Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[N:40]=[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]4[CH:47]=3)=[CH:35][CH:34]=2)O1>>[N:40]1[C:39]([C:36]2[CH:37]=[CH:38][C:33]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:34][CH:35]=2)=[CH:47][N:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(-c3cn4ccccc4n3)cc2)OC1(C)C
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(-c5cn6ccccc6n5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-3-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine was prepared from cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.453 mmol) and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazo[1,2-a]pyridine (0.250 g, 0.679 mmol) in a manner similar to that used for the preparation of cis-N-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a white powder (0.021 g, 9%). 1H NMR (DMSO-d6, 400 MHz) 1.57-1.73 (m, 4H), 2.08-2.50 (m, 12H), 2.16 (s, 3H), 3.37 (m, 1H), 4.82 (m, 1H), 6.92 (t, 1H), 7.27 (t, 1H), 7.61 (d, 1H), 7.74 (d, 2H), 8.15 (d, 2H), 8.24 (s, 1H), 8.56 (d, 1H); RP-HPLC Rt 8.16 min, 97% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 508 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(O)c1cc(Br)ccc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 1-(5-Bromo-2-fluoro-phenyl)-ethanol 102 (105 g, 0.479 mol) in dioxane (2 L) was added manganese dioxide (203 g, 2.35 mol). The reaction mixture was heated under reflux for 5 hours. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through Celite and the solid was washed with ether (1 L). The combined filtrate was evaporated under reduced pressure to afford the 1-(5-Bromo-2-fluoro-phenyl)-ethanone 103 (95.7 g, 0.441 mol) which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].N[C:9](N)=[O:10]>O>[OH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][NH:7][C:9]1=[O:10]
Reactant: NCCNCCO
Reactant: NC(N)=O
Solvent: O
Product: O=C1NCCN1CCO
Temperature: 210 °C
Yield: 76.9 %

Procedure:
A mixture of N-(2-hydroxyethyl)ethylenediamine (31.2 g), urea (23.4 g) and water (3 ml) was heated at 130° C. for 3 hours and at 210° C. for 8 hours and then distilled directly from the reaction mixture to give 1-(2-hydroxyethyl)-2-imidazolidinone (30 g) as an oil [(b.p. 150°-160° C. (0.2 mm)] which solidified to give a solid (m.p. 50-51).
Reaction SMILES: C([Cl:4])(=O)C.[OH:5][N:6]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([O:27][CH3:28])[C:19]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[CH:11]3)[C:7]1=[O:29]>C(O)C>[ClH:4].[OH:5][N:6]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([O:27][CH3:28])[C:19]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[CH:11]3)[C:7]1=[O:29]
Reactant: CC(=O)Cl
Agent: COc1cc2c3c(cccc3c1N1CCN(C)CC1)C(=O)N(O)C2=O
Solvent: CCO
Product: Cl
Reaction time: 0.5 h

Procedure:
2-Benzyloxy-6-bromo-5-methoxy-benzo[de]isoquinoline-1,3-dione (0.5 g, from Example Z) was reacted with N-methylpiperazine (30 mL) following the procedure of Example 18 to give 0.5 g of 2-benzyloxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione. Hydrogenation of 2-benzyloxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.3 g) at 40 psi in the presence of Pd/C (10%) in DMA (20 mL) afforded 0.2 g of the title compound as the free base. A solution of acetyl chloride (0.03 mL) in ethanol (1 mL) was added to a solution of 2-hydroxy-5-methoxy-6-(4-methyl-piperazin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.12 g, 0.4 mmol) in ethanol (5 mL). The solution was stirred for 30 minutes, and the precipitate was filtered, washed with ether, and dried to give 0.13 g of the title compound as the HCl salt, mp 296-300° C.;
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C([Cl:32])(C)=O>CO>[ClH:32].[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(=O)Cl
Agent: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccccn4)cc3C)c(C)nc12
Solvent: CO
Product: Cl

Procedure:
To a solution of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-pyridin-2-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine (0.15 g, 38 mmol) and MeOH (2 mL) is added AcCl (0.028 mL, 0.39 mmol). After one hour the solution is concentrated and the residue recrystallized from EtOAc/hexane furnish the title compound (0.11 g, 0.26 mmol, 69%). 1H NMR (CDCl3), δ 0.97 (t, J=7.4 Hz, 6H), 1.75-2.03 (m, 4H), 2.17 (s, 3H), 2.66 (s, 3H), 2.77 (s, 3H), 3.86-3.98 (m, 1H), 7.17 (s, 1H), 7.21-7.30 (m, 2H), 7.62 (bs, 1H), 7.67-7.7.82 (m, 2H), 8.60 (d, J=4.8 Hz, 1H). LC/MS (m/z): calcd. for C23H26ClN5S (M+H)+: 428.1; found: 391.2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]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>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:8])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: CN1CCC(N)CC1
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(N)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a solution of 4-amino-3-(trifluoromethoxy)benzoic acid (Maybridge; 1.05 g, 4.75 mmol) in DMF (20 ml) was added 4-amino-1-methylpiperidine (Fluorochem; 604 mg, 5.29 mmol) followed by DIPEA (1.6 ml, 9.19 mmol) and HATU (2.06 g, 5.42 mmol). The reaction mixture was stirred at ambient temperature O/N. The reaction mixture was evaporated to dryness and the residue partitioned between DCM (75 mL) and saturated aqueous sodium bicarbonate solution (75 mL). The aqueous phase was re-extraced with DCM (50 ml) and the combined organic phases washed with brine, dried over magnesium sulphate, filtered and evaporated to give the title compound as an amber gum (1.17 g, 78%)
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH3:13]>CCCCCCC>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: CCCCO
Solvent: CCCCCCC
Product: CCCCOC(=O)c1cccnc1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
Nicotinic Acid (24.6 g, 0.2 mol), n-butanol (100.0 g, 1.33 mol) and heptane (20.1 g) were charged to a 500 mL reaction kettle and equipped with mechanical stir, a Dean-Stark trap, and thermocouple. The mixture was stirred at 300 rpm under nitrogen atmosphere and alkylbenzenesulfonic acid (480 mw, 120 g, 0.25 mol) was added dropwise through an addition funnel over 2 hours. The mixture was heated to 115° C. and held for 3 hours. A second portion of Nicotinic Acid (24.6 g, 0.2 mol) was added through a powder funnel and the temperature was increased to 150° C. and vacuum was applied to −29.5 in Hg and held for 1 hour. The distillate was then taken and solvents removed under vacuum on a rotary evaporator to yield the desired product. This process was repeated 2 additional times using the same Alkylbenzenesulