1 to 12/1) of N-(1-cyanocyclopropyl)-2-(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionamide and (9.83 g) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8](Cl)=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:15](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]([CH3:15])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ncc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 77.4 %

Procedure:
To a solution of 5-tert-butyl-2-chloro-3-nitro-pyridine (554 mg, 2.58 mmol) dissolved in 10% aqueous dioxane (5.0 mL) was added potassium carbonate (1.07 g, 7.74 mmol), trimethylboroxine (395 mL, 2.84 mmol), and lastly tetrakis-(triphenylphosphine)palladium (149 mg, 0.129 mmol). The solution was heated in a sealed tube to 100° C. for 18 h, cooled to room temperature and diluted with ether. The organic layer was washed twice with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica-gel chromatography (10% ethyl acetate in hexane) provided 5-tert-butyl-2-methyl-3-nitro-pyridine (388 mg, 75%) as colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:15]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].I.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](SC)=[NH:34].CO.C(Cl)Cl.N>[Pd].CO.C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([NH:24][C:33]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)=[NH:34])[CH:22]=[CH:23][C:15]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2cc([N+](=O)[O-])ccc21
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Yield: 52.7 %

Procedure:
A round bottom flask containing tert-butyl 2-hydroxyethyl(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (220 mg, 0.574 mmol) under argon was charged with palladium on activated carbon (10% wt; 61.0 mg, 0.057 mmol). The mixture was purged with argon prior to the addition of EtOH (20 mL). The resulting suspension was evacuated using a pump, and hydrogen was let into the system via a balloon. The mixture was stirred under a balloon filled with hydrogen for 3 hours. The hydrogen balloon was removed, and methyl thiophene-2-carbimidothioate hydroiodide (327 mg, 1.147 mmol) was added to the reaction. The suspension was stirred at room temperature for 17 hours (overnight). After this time, the mixture was filtered through a pad of Celite, which was then rinsed with MeOH (10 mL). The filtrate was concentrated, and the residue was partitioned between saturated sodium bicarbonate solution (50 mL) and CH2Cl2 (100 mL). The mixture was transferred to a separatory funnel and extracted. After extraction, the organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a dark residue. This residue was subjected to flash chromatography on silica gel using 2:98 MeOH/CH2Cl2 followed by 3.5:96.5 (2M NH3 in MeOH):CH2Cl2 to give a yellow solid (140 mg, 52.7%). 1H-NMR (DMSO-d6) δ 7.69 (brd, J=3.0 Hz, 1H), 7.57 (d, J=5.1 Hz, 1H), 7.07 (dd, J=3.9, 4.8 Hz, 1H), 6.82-6.75 (m, 1H), 6.53-6.42 (m, 2H), 6.32 (brs, 2H), 4.73 (t, J=5.4 Hz, 1H), 3.54 (brs, 2H), 3.50-3.42 (m, 2H), 3.38 (brs, 4H, overlap with solvent peak), 3.27-3.19 (m, 2H), 3.08-2.96 (m, 2H), 1.41 (brs, 9H); ESI-MS (m/z, %): 463 (MH+, 100), 398 (60); HPLC purity: 96.4% a/a.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.ClC(N(C)C)=C(C)C.[NH2:26][CH2:27][C:28]([CH:31]1[CH2:33][CH2:32]1)([OH:30])[CH3:29].C(N(C(C)C)C(C)C)C>ClCCl>[CH:31]1([C:28]([OH:30])([CH3:29])[CH2:27][NH:26][C:15]([C:5]2[CH:4]=[N:3][C:2]([Br:1])=[C:7]([C:8]3[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=3)[N:6]=2)=[O:17])[CH2:33][CH2:32]1
Reactant: CC(O)(CN)C1CC1
Reactant: O=C(O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(CNC(=O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1)C1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 0.700 g (0.00223 mol) 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid in 7.0 ml dichloromethane was added a solution of 0.35 g (0.00262 mol) (1-chloro-2-methyl-propenyl)-dimethyl-amine and the mixture was stirred at room temperature for 45 min. To the resulting yellow solution was added dropwise during 15 minutes a solution of 0.296 g (0.00257 mol) 1-amino-2-cyclopropyl-propan-2-ol and 0.433 g ethyldiisopropylamine in 4.0 ml dichloromethane and the mixture was stirred at room temperature for 1 h. The resulting mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with heptane to ethyl acetate=7:3 to yield 0.748 g (81% Th) of the title compound as slightly yellow foam. MS (ISP) (M+H+)=410.1 and 412.0.
Reaction SMILES: [C:1]1(=[CH:7][CH2:8][C:9]2([CH3:38])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=4[S:22](=[O:36])(=[O:35])[N:21]=3)[C:10]2=[O:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO.O1CCCC1>[CH:1]1([CH2:7][CH2:8][C:9]2([CH3:38])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=4[S:22](=[O:35])(=[O:36])[N:21]=3)[C:10]2=[O:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(CC=C2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(CCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.9 %

