Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15].[C:16]([Cu])#[N:17]>CN1CCCC1=O.O.C(OCC)(=O)C>[OH:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:16]#[N:17])=[C:13]([O:14][CH3:15])[C:6]=2[C:7]=1[CH3:12]
Reactant: N#C[Cu]
Reactant: COc1c(Br)ccc2oc(CO)c(C)c12
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1c(C#N)ccc2oc(CO)c(C)c12
Yield: 71.1 %

Procedure:
A suspension of (5-bromo-4-methoxy-3-methyl benzofuran-2-yl)-methanol (0.31 g; 1.1 mmol, Example 136, Step 1) and CuCN (0.21 g; 2.3 mmol; 2 eq) in N-methylpyrrolidinone (1.5 mL) was subjected to microwave radiation at 200° C. for 10 minutes. The reaction was diluted with water and ethyl acetate (10 mL each) and filtered. The layers were separated and the aqueous phase was washed with a second portion of ethyl acetate. The combined organic layers were washed twice with water and once with brine. After drying over magnesium sulfate, filtration and concentration in vacuo gave the crude product. Chromatography on silica gel, eluting with 20% to 30% ethyl acetate/hexanes gave pure 2-hydroxymethyl-4-methoxy-3-methyl benzofuran-5-carbonitrile (0.17 g; 67% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.Cl>C(#N)C.O1CCOCC1>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: COC(=O)C[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COC(=O)C[C@@H](Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C(C)(C)C
Temperature: 65 °C

Procedure:
To a solution of (R)-methyl 3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate, 8a, (21 g, 39 mmol) in acetonitrile (157 mL) was added 4M HCl in dioxane (174 mL). The reaction mixture was heated to 65° C. for 4 h. The solution was cooled to room temperature and the solvents were removed under reduced pressure. The mixture was flushed with acetonitrile after which dichloromethane (100 mL), sat. aqueous NaHCO3 (355 mL) and ethyl acetate (400 mL) were added. The phases were separated and the aqueous layer washed with ethyl acetate (500 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified on silica gel (EtOAc/Hexanes) to provide the desired product, 9a, (12.1 g): LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT=2.26 minutes (M+H) 391.05.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](O)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2].P(Cl)(Cl)([Cl:20])=O.C(N(CC)CC)C>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([Cl:20])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1nc(O)c(-c2ccccc2)nc1C#N
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1nc(Cl)c(-c2ccccc2)nc1C#N
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
The 2,3-dicyano-5-hydroxy-6-phenylpyrazine (7.00 g; 0.0315 mole) was dissolved in 40.00 g (0.26 mole) of phosphorus oxychloride, and while the solution was cooled to 5° to 10° C., 3.53 g (0.035 mole) of triethylamine was added dropwise over the period of 20 minutes. After the addition, the mixture was stirred at 70° to 80° C. for 1.5 hours. The reaction mixture was worked up in the same way as in Example 3, and recrystallized from benzene to afford 6.10 g (yield 80%) of 2,3-dicyano-5-chloro-6-phenylpyrazine.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:3]1=[O:12].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)#[N:14].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:6]2[N:2]([CH3:1])[C:3](=[O:12])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:5]2=[O:7])=[CH:17][CH:16]=1)#[N:14]
Reactant: CN1CC(=O)N(CC(=O)O)C1=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN1C(=O)N(CC(=O)O)C(=O)C1=Cc1ccc(C#N)cc1

Procedure:
2.6 g (15 mmol) of (1-methyl-2,4-dioxoimidazolidin-3-yl)-acetic acid, 2.9 g (22 mmol) of 4-cyanobenzaldehyde, 1.8 g (22 mmol) of sodium acetate and 2.1 ml (22 mmol) of acetic anhydride are heated under reflux in 25 ml of acetic acid for 6 hours. After cooling, the mixture is poured onto ice and extracted with ethyl acetate. The ethyl acetate phase is extracted with sodium bicarbonate solution and the aqueous phase is acidified. The product which has precipitated is filtered off with suction and dried.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](OC)(=O)C(OC)=O.CC(C)([O-])C.[K+]>CN(C=O)C.O>[CH3:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2ccccc21
Temperature: 25 °C
Yield: 226.3 %

