Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:6](O)[C@@H:5]([OH:8])[C@H:4]([OH:9])[CH2:3][C@@:2]1([C:11]([OH:13])=[O:12])[OH:10].CN(C=O)C.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[OH:10][C:2]12[CH2:1][CH:6]([O:13][C:11]1=[O:12])[CH:5]([OH:8])[CH:4]([OH:9])[CH2:3]2
Reactant: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C1OC2CC1(O)CC(O)C2O
Temperature: 25 °C
Yield: 77.3 %

Procedure:
In a 200 mL round-bottom flask fitted with a stirring bar, reflux condenser, Dean-Stark trap, and argon inlet, 5 g of quinic acid (1, 26 mmol) was placed and 10 mL of dry DMF was added via syringe and the slurry stirred at room temperature. Next, benzene 60 mL and p-toluenesulfonic acid 0.5 g were added, and the slurry was heated to reflux for 26 h. TLC was used confirm the completion of reaction. A 1:1 mixture of EtOAc and 12eptanes (100 mL) was added to the cooled reaction mixture. The mixture was stirred for 1 h at room temperature and filtered. The collected solid was again stirred with a 1:1 mixture of EtOAc and 12eptanes (100 mL) for 1 hr at room temperature and filtered. Titration was repeated one more time with a 1:1 mixture of EtOAc and 12eptanes (100 mL) and the precipitate collected to give 3.5 g of Lactone 2 (78% yield). Mp: 192-193° C., Rf 0.25 (EtOAc); MS: [M-H]−: 171; 1H NMR (300 MHz, DMSO) δ 1.72 (t, J=1.6 Hz, 1H), 1.82-1.88 (m, 1H), 2.07-2.13 (m, 1H), 2.25 (d, J=1.1 Hz, 1H), 3.49 (ddd, J=11.4, 6.3, 5.7 Hz, 1H), 3.82 (t, J=4.5 Hz, 1H), 4.61 (t, J=5.1 Hz, 1H), 4.816 (d, J=6.0 Hz, 1H), 5.23 (d, J=4.5 Hz, 1H), 5.89 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([C:18](I)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=1)#[CH:23]>>[F:1][C:2]1[C:3]2[N:4]([C:18]([C:23]#[C:22][C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Fc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Reactant: C#Cc1ccc(N)nc1
Product: Nc1ccc(C#Cc2cnc3c(F)cc(-c4ccc(C(F)(F)F)cc4)cn23)cn1