Procedure:
To a solution of Example 147 (18 mg, 0.032 mmol), 10% palladium on carbon (5 mg) in methanol (5 mL) and tetrahydrofuran (5 mL) was added a hydrogen balloon. After evacuating the solution two times the mixture was stirred under the hydrogen atmosphere at room temperature for 24 hours. The solution was then filtered through celite and the filtrate concentrated to provide the title compound (18 mg, 100%). MS (ESI+) m/z=558 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 0.42 (m, 1H), 0.62 (m, 2H), 0.78 (m, 2H), 1.03 (m, 4H), 1.50 (m, 4H), 1.54 (s, 3H), 2.12 (m, 2H), 3.08 (s, 3H), 7.56 (m, 3H), 7.73 (m, 3H), 8.16 (d, J=8.1 Hz, 1H), 10.26 (s, 1H), 13.74 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[OH:13].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)(=O)=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[O:13][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of methyl 3-hydroxy-4-methoxy benzoate (2.0 g, 11 mmol) in DMF (25 mL) was added cesium carbonate (7.2 g, 22 mmol) and 1,1-dimethylethyl 4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (3.2 g, 11 mmol). The mixture was heated to 70° C. and stirred for 2 h. After cooling to rt, water was added and the resulting aqueous mixture was extracted with ether followed by ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (70% hexanes, 30% ethyl acetate) to provide 3.54 g of 1,1-dimethylethyl 4-[({2-(methyloxy)-5-[(methyloxy)carbonyl]phenyl}oxy)methyl]piperidine-1-carboxylate (9.3 mmol, 85% yield). 1H NMR (400 MHz, CDCl3): δ7.69-7.66 (dd, 1H), 7.52 (d, 1H), 6.88 (d, 1H), 4.15 (br m, 2H), 3.92 (s, 3H), 3.91-3.88 (m, 2H), 3.90 (s, 3H), 2.76 (br m, 2H), 2.06 (m, 1H), 1.88 (br d, 2H), 1.47 (s, 9H), 1.31-1.25 (m, 2H); MS (EI) for C20H29NO6: 402 (MNa+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:17][CH2:18][CH2:19][Cl:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: ClCCCOc1ccccc1OCc1ccccc1
Yield: 97.1 %

Procedure:
A mixture of 50 g (0.25 mole) of 2-benzyloxyphenol, 78.7 g (0.5 mole) of 1-bromo-3-chloropropane and 103.7 g of anhydrous potassium carbonate in 1 liter of actone was heated at reflux for 24 hr. The reaction mixture was cooled, filtered and concentrated in vacuo to give 67.2 g of a tan oil as residue. The oil was dissolved in 300 ml of ethyl ether and washed with 100 ml of a 5% sodium hydroxide solution. A solid precipitated, about 200 ml of water was added and the precipitated sold redissolved. Solvent layers were separated and the ethyl ether layer washed twice with a 5% sodium hydroxide solution. The organic layer was next washed with water, brine, and dried over sodium sulfate and concentrated to give 58.4 g (84%) of oil as product.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([N:19]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]4[C:20]3=[O:29])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][CH2:39][CH2:40]Br.O>CN(C)C=O>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:40][CH2:39][O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)[C:10](=[O:18])[CH:9]([N:19]3[C:20](=[O:29])[C:21]4=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]4[C:23]3=[O:24])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1N1C(=O)c2ccccc2C1=O
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1CCOC1CCCCO1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a solution of (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepine-2-one (1.90 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (62% suspension in mineral oil; 0.20 g) gradually with stirring under cooling in an ice-bath (<3° C.). The mixture was stirred for 10 minutes under the same conditions. To the resultant mixture was added 2-[(tetrahydropyran-2-yl)oxy]ethyl bromide (1.60 g) in one portion. The mixture was stirred at ambient temperature for one hour and at 45° C. for 4.5 hours and allowed to stand overnight. The resultant reaction mixture was poured into water and extracted with ethyl acetate twice. The extract was washed with water and dried over magnesium sulfate. Removal of the solvent gave light yellow powder, which was washed with a mixture of ethyl acetate and diethyl ether and collected by filtration to afford a mixture (1.48 g) of (3RS)-1,3-dihydro -5-phenyl-3-phthalimido-1-{2-((RS)-2-tetrahydropyranyloxy) ethyl}-2H-1,4-benzodiazepine-2-one and (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-{2-((SR)-2tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[F:49]>C(#N)C>[Cl:42][C:43]1[CH:44]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:46]=[CH:47][C:48]=1[F:49]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(F)c(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 17.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-chloro-4-fluorobenzenesulfonyl chloride (0.0280 mL, 0.195 mmol) to obtain 4-(3-chloro-4-fluorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.00740 g, yield 17%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].CC1C=CC(S(O[CH2:23][CH2:24][CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30](/[C:33](/[C:40]3[NH:41][C:42](=[O:47])[C:43]([CH3:46])=[CH:44][CH:45]=3)=[CH:34]\[CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:29][C:28]=2[Cl:48])(=O)=O)=CC=1.O>C(#N)C>[Cl:48][C:28]1[CH:29]=[C:30](/[C:33](/[C:40]2[NH:41][C:42](=[O:47])[C:43]([CH3:46])=[CH:44][CH:45]=2)=[CH:34]\[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:31]=[CH:32][C:27]=1[S:26][CH2:25][CH2:24][CH2:23][N:9]([CH2:10][CH3:11])[CH2:7][CH3:8]
Reactant: Cc1ccc(S(=O)(=O)OCCCSc2ccc(/C(=C\C3CCCC3)c3ccc(C)c(=O)[nH]3)cc2Cl)cc1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(CC)CCCSc1ccc(/C(=C\C2CCCC2)c2ccc(C)c(=O)[nH]2)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
Potassium carbonate (290 mg) and diethylamine (219 μL) were sequentially added to a solution of 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-methyl-6-oxo-1,6-dihydropyridin-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (33 mg) in acetonitrile (3 mL), and the mixture was stirred at 90° C. for two hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give the title compound (18 mg, 66%) as a colorless amorphous.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][C:16]=3[F:28])=[N:6]2)[CH2:2]1.[C:29]([C:31](=[CH:35][CH:36]([CH3:38])[CH3:37])[C:32](O)=[O:33])#[N:30].C1CN([P+](ON2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:32]([C:31](=[CH:35][CH:36]([CH3:38])[CH3:37])[C:29]#[N:30])=[O:33])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][C:16]=3[F:28])[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C1CNC1
Reactant: CC(C)C=C(C#N)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CC(C)C=C(C#N)C(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 1-(azetidin-3-yl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.210 mmol, 2-cyano-4-methyl-pent-2-enoic acid (44.4 mg, 0.320 mmol), PyAOP (121.9 mg, 0.230 mmol) and TEA (0.09 mL, 0.640 mmol) in DCM (3 mL), were stirred overnight at room temperature. The solvent was removed and the residue was purified on a silica gel plate using 6:94 MeOH:CH2Cl2 to get 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]azetidine-1-carbonyl]-4-methyl-pent-2-enenitrile (34 mg) as white powder. LC-MS (ES, m/z): 498 [M+H].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].ClCCl.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]([CH2:21][OH:22])[CH2:19][O:18][C:17]2=[O:23])=[CH:12][CH:11]=1>C(N(CC)CC)C>[CH3:1][S:2]([O:22][CH2:21][CH:20]1[CH2:19][O:18][C:17](=[O:23])[N:16]1[C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OCC(CO)N1c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1COC(=O)N1c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 91.3 %