Procedure:
To a solution of the indole product from Example 52 (160 mg, 0.539 mmol) and dimethyl oxalate (70 mg, 0.59 mmol) in DMF (5 mL), potassium tert-butoxide (66 mg, 0.59 mmol) was added in one portion at room temperature under nitrogen. The reaction mixture was warmed to reflux under nitrogen for 30 min and then was cooled to room temperature. The mixture was diluted with water (50 mL) and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, EtOAc/hexanes, 1:1) to afford the N-methyl indole product as a white solid (160 mg, 96%): mp 90-92° C.; 1H NMR (300 MHz, CDCl3) δ 7.03-7.23 (m, 6H), 6.71 (d, J=8.5 Hz, 1H), 6.41 (dd, J=3.0, <1 Hz, 1H), 4.33 (t, J=7.5, 5.0 Hz, 1H), 3.94 (d, J=15.1 Hz, 1H), 3.88 (d, J=15.1 Hz, 1H), 3.74 (s, 3H), 3.01 (dd, J=11.4, 5.0 Hz, 1H), 2.66 (dd, J=11.4, 7.5 Hz, 1H), 2.48 (s, 3H); CI MS m/z=311 [C19H19ClN2+H]+; IR (KBr) 2937, 2766, 1594, 1497, 1265 cm−1; Anal. Calcd for C19H19ClN2-0.l H2O: C, 73.00; H, 6.19; N, 8.96. Found: C, 72.78; H, 6.09; N, 8.78.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.C(O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH2:13][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:3]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: O=C(OCc1ccccc1)c1cc(Cl)c(Cl)c(Cl)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A mixture of methyl 4,5,6-trichloropicolinate (25 g, 0.10 moles (mol)) and benzyl alcohol (100 g, 0.2 mol) in a 250 mL three-neck round bottom flask was heated under nitrogen at 100° C. Titanium isopropoxide (0.6 g, 0.02 mol) was added. After 4 h at 100° C., the nearly colorless solution was cooled and transferred to a 250 mL round bottom single neck flask. Excess benzyl alcohol was removed under vacuum to give a nearly white solid (31 g, 94%): mp 125-126.5° C.; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H, pyridine H), 7.42 (m, 2H, phenyl), 7.31 (m, 3H, phenyl), 5.40 (s, 2H, CH2Ph); 13C{1H} NMR (101 MHz, CDCl3) δ 162.0 (CO2R), 150.4, 145.0, 144.9, 134.7, 133.1, 128.3 (phenyl CH), 125.4 (pyridine CH), 67.88 (CH2Ph).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20]#[N:21]>CN(C)C=O.O>[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]#[N:21])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: N#CCCl
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
10.88 g of a 50% sodium hydride suspension in mineral oil are diluted with 230 ml of absolute dimethylformamide and treated within 30 minutes with a solution of 50 g of p-(p-chlorophenoxy)phenol in 230 ml of absolute dimethylformamide while the temperature rises slightly. The mixture is then stirred at room temperature for 30 minutes. A solution of 18.8 g of chloroacetonitrile in 200 ml of absolute dimethylformamide is added dropwise while cooling the mixture in a water-bath. The mixture is stirred at 50° C. overnight, then cooled and diluted with 1 liter of water. This mixture is extracted five times with 200 ml of ethyl acetate each time. The organic phases are washed twice with 100 ml of 2-N sodium carbonate solution, once with 100 ml of saturated sodium chloride solution and then dried over magnesium sulfate and evaporated. The crude product (80 g of a dark oil) is purified by chromatography on silica gel using toluene for the elution to yield 45 g of [p-(p-chlorophenoxy)phenoxy]acetonitrile (76%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-])=O.C(O)C.O.O.[Sn](Cl)Cl>C(=O)(O)[O-].[Na+]>[CH2:11]1[C:12]2[NH:13][C:14]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=3)[C:7]=2[CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2[nH]c3c(c2c1)CCCC3
Temperature: 70 °C
Yield: 95.3 %