Procedure:
The title compound was prepared from 8-fluoro-3-iodo-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.29 step 6) (350 mg, 0.85 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (122 mg, 0.85 mmol) according to general procedure II. Obtained as an off-white solid (130 mg, 38%). MS (ISP) 397.2 [(M+H)+]; mp 281-282° C.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:12][C:11]=1[S:25]([NH2:28])(=[O:27])=[O:26]>C(#N)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[CH:12][C:11]=1[S:25]([N:28]=[CH:3][N:4]([CH3:5])[CH3:6])(=[O:27])=[O:26]
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1cc(C(=O)c2ccc(O)cc2)ccc1Cl
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc(C(=O)c2ccc(O)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
A solution of N,N,-dimethylformamide dimethyl acetal (1.2 g, 10.1 mmol) in acetonitrile (10 mL) is slowly added to a solution of 2-chloro-5-(4-hydroxy-benzoyl)-benzenesulfonamide (2.61 g, 8.4 mmol) in acetonitrile (10 mL). The reaction is allowed to stir for 5 hours at ambient temperature. Volatiles were removed in vacuo. The residue is partitioned between ethyl acetate and water, the organic layer is separated and the solvent is removed in vacuo, affording 2.5 g (81% yield) of the title compound which is carried on directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(N(CC)CC)C.[OH-].[Na+]>N1C=CC=CC=1>[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:6]([C:5]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:7]
Reactant: Cn1ccnc1
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2nccn2C)cc([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 16.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 80 ml of pyridine is added dropwise to a solution of 2.68 g of 1-methylimidazole and 6.6 g of triethylamine in 80 ml of pyridine, whereupon the mixture is stirred at 60° for 3 hours. After treatment with 1.70 ml of 3N sodium hydroxide solution the mixture is stirred for an additional 1 hour and subsequently poured into ice-water. The separated grey crystals are filtered under suction and taken up in ethyl acetate, whereupon the organic phase is dried over magnesium sulfate and the solvent is distilled. After recrystallization from ethyl acetate/hexane there is obtained 3,4-dimethoxy-5-nitrophenyl (1-methylimidazol-2-yl) ketone in the form of colorless crystals of m.p. 144°-145°.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])O1>>[C:41]([C:40]1[CH:43]=[C:36]([C:2]2[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:37]=[N:38][CH:39]=1)#[N:42]
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncc(C#N)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 156.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a white solid. UPLC-MS (Condition 3) tR=1.05 min, m/z=472.2 [M+H]+, m/z=470.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=6.97 Hz, 3H) 3.14 (q, J=7.01 Hz, 2H) 3.32-3.41 (m, 2H) 3.49 (q, J=5.71 Hz, 2H) 4.62 (t, J=5.26 Hz, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.77-7.92 (m, 2H) 8.10 (d, J=2.20 Hz, 1H) 8.54 (t, J=1.96 Hz, 1H) 8.78 (d, J=2.20 Hz, 1H) 9.04 (dd, J=5.50, 2.08 Hz, 2H) 10.25 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[C:27][Si](C)(C)C)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[CH:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Yield: 79.7 %

Procedure:
The (4-benzyloxy-phenyl)-(6-(trimethylsilylethynyl)quinazolin-4-yl)-amine (0.65 g, 1.53 mmol) was reacted with tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 5.0 ml, 5.0 mmol) at room temperature for 20 min. The solvent was removed in vacuo, and the residual oil was partitioned between water (20 ml) and ethyl acetate (20 ml). After separation, the aqueous was extracted with further ethyl acetate (2×20 ml). The combined organic solutions were dried (Na2SO4) and concentrated in vacuo to give the title compound as an off-white solid (0.43 g, 1.22 mmol, 80%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21]>C(#N)C>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:20](=[O:21])[C:19]([F:26])([F:25])[F:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCCc1ccccc1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 9.37 g (69.3 mM) of 3-phenylpropylamine and 14 ml (100.4 mM) of triethylamine in acetonitrile (70 ml) was added 16.4 ml (122.7 mM) of ethyl trifluoroacetate at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. The solvent was then distilled off and the residue was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. The organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=O)[C:5](=[O:8])[NH:6][N:7]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:19][C:9]([C:4]1[C:5](=[O:8])[NH:6][N:7]=[C:2]([Cl:1])[CH:3]=1)=[O:11]
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1cc(Cl)n[nH]c1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1cc(Cl)n[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
30.5 g of 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 18 g of ortho-phenylenediamine and 2 g of DMAP are dissolved in 800 ml of DMF, at room temperature 32.2 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added, and the resulting solution is stirred at room temperature for 4 hours. For workup, the solvent is distilled off and the residue is suspended in water at 70° C. The precipitate is filtered off, washed several times with water and then dried in vacuo.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[N:9]=1.Cl[C:16]1[C:17]2[CH2:27][CH2:26][CH2:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[C:18]=2[N:19]=[C:20]([NH2:22])[N:21]=1>>[NH2:14][C:10]1[N:9]=[C:8]([NH:7][CH2:6][CH2:5][N:4]([CH3:3])[C:16]2[C:17]3[CH2:27][CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[C:18]=3[N:19]=[C:20]([NH2:22])[N:21]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CNCCNc1ccnc(N)n1
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Agent: Cl
Product: CN(CCNc1ccnc(N)n1)c1nc(N)nc2c1CCCc1ccccc1-2

