Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([F:20])[CH:3]=1.[CH2:21]([S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:22].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:28]=[CH:27][C:26]([S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:31][CH:30]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([F:20])[CH:3]=1
Reactant: Cn1cc(C(=O)/C=C/c2ccc(Cl)cc2F)ccc1=O
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: C1=CCCC=CCC1
Solvent: O
Product: CCS(=O)(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)cc1

Procedure:
In analogy to example 203, step 1, (E)-5-(3-(4-chloro-2-fluorophenyl)acryloyl)-1-methyl-pyridin-2(1H)-one (example 314, step 2) was reacted with 4-(ethylsulfonyl)phenylboronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a yellow foam, MS (ESI+): m/z=462.2 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[C:19]([C:21]#[N:22])[CH:20]=[C:8]2[C:7]=1[OH:23])=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][C:26]=1[S:36]([NH2:39])(=[O:38])=[O:37].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[C:21]([C:19]1[CH:20]=[C:8]2[C:7]([OH:23])=[C:6]([C:4]3[NH:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:27][C:26]=4[S:36](=[O:38])(=[O:37])[N:39]=3)[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[N:9]2[CH:18]=1)#[N:22]
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CCOC(=O)c1c(O)c2cc(C#N)cn2n(CCC(C)C)c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cc(C#N)cn21
Temperature: 120 °C
Yield: 6.7 %

Procedure:
A solution of 6-cyano-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 15e, 0.25 g, 0.788 mmol) and 2-amino-5-methanesulfonylamino-benzenesulfonamide (Example 3d, 0.209 g, 0.788 mmol) in pyridine (4 mL) was heated to 120° C. for 3 h. 1,8-Diazabicyclo[5.4.0]undec-7-ene (200 μL) was added and the mixture was heated at 120° C. for 16 h. The reaction mixture was passed through a plug of silica gel and eluted with 50%→100% ethyl acetate in hexanes. The solvents were removed in vacuo and purification by preparative HPLC (Column Luna 5μ C18 (2) 100 Å size 150×21.2 mm, 5 micron, 40%-95% in 11 min 25 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water) afforded the desired product, N-{3-[6-cyano-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.0275 g, 0.0531 mmol, 6.7% yield). 1H NMR (400 MHz, DMSO-d6) δ: 0.94 (3H, s), 0.96 (3H, s), 1.17-1.23 (2H, m), 1.51-1.57 (2H, m), 1.65-1.75 (1H, m), 5.74 (1H, s), 3.05 (3H, s), 7.40 (1H, s), 7.49-7.57 (3H, m), 8.51 (1H, s), 10.12 (1H, s), 13.75 (1H, s). LC-MS (ESI) calcd for C21H22N6O6S2 518.10, found 519.4 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([C:15]([O-:17])=O)=[CH:4][CH:3]=1.[Na+].C(Cl)CCl.C1C=CC2N(O)N=[N:29]C=2C=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([C:15]([NH2:29])=[O:17])=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C([O-])c1ccc(Cl)nc1CN1CCOCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(Cl)nc1CN1CCOCC1
Reaction time: 24 h