Procedure:
6-Nitro-2,3,4,9-tetrahydro-1H-carbazole (0.100 g, 0.462 mmol) was dissolved in a 40 mL scintillation vial containing a magnetic stir bar and 2 mL of ethanol. Tin(II) chloride dihydrate (1.04 g, 4:62 mmol) was added to the reaction mixture and the resulting suspension was heated at 70° C. for 16 h. The crude reaction mixture was then diluted with 15 mL of a saturated aqueous solution of sodium bicarbonate and extracted three times with an equivalent volume of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate, and evaporated to dryness to yield 2,3,4,9-tetrahydro-1H-carbazol-6-amine (82 mg, 95%) which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]1[CH2:20][O:19][C:18]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[O:11]1>>[CH2:10]1[CH2:20][O:19][C:18]2[CH:17]=[CH:16][C:14]([NH:15][C:2]3[N:7]=[C:6]([NH:15][C:14]4[CH:16]=[CH:17][C:18]5[O:19][CH2:20][CH2:10][O:11][C:12]=5[CH:13]=4)[C:5]([F:9])=[CH:4][N:3]=3)=[CH:13][C:12]=2[O:11]1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3,4-ethylenedioxyaniline were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.88 (d, 1H, J=3.6 Hz), 7.23 (d, 1H, J=2.3 Hz), 7.15 (d, 1H, J=2.4 Hz), 7.00 (dd, 1H, J=3 and 8.1 Hz), 6.98 (dd, 1H, J=3 and 8 Hz), 6.83 (d, 1H, J=8.7 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.7 (s, 1H), 6.58 (s, 1H), 4.23 (m, 4H), 4.24 (m, 4H); 19F NMR (CDCl3): δ −47445; LCMS: ret. time: 21.81 min.; purity: 96%; MS (m/e): 397 (MH+).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:12]([O:16][C:17](=[O:20])[CH:18]=[CH2:19])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.P(OC)(OC)OC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:12]([O:16][C:17](=[O:20])[CH:18]=[CH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Brc1cncc2ccccc12
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COP(OC)OC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C=Cc1cncc2ccccc12
Temperature: 120 °C

Procedure:
To a mixture of 3 g of 4-bromoisoquinoline, 6.2 mL of acrylic acid tert.-butyl ester and 2.66 mL of DIPEA in 30 mL of DMF under argon was added 0.169 mL of P(OMe)3 and 160 mg of Pd(OAc)2. The reaction mixture was heated for 2 h at 120° C. and the DMF was evaporated under vacuo. The resulting residue was diluted with DCM and filtered over a pad of silica gel. The filtrate was washed with 10%-citric acid, water and brine. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc from 94/6 to 50/50 as eluant to yield 2.7 g of 3-isoquinolin-4-yl-acrylic acid tert.-butyl ester as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH2:22][NH2:23])=[CH:7]2.CCN(C(C)C)C(C)C.Cl[C:34]1[N:42]=[CH:41][N:40]=[C:39]2[C:35]=1[NH:36][CH:37]=[N:38]2>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:19])[F:20])[C:8]([CH2:22][NH:23][C:34]1[N:42]=[CH:41][N:40]=[C:39]3[C:35]=1[N:36]=[CH:37][NH:38]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Cc1cccc2cc(CN)c(-c3ccccc3C(F)(F)F)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cccc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure H using (8-methyl-2-(2-(trifluoromethyl)-phenyl)quinolin-3-yl)methanamine (0.1 g, 0.316 mmol, 1 eq) in EtOH (2 mL) was treated with iPr2NEt (0.07 mL, 0.4 mmol, 1.2 eq) followed by 6-chloropurine (0.049 g, 0.317 mmol, 1 eq). After purification, N-((8-methyl-2-(2-(trifluoro-methyl)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine as yellow syrup. The yellow syrup was triturated with CH2Cl2 and filtered to provide N-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=91nM] as yellow syrup. 1H NMR (DMSO-d6) δ ppm 12.93 (1 H, s), 7.98-8.31 (4 H, m), 7.90 (1 H, d, J=7.8 Hz), 7.74-7.82 (2 H, m), 7.69 (2 H, t, J=6.5 Hz), 7.59 (1 H, d, J=7.0 Hz), 7.42-7.52 (1 H, m), 4.42-4.77 (2 H, m), 2.62 (3 H, s). Mass Spectrum (ESI) m/e=435.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)CC.OCC(C)(CO)C.CC(C)=O>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]1([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1ccc(B(O)O)cc1
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(CO)CO
Solvent: CC(C)O
Solvent: CC(C)=O
Product: c1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 89 %