Procedure:
The product from Example 2A (95 mg, 0.237 mmol) and the product from Example 1C (50 mg, 0.203 mmol) were combined under the conditions described in Example 1F to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.62-7.67 (m, 1H) 7.58 (d, J=5.43 Hz, 1H) 7.28-7.37 (m, 2H) 7.23-7.28 (m, 1H) 6.89 (s, 1H) 5.94 (s, 2H) 5.82 (s, 2H) 5.70 (d, J=5.76 Hz, 1H) 3.43-3.55 (m, 4H) 2.99-3.04 (m, 3H) 2.50-2.58 (m, 2H) 2.15 (dd, J=16.11, 5.93 Hz, 4H); MS (ESI+) m/z 377.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([Cl:12])([Cl:11])[C:3]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][N:9]=1)=[O:4].C1C(=O)N([Br:20])C(=O)C1>C1COCC1>[Br:20][C:8]1[N:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:11])[Cl:12])[N:6]([CH3:10])[CH:7]=1
Reactant: Cn1ccnc1C(=O)C(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cn1cc(Br)nc1C(=O)C(Cl)(Cl)Cl
Temperature: -10 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To the solution of 2,2,2-trichloro-1-(1-methyl-1H-imidazol-2-yl)ethanone (1.5 g, 6.6 mmol) in 26 mL of anhydrous THF was added 2.35 g of NBS at −10° C. The resulting mixture was stirred at −10° C. for 2 h, then 25° C. for 16 h. The solution was evaporated and the residue was purified by silica gel column (DCM as eluent) to give 1-(-4-bromo-1-methyl-1H-imidazol-2-yl)-2,2,2-trichloroethanone (1.18 g, yield 58%). 1H NMR (300 MHz, CDCl3) δ 7.15 (s, 1H), 4.05 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][NH:6][C:7](=[O:36])[CH2:8][CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[N:21]=[C:20]([C:22]3[S:23][C:24]([CH2:28][N:29]([CH:31]([CH3:33])[CH3:32])[CH3:30])=[C:25]([CH3:27])[CH:26]=3)[O:19][N:18]=2)=[CH:12][C:11]=1[CH2:34][CH3:35])C>C(O)C.[OH-].[Na+]>[CH2:34]([C:11]1[CH:12]=[C:13]([C:17]2[N:21]=[C:20]([C:22]3[S:23][C:24]([CH2:28][N:29]([CH:31]([CH3:33])[CH3:32])[CH3:30])=[C:25]([CH3:27])[CH:26]=3)[O:19][N:18]=2)[CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][CH2:8][C:7]([NH:6][CH2:5][C:4]([OH:37])=[O:3])=[O:36])[CH3:35]
Reactant: CCOC(=O)CNC(=O)CCc1c(C)cc(-c2noc(-c3cc(C)c(CN(C)C(C)C)s3)n2)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(C)C(C)C)s3)n2)cc(C)c1CCC(=O)NCC(=O)O
Yield: 89.1 %

Procedure:
A solution of {3-[2-ethyl-4-(5-{5-[(isopropyl-methyl-amino)-methyl]-4-methyl-thiophen-2-yl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenyl]-propionylamino}-acetic acid ethyl ester (5 mg, 9 μmol) in ethanol (500 μL) and 1 N aq. NaOH (100 μL) is stirred at rt for 1 h before it is concentrated, diluted with formic acid (1 mL) and separated by prep. HPLC (column: Atlantis T3 C18, 30×75 mm, 10 μm, eluting with a gradient of acetonitrile in water containing 0.5% of formic acid) to give the title compound (4 mg) as a resin; LC-MS*: tR=0.66 min; [M+1]+=498.97, 1H NMR (D6-DMSO): δ 1.05 (d, J=6.5 Hz, 6H), 1.23 (t, J=7.3 Hz, 3H), 2.23 (s, 6H), 2.28-2.35 (m, 2H), 2.41 (s, 3H), 2.74 (q, J=7.5 Hz, 2H), 2.87-2.98 (m, 3H), 3.70 (s, 2H), 3.76 (d, J=5.5 Hz, 2H), 7.69 (s, 2H), 7.81 (s, 1H), 8.23 (t br, J=5.5 Hz).
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(OCC)(=O)C>CCOCC>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:15]2[CH:16]=[N+:17]([O-:37])[CH:18]=[CH:19][CH:20]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1cccnc1)c1cc(F)ccc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1ccc[n+]([O-])c1)c1cc(F)ccc1F
Reaction time: 24 h
Yield: 40.2 %