Procedure:
Methanesulfonyl chloride (3.0 g) was added dropwise to a dichloromethane (50 ml) solution of 5.30 g of 3-(4-chlorophenyl)-2-oxooxazolidin-4-ylmethyl alcohol obtained in Reference Example 17 and 8.5 ml of triethylamine with ice-cooling, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was washed with water, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by chloroform-ethanol gradient elution to give 6.50 g of the title compound (yield 91%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8]Br)(=O)C.[CH2:10]([NH:17][C:18](=[O:40])[N:19]([C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][C:28]=2[OH:39])[CH:24]=[CH:25][CH:26]=1)[CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:10]([NH:17][C:18](=[O:40])[N:19]([C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][C:28]=2[O:39][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[CH:24]=[CH:25][CH:26]=1)[CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: CC(=O)OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCCO)c1
Yield: 87.4 %

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (3.45 mmol, 4.9 eq) of 4-bromobutyl acetate and 300 mg (0.7 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 6 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 5.1 eq) of potassium carbonate at 80° C. for 15 hours, 305 mg of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(4-hydroxybutoxy)biphenyl-4-yl]propanoate are obtained in oil form. Yield=80%
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CC=CC=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][S:36]([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)(=[O:38])=[O:37]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 30 g (0.09 mol) of 5,9,13,17-tetramethyl-1-octadecanol and 8.72 g (0.11 mol) of pyridine in 200 ml of dry methylene chloride was added dropwise to a solution of 19.3 g (0.10 mol) of p-toluenesulfonyl chloride in 100 ml of dry methylene chloride under ice cooling. After the dropwise addition, the mixture was agitated at room temperature overnight, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and it was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated under reduced pressure to obtain 42 g of (5,9,13,17-tetramethyloctadecyl)tosylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>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.C1(C)C=CC=CC=1.CCO>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: OB(O)c1ccccc1
Reactant: CN1CCN(c2ccnc(Cl)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(c2ccnc(-c3ccccc3)n2)CC1
Temperature: 140 °C

Procedure:
To a microwave tube was added 2-chloro-4-(4-methyl-piperazin-1-yl)-pyrimidine (30 mg, 0.14 mmol), Pd(PPh3)4 (10 mg), phenylboronic acid (24 mg, 0.2 mmol), toluene/EtOH (4:1, 1 mL) and 2 M aqueous K2CO3 (0.2 mL). The resulting mixture was heated at 140° C. for 30 minutes using the microwave instrument. The resulting mixture was extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield the title compound as a solid.