Procedure:
A solution of (2 mmol) of 8, (2.2 mmol) of 4-propylphenylboronic acid, 250 mg (2.40 mmol) of neopentyl glycol, 1:53 g (4.84 mmol) of Ba(OH)2. 8H2O, 1.35 ml (0.103 mmol, 5 mol %) of a 76 mM acetone solution of Pd(OAc)2 in 20 ml of 95% i-PrOH is stirred at 80° for 12 hours. The solvent is subsequently removed under reduced pressure. 5 ml of 2 M HCl are added to the residue, and the mixture is extracted with dichloromethane (3×5 ml). The combined organic phases are dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, and the residue is converted into 10 (yield: 89%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[CH3:20])[CH:3]=1.[N:34]1([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O>[CH3:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[CH:15][C:14]=1[NH:13][C:9]1[N:8]([C:4]2[CH:3]=[C:2]([NH:48][C:45]3[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[CH:43][CH:44]=3)[N:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(CCN2CCOCC2)cc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nccn1-c1cc(Cl)ncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nccn1-c1cc(Nc2ccc(CCN3CCOCC3)cc2)ncn1

Procedure:
A Smith vial (2-5 mL) is charged with N-{3-[1-(6-chloro-pyrimidin-4-yl)-1H imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (16.8 mg, 0.035 mmol), 4-(2-morpholin-4-yl-ethyl)-phenylamine (22 mg, 0.11 mmol), p-toluenesulfonic acid monohydrate (4.4 mg, 0.023 mmol) and DMSO (0.5 mL). After purging with Argon, the vial is sealed and irradiated at 100° C. for 1.5 hours in a Smith Synthesizer. The resulting solution is subjected to purification by reverse-phase LC-MS to yield the title compound. 1H NMR 600 MHz (DMSO-d6) δ 11.00 (s, 1H), 10.54 (s, 1H), 10.09 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.97 (d, J=6.6 Hz, 1H), 7.79 (t, J=8.4 Hz 1H), 7.64 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.28 (m, 3H), 7.06 (s, 1H), 6.95 (s, 1H), 4.03 (d, J=12.6 Hz, 2H), 4.03 (d, J=12.6 Hz, 2H), 3.69 (t, J=12.6 Hz, 2H), 3.52 (d, J=12.0 Hz, 2H), 3.36 (t, J=7.8 Hz, 2H), 3.13 (br, 2H), 2.98 (t, J=7.8 Hz, 2H), 2.33 (s, 3H); MS m/z 643.4 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([CH2:23][CH2:24][CH2:25][CH3:26])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].[NH2:28][CH2:29][C@@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[OH:31]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([CH2:23][CH2:24][CH2:25][CH3:26])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][CH2:18][CH:19]([NH:28][CH2:29][C@H:30]([OH:31])[C:32]3[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=3)[CH2:20][CH2:21]2)=[CH:12][CH:11]=1)(=[O:8])=[O:9])[CH3:2]
Reactant: CCCCN(CC(=O)OCC)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCCCN(CC(=O)OCC)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 from 1.03 g (2.6 mmol) of Reference Example 43, {butyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic acid ethyl ester, and 0.77 g (3.1 mmol) of (R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide, yielding 1.05 g of a light yellow solid; m.p. 94-95° C.; MS (ES) m/z 627.2 (MH+); HRMS (ES) Calcd. for C28H43N4O8S2 (MH+): 627.2517, Found: 627.2505.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][O:3]2.C1(C)C=CC=CC=1.C[Al](C)C.[Cl:20][C:21]1[C:22]2[N:23]([C:31]([C:34](OCC)=[O:35])=[N:32][N:33]=2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.Cl>C1COCC1>[C@H:2]12[CH2:8][C@H:5]([N:6]([C:34]([C:31]3[N:23]4[CH:24]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:26]=[C:21]([Cl:20])[C:22]4=[N:33][N:32]=3)=[O:35])[CH2:7]1)[CH2:4][O:3]2
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: CCOC(=O)c1nnc2c(Cl)cc(C(F)(F)F)cn12
Agent: C[Al](C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(c1nnc2c(Cl)cc(C(F)(F)F)cn12)N1C[C@@H]2C[C@H]1CO2
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a mixture of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (100 mg) and anhydrous THF (4 mL) was added dropwise trimethylaluminium toluene solution (1.8 M, 0.410 mL) in an ice bath. The reaction solution was stirred at the same temperature for 1 hr under argon gas atmosphere, ethyl 8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (180 mg) was added thereto, and the mixture was stirred at room temperature for 2 days. The reaction mixture was slowly added to 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (47 mg).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)#[N:4].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[S:15]>O>[CH3:12][N:13]([CH3:17])[C:14]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=1)=[S:15]
Reactant: CN(C)C(=S)Cl
Reactant: N#Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C)C(=S)Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.6 %