Procedure:
Sodium 6-chloro-2-(morpholin-4-ylmethyl)pyridine-3-carboxylate (0.3 g, 1.077 mmol), EDC (0.619 g, 3.23 mmol), HOBt (0.495 g, 3.23 mmol), ammonium chloride (0.173 g, 3.23 mmol) and DIPEA (1.128 mL, 6.46 mmol) were stirred in DMF (10 mL) at room temperature overnight. Additional EDC (0.619 g, 3.23 mmol), HOBt (0.495 g, 3.23 mmol), ammonium chloride (0.173 g, 3.23 mmol) and DIPEA (1.128 mL, 6.46 mmol) were then added and stirring continued at room temperature for 24 hours. Saturated aqueous NaHCO3 was added and the products were extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:3]1.P(Cl)(Cl)(Cl)(Cl)Cl.II.[Br:25]Br>C(Cl)Cl>[Br:25][C@H:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:3][C:2]1=[O:1]
Reactant: CCOC(=O)C1CCCCCCCC(=O)N1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCCCCC[C@H](Br)C(=O)N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Ethyl 2-oxo-1-azacyclodecane-10-carboxylate (4.0 g, 17.6 mmol) is dissolved in methylene chloride (50 mL), and cooled to 0° C. Phosphorus pentachloride (3.85 g, 18.5 mmol) and iodine (0.051 g, 0.2 mmol) are added. The reaction is stirred for 15 minutes at 0° C. Then, bromine (3.10 g, 19.4 mmol) is added, and the reaction is stirred at 0° C. for 4 hours. The reaction is quenched by adding saturated sodium sulfite (until the color of excess bromine disappears), and extracted several times with methylene chloride. The combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (15% ethyl acetate/hexane) to give cis ethyl 3-bromo-2-oxo-1-azacyclodecane-10-carboxylate, m.p. 132°-134° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(#N)C.O>[Br:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[O:9][CH2:8][CH2:7][CH2:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc2c(c1)OCCC2
Solvent: CC#N
Solvent: O
Product: Fc1cc2c(cc1Br)CCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-fluorochroman (4.42 g, 29.0 mmol) in acetonitrile (40 mL) at 0° C. was treated with NBS ((5.16 g, 29 mmol)) and the mixture was stirred at ambient temperature for 2 hours. The reaction was diluted with water, stirred for 1 hour and then extracted with ethyl acetate, dried over sodium sulfte and concentrated under reduced pressure give a 6-bromo-7-fluorochroman as the major product in a 3:1 mixture of regioisomers as a colorless oil (4.05 g). This material was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.19 (d, J=7.8 Hz, 1 H), 6.59 (d, J=10.0 Hz, 1 H), 4.19-4.16 (m, 2 H), 2.74 (t, J=6.5 Hz, 2 H), 2.04-1.95 (m, 2 H); LCMS (m/z) ES+=230 (M−1).
Reaction SMILES: C=O.[CH3:3][C:4]1[C:5]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][C:32]([NH2:34])=[O:33])=[N:6][C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[N:8][CH:9]=1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:3][C:4]1[C:5]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][C:32]([NH2:34])=[O:33])=[N:6][C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:35])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[N:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cnc(Nc2ccc(C3CCNCC3)nc2)nc1CCc1ccccc1CC(N)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(Nc2ccc(C3CCN(C)CC3)nc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Formaldehyde (37% wt. in H2O; 0.017 mL, 0.22 mmol) was added to a solution of 2-(2-(2-(5-methyl-2-((6-(piperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide (4) (32 mg, 0.07 mmol) in MeOH (4 mL) under an atmosphere of nitrogen. The resulting solution was stirred for 15 minutes at room temperature then sodium triacetoxyborohydride (63 mg, 0.30 mmol) was added in one portion. After stirring at room temperature for 18 hours a further portion of formaldehyde (37 wt. % in H2O; 0.017 mL, 0.22 mmol) was added and after 15 minutes sodium triacetoxyborohydride (63 mg, 0.30 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 20 hours then the volatiles were removed in vacuo and the residue partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over Na2SO4. The volatiles were removed under reduced pressure to give the title compound 5 as an off white solid (20 mg, 61%); 1H NMR (400 MHz, d4-MeOH) δ 8.79 (d, J=2.2 Hz, 1H), 8.15 (dd, J=8.6, 2.7 Hz, 1H), 8.12 (d, J=0.6 Hz, 1H), 7.27-7.23 (m, 2H), 7.20-7.15 (m, 3H), 3.64 (s, 2H), 3.16-3.06 (m, 4H), 2.98 (dd, J=9.2, 6.0 Hz, 2H), 2.72 (tt, J=12.0, 3.9 Hz, 1H), 2.40 (s, 3H), 2.32 (td, J=12.0, 2.4 Hz, 2H), 2.11 (s, 3H), 1.97 (d, J=11.9 Hz, 2H), 1.92-1.80 (m, 2H). LCMS-A: rt 4.237 min; m/z 445 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH3:15][CH:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:22](=[O:23])[CH:16]([CH3:15])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Nc1cccc(F)c1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cccc(F)c1