Procedure:
To methylene chloride (15 ml) of the 3-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine (162 mg, 0.427 mmol) obtained in Example 19 was added 3-chloroperbenzoic acid (81 mg, 0.47 mmol). The resulting mixture was stirred for 24 hours. The reaction mixture was diluted with ether (60 ml). The diluted mixture was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried and filtered. The filtrate was concentrated under reduced pressure to give a residue. The resulting residue was subjected to silica gel chromatography (ethyl acetate) to give the title compound (68 mg, 40%). The compound was crystallized from ethanol to afford colorless needle crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=O.[CH3:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][NH2:26])[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[CH3:16][O:15][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH3:14])[C:6]([NH:26][CH2:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[CH:19]=1)=[O:8]
Reactant: Cc1cccc(CCN)c1
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1
Solvent: ClCCl
Product: COc1cc(C(=O)NCCc2cccc(C)c2)cc(OC)c1OC

Procedure:
A solution of methyl 3,4,5-trimethoxybenzoate (31.1 g, 0.138 mol) and 2-(3-methylphenyl)ethylamine (18.6 g, 0.138 mol) was heated at 180° for 6 h. The dark reaction mixture was taken up in methylene chloride and washed with dilute HCl. The solvent was evaporated and the residue was chromatographed on 150 g of neutral alumina. Elution with methyl chloride/hexane (3:1) removed some by-products and elution with methylene chloride gave nearly pure amide F1 which was recrystallized from i-PrOH to give pure F1 (5.2 g, 11%), mp 105-108°.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 72 h