Procedure:
Add sodium hydride (1.21 g, 95%) to a solution of 4-cyanophenol (5.71 g, 47.98 mmol) in anhydrous TI-IF (70 mL) and stir the mixture for 5 min. Add dimethylthiocarbamoyl chloride (5.93 g, 47.98 mmol) and heat the mixture at reflux for 3 h. Cool the mixture to room temperature and add water. Extract the aqueous phase with EtOAc, dry the organic phase over MgSO4, filter and concentrate in vacuo to obtain a solid. Wash the solid with diethyl ether, filter and dry in vacuo to obtain the desired intermediate as a solid (4.41 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][S:7][CH:8]([CH2:11][OH:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:27]=[CH:26][C:20](/[CH:21]=[C:22](\[CH3:25])/[CH:23]=O)=[CH:19][CH:18]=1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7][C@@H:8]2[CH2:11][O:12][C@@H:23](/[C:22](/[CH3:25])=[CH:21]/[C:20]3[CH:26]=[CH:27][C:17]([C:16]([F:15])([F:28])[F:29])=[CH:18][CH:19]=3)[O:10][CH2:9]2)=[CH:13][CH:14]=1
Reactant: OCC(CO)SCc1ccc(Cl)cc1
Reactant: C/C(C=O)=C\c1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C/C(=C\c1ccc(C(F)(F)F)cc1)[C@H]1OC[C@H](SCc2ccc(Cl)cc2)CO1

Procedure:
In 12 ml of benzene were dissolved 341 mg (1.46 mmol) of 2-[(4-chlorobenzyl)thio]-1,3-propanediol and 375 mg (1.75 mmol) of (E)-4-(trifluoromethyl)-a-methylcinnamaldehyde, and 3 mg of p-toluenesulfonic acid were added to the solution, followed by heating of the resulting mixture with reflux under nitrogen atmosphere for 2 hours. After cooling, the reaction mixture was washed with an aqueous sodium hydrogencarbonate solution. The residue obtained by evaporation of the solvent was subjected to column chromatography using 15 g of silica gel. The fractions eluted with a mixed solvent of hexane-ethyl acetate (9:1) were collected and the thus obtained solid was washed with hexane to obtain 370 mg (yield: 59%) of the title compound having a melting point of 93 to 95° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:19]>CO.CCCCCC>[CH3:19][O:16][C:15]([CH:9]1[CH2:10][C:11](=[O:14])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:17]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C[C@H]1C(=O)O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (2S)-4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.52 g, 2.15 mmol) in methanol (10 mL), 2 M solution of TMS-diazomethane (2 mL, 4 mmol) in hexane was added and stirred at room temperature for 15 min. The reaction solvent was removed and the methyl ester product obtained (4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester) was used as such for the next reaction (0.55 g, 100%): MS (ESPOS): 258 [M+H]+; 1H NMR (300 MHz, CD3OD) δ 5.13, 4.86 (bs, 1), 4.02-4.11 (m, 1), 3.73 (s, 3), 3.67-3.72 (m, 1), 2.78 (d, J=4.2 Hz, 2), 2.51 (bs, 2), 1.46 (bs, 9).
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.[CH3:18][C:19]1[N:20]=[C:21]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])[S:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:31]2[CH2:32][CH2:33][N:29]([C:21]3[S:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:19]([CH3:18])[N:20]=3)[C:30]2=[O:34])=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Fc1ccc(CBr)cc1
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 98 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-fluorobenzyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 98% yield: MS (ES+) m/z 364.2 (M+1).