Procedure:
Prepared according to Procedure A using 3-fluoroaniline (18 mL, 187 mmol), pyridine (31 mL, 374 mmol) and diethyl methylmalonate (48 mL, 281 mmol). The crude was purified by column chromatography on silica (using a gradient of hexanes:EtOAc, 1:0 to 3:1 as eluant) to give ethyl 3-(3-fluorophenylamino)-2-methyl-3-oxopropanoate as a light brown solid. Mass Spectrum (ESI) m/e=240.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]([NH2:11])=[O:10].[NH3:12]>O1CCOCC1>[NH2:12][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Reactant: N
Solvent: C1COCCO1
Product: NC(=O)c1cnc(Cl)cc1N

Procedure:
To a well stirred solution of 4,6-dichloropyridine-3-carboxamide (11.0 g, 57.59 mmol) in 1,4-dioxane (20 mL) in steel bomb was added the liquid ammonia (50 mL, 57.59 mmol). The steel bomb was closed and heated the reaction to 100° C. for 9 h. The progress of the displacement reaction was monitored by TLC and LCMS. After completion the solid formed was filtered. The filtrate was also concentrated as it also contains 50% product. The combined solids were dried under vacuum to afford 4-amino-6-chloro-pyridine-3-carboxamide (2) as a light brown solid. Yield: 10.6 g, crude, 47%; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.97 (s, 1H), 7.50 (s, 1H), 7.37 (s, 1H), 6.65 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH3:5])[CH:3]=[CH2:4].[CH2:7]([SiH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH3:8]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)CCC>[CH3:1][C:2]([OH:6])([CH3:5])[CH2:3][CH2:4][Si:9]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:7][CH3:8]
Reactant: C=CC(C)(C)O
Reactant: CC[SiH](CC)CC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CCCCO
Product: CC[Si](CC)(CC)CCC(C)(C)O
Temperature: 80 °C
Yield: 81.1 %

Procedure:
Into a four-necked 500 mL-flask equipped with a stirring apparatus, a thermometer and a dropping funnel, 81.2 g (0.943 mole) of 3-methyl-1-buten-3-ol and 0.2 g of an n-butanol solution containing chloroplatinic acid at a concentration of 2 weight % were charged, and they were heated to 80° C. with stirring. From the dropping funnel, 109.6 g (0.943 mole) of triethylsilane was dropwise added into the four-necked flask. After the completion of the addition, they were heated and stirred for about 20 hours. Meanwhile, the proceeding of reaction was traced by gas chromatography analysis. At the stage when the proceeding of the reaction stopped, an additional mount of the above n-butanol solution containing chloroplatinic acid was added for the proceeding of the reaction. The reaction mixture was distilled under reduced pressure to obtain 154.9 g (0.765 mole) of 1,1-dimethyl-3-(triethylsilyl)propyl alcohol as a fraction at 105° C./14-16 torr.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH3:13])[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[N:5]1)([CH3:3])[CH3:2].B(Br)(Br)Br.C1CCCCC=1>>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH3:13])[C:6]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2nn(C(C)C)c3c(C)cccc23)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Cc1cccc2c(-c3ccc(O)cc3)nn(C(C)C)c12
Yield: 50.7 %

Procedure:
Prepared according to Method D step C from 1-isopropyl-3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.057 g, 0.20 mmol), boron tribromide (0.094 mL, 1.0 mmol) and 0.3 mL of cyclohexene to give the product (0.027 g) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17]>>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccccc2F)c1Br
Yield: 44 %

Procedure:
2-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2-fluorobenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a white solid, m.p. 87-89° C., yield 44%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:53]([N:56]1[C:64]2[C:59](=[CH:60][C:61]([O:66][CH3:67])=[C:62](Br)[CH:63]=2)[CH2:58][CH2:57]1)(=[O:55])[CH3:54].[CH3:68][N:69]1[C@H:74]([CH3:75])[CH2:73][NH:72][CH2:71][C@@H:70]1[CH3:76]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:53]([N:56]1[C:64]2[C:59](=[CH:60][C:61]([O:66][CH3:67])=[C:62]([N:72]3[CH2:73][C@H:74]([CH3:75])[N:69]([CH3:68])[C@H:70]([CH3:76])[CH2:71]3)[CH:63]=2)[CH2:58][CH2:57]1)(=[O:55])[CH3:54]
Reactant: C[C@@H]1CNC[C@H](C)N1C
Reactant: COc1cc2c(cc1Br)N(C(C)=O)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: COc1cc2c(cc1N1C[C@@H](C)N(C)[C@@H](C)C1)N(C(C)=O)CC2
Yield: 22.9 %