Procedure:
Benzyl bromide (13.1 ml) was added to a stirred mixture of 2-bromo-4-chlorophenol (20.7 g) and potassium carbonate (27.6 g) in DMF (200 ml). After 72 h, the mixture was partitioned between diethylether and water, the organic layer washed with water, dried and the solvent evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 2% EtOAc/isohexane. Yield 18.1 g
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]=O)=[C:10]([O:17][CH:18]([CH3:20])[CH3:19])[CH:9]=2)[CH2:4][CH2:3]1.CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[C:54]2[N:55]=C(S(C)(=O)=O)[N:57]=[CH:58][C:53]=2[S:52][C:51]=1[C:63]([O:65][CH3:66])=[O:64]>CN(C=O)C.C(OCC)(=O)C>[CH3:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[C:54]2[N:55]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:9][C:10]=3[O:17][CH:18]([CH3:20])[CH3:19])[N:57]=[CH:58][C:53]=2[S:52][C:51]=1[C:63]([O:65][CH3:66])=[O:64]
Reactant: CC(C)Oc1cc(C2CCN(C)CC2)ccc1NC=O
Reactant: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1-c1ccccc1OC
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1sc2cnc(Nc3ccc(C4CCN(C)CC4)cc3OC(C)C)nc2c1-c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A mixture of 527 mg of N-[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]formamide and 953 mg of 1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]-pyrrolidine (BTPP) in 10 ml of anhydrous DMF is stirred at ambient temperature for 30 min, and then a solution of 577 mg of methyl 7-(2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate in 15 ml of anhydrous DMF is slowly added. The mixture is stirred at ambient temperature for 48 h, and then diluted with ethyl acetate and washed three times with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product is purified on 80 g of silica, elution being carried out with 5-10% of methanol in dichloromethane, so as to obtain 615 mg of methyl 7-(2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxylate in the form of a yellow solid. The crude product is diluted with 600 ml of 7N ammoniacal methanol and the solution is stirred at ambient temperature for 48 h, and then concentrated under vacuum. The residue is solubilized with 100 ml of hot ethyl acetate and the solution is left to cool in order to obtain a suspension. The suspension is cooled in an ice bath and filtered. The solid is washed with ethyl ether and dried under vacuum, so as to obtain 477 mg of 7-(2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide in the form of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:5][C:4]=1[C:17]#[C:18][Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:17]([C:4]1[CH:5]=[C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])#[CH:18]
Reactant: COc1ccc(NC2CCN(C)CC2)cc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(NC2CCN(C)CC2)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of N-{4-methoxy-3-[(trimethylsilyl)ethynyl]phenyl}-1-methylpiperidin-4-amine (128 mg, 0.404 mmol) in methanol (2 mL) powdered anhydrous potassium carbonate (56 mg, 0.404 mmol) was added and the mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum and the residue was taken up with EtOAc (30 mL). The solution obtained was washed with brine, (3×5 mL), water (5 m), dried over sodium sulfate and the solvent was removed under vacuum. The dark brown oil was purified by flash chromatography (EtOAc/MeOH/33% NH4OH 90/10/0.1) to yield the title compound as a yellow solid (85 mg, 86%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH:12]([CH2:29]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([OH:34])(=[S:33])[CH3:32]>>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)(=[O:17])=[O:18])[CH2:13][CH:12]([CH2:29][S:33][C:31](=[O:34])[CH3:32])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CC(CO)CC(COCc2ccccc2)C1
Reactant: CC(O)=S
Product: CC(=O)SCC1CC(COCc2ccccc2)CN(S(=O)(=O)c2ccc3ccccc3c2)C1

Procedure:
(3SR,5RS)-[5-Benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidin-3-yl]-methanol (1.35 g) was reacted with thioacetic acid (see Mitsunobu reaction described in Example 17) to obtain thioacetic acid (3SR,5RS)-S-[5-benzyloxymethyl-1-(naphthalene-2-sulfonyl)-piperidin-3-ylmethyl] ester (0.92 g) as a syrup, MS: 484 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:14][C:11]1[C:10]([NH2:13])=[CH:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(-c2ccccc2)nc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a solution of 1B (85 mg, 0.5 mmol) in DMF (1 mL) at RT was added N-bromosuccinimide (89 mg, 0.5 mmol). The reaction was stirred at RT for 16 h. After this time, no starting material was detected by LC-MS. The reaction was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel (10 g) column chromatography, eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as a light brown foam (100 mg, 80%). LC/MS (method A): retention time=2.96 min, (M+H)+=249. 1H NMR (CDCl3, 400 MHz): δ 7.80-7.91(m, 2H), 7.50 (d, J=8.2 Hz, 1H), 7.38-7.44 (m, 2H), 7.31-7.35 (m, 1H), 7.05 (d, J=8.2 Hz, 1H), 4.15 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].F[B-](F)(F)F.[O:15]=[N+:16]=[O:17]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([N+:16]([O-:17])=[O:15])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: O=[N+]=O
Reactant: Cc1cc(F)ccc1Br
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 0 °C
Yield: 96.4 %

Procedure:
To a stirred solution of 1-bromo-4-fluoro-2-methyl-benzene (15.0 g, 79.8 mmol) in dichloromethane (300 mL) was added nitronium tetrafluoroborate (11.7 g, 87.8 mmol) in portions at 0° C. The mixture was heated at reflux for 5 h and was then poured into ice water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give crude 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (18.0 g), which was used directly in the next step.