Procedure:
A mixture of palladium (II) acetate (500 mg), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2.0 g) and cesium carbonate (10.3 g) in dry degassed 1,4-dioxane (120 ml) under argon was sonicated at 28° C. for 0.5 h producing a pink heterogeneous mixture. This was treated with D1 (6.0 g, 22 mmole) followed by cis-1,2,6-trimethylpiperazine (J. Med. Chem. 1968, 11, 592; 4.8 g, 38 mmole) and heated with rapid stirring at reflux for 70 h. The mixture was allowed to cool, filtered, then concentrated under vacuum. The residue was treated with water and extracted with EtOAc. The organic solution was then extracted with 1M HCl acid and the aqueous extract was basified by addition of K2CO3 and extracted with EtOAc. The extract was dried (Na2SO4) and concentrated under vacuum to leave an orange solid, which was chromatographed on silica gel eluting with 0-10% MeOH/DCM to afford the required product as a pale yellow solid (1.6 g, 23%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:18])=[CH:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:3][C:4]([CH3:18])=[CH:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][O:15][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:10][CH:9]=1
Reactant: CC(C)=CCOc1ccc(OCCO)cc1
Reactant: Clc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)=CCOc1ccc(OCCOc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of sodium hydride (0.13 g) in 5 ml of THF and 5 ml of HMPA, cooled in an ice bath, is added, dropwise, 2-[4-(3-methyl-2-butenoxy)phenoxy]ethanol (1.00 g) in 5 ml of THF. The mixture is stirred at RT for 1 hour, after which 2-chloropyridine (0.61 g) is added and the mixture is stirred at 60° for 2 hours. The solvent is removed by rotoevaporation. The residue is taken up in ether, washed with water, dried and concentrated, and the remaining oil is purified by column chromatography to give 2-{2-[4-(3-methyl-2-butenoxy)phenoxy]ethoxy}pyridine, MS m/e 300 (M+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH:27]([CH3:31])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].CN(C)C=O>O.C1C=CC=CC=1>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]3[CH:10]=[C:9]([CH3:11])[S:8][C:6]=3[N:7]=2)[CH:27]([CH3:31])[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cc2c(-c3ccccc3)nc(Cl)nc2s1
Reactant: CC1CN(Cc2ccccc2)CCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc2c(-c3ccccc3)nc(N3CCN(Cc4ccccc4)CC3C)nc2s1
Yield: 90.1 %

Procedure:
A mixture of 3 g of 2-chloro-6-methyl-4-phenyl-thieno[2,3-d]pyrimidine, 2.2 g of 1-benzyl-3-methylpiperazine, 1.1 g of sodum carbonate and 4 ml of dimethylformamide is reacted under reflux for 3 hours. After cooling, 80 ml of benzene and 80 ml of water are added and two layers are separated. The benzene layer is washed twice with 100 ml of water and then with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After distilling off benzene, purification of the product by silica gel chromatography using 180 g of silica gel and n-hexane/ethyl acetate (10:1) as an eluent is carried out. There is obtained 4.3 g of oily 2-(4-benzyl-2-methylpiperazinyl)-6-methyl-4-phenyl-thieno[2,3-d]pyrimidine.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:19])[CH3:18])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: CC(O)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Yield: 64.4 %

Procedure:
Manganese dioxide (691 mg) was added to a solution of 1-[4-(6-iodoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-ethanol (579 mg) in chloroform (50 mL), and the mixture was refluxed for 8 hours. The reaction mixture was filtered through Celite, and the mother liquor was concentrated. The residue was purified through silica gel column chromatography (dichloromethane:methanol=95:5), followed by concentration under reduced pressure, to thereby yield the title compound (371 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1(O)[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1.O=S(Cl)Cl>N1C=CC=CC=1>[O:14]1[C:10]2([CH2:15][CH2:16][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: OC1(c2ccccn2)CCC2(CC1)OCCO2
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C1=C(c2ccccn2)CCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
The ketal (2 g, 8.5 mmol) obtained from step A, Example 7 was dissolved in pyridine (40 mL) and the solution was cooled in an ice bath. To it was added SOCl2 (3.1 mL, 42.5 mmol). The solution was allowed to warm to room temperature and stirring was continued overnight. The reaction was quenched by addition of ice and then water. The resulting solution was extracted with EtOAc three times. The combined EtOAc layer was dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 0 to 55% EtOAc/hexanes provided 1.54 g of the title compound. MS calculated (M+H)+ 218, found 218.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O.CC(C)=O>[C:16]1(=[O:25])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=2)[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]12
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1cc(Br)cc(Br)c1
Yield: 37.3 %

Procedure:
3,5-dibromophenol (970 mg, 3.85 mmol) was recrystallized from hexanes. After removal of solvent, N-(4-bromobutyl)phthalimide (1.38 g, 4.89 mmol), K2CO3 (1.88 g, 13.6 mmol), 18-crown-6 (53 mg, 0.20 mmol), and acetone (20 mL) were added. This was refluxed for 1 hour, and then poured into 100 mL of water. The aqueous layer was extracted with dichloromethane (4×30 mL). The organic layers were combined, washed with water, saturated NaHCO3, and brine, then dried over MgSO4 and filtered. Removal of solvent yielded a white solid, which was purified by column chromatography (4:1 hexanes:CH2Cl2) followed by recrystallization in hexanes to yield colorless needles (650 mg, 87%). 1H NMR (CDCl3): 7.860 (m, 2H); 7.733 (m, 2H); 7.220 (t, J=1.6 Hz, 1H); 6.964 (d, J=2.0 Hz, 2H); 3.962 (t, J=6.0 Hz, 2H); 3.770 (t, J=6.6 Hz, 2H); 1.846 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[CH:7]=[C:8]([C:10]#[N:11])[O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][C:29]([F:32])([F:31])[F:30])[NH2:24]>CN(C=O)C.CCOC(C)=O.O>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][CH2:2][C:3]2[CH:13]=[CH:12][C:6]3[CH:7]=[C:8]([C:10]#[N:11])[O:9][C:5]=3[CH:4]=2)[CH:25]=[CH:26][C:27]=1[O:28][C:29]([F:31])([F:32])[F:30]
Reactant: Nc1ccc(OC(F)(F)F)c(Br)c1
Reactant: N#Cc1cc2ccc(CBr)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc2ccc(CNc3ccc(OC(F)(F)F)c(Br)c3)cc2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
6-(bromomethyl)benzofuran-2-carbonitrile (0.5 g, 2.12 mmol) was dissolved in DMF (21.2 ml). K2CO3 (0.44 g, 3.18 mmol) was added, followed by 3-bromo-4-(trifluoromethoxy)aniline (314 μL, 2.12 mmol), and the mixture was stirred at RT for 18 hr. The reaction was diluted with EtOAc and water. The organic layer was washed with water×6, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was diluted with DCM and silica gel was added. The mixture was concentrated under reduced pressure to dry-load material for purification. The crude mixture was purified via silica gel FCC, 100% Heptane-50% EtOAc/50% Heptane to give 6-(((3-bromo-4-(trifluoromethoxy)phenyl)amino)methyl)benzofuran-2-carbonitrile (651 mg). LCMS retention time=1.57 minutes (LC method 1); MS (m+1)=412.1. 1H NMR (400 MHz, DMSO-d6) δ 4.46 (d, J=6.0 Hz, 2H), 6.62 (dd, J=9.0, 2.8 Hz, 1H), 6.88-6.95 (m, 2H), 7.17 (dq, J=9.0, 1.3 Hz, 1H), 7.44 (dd, J=8.2, 1.4 Hz, 1H), 7.70 (s, 1H), 7.80 (dd, J=8.1, 0.7 Hz, 1H), 8.08 (d, J=1.0 Hz, 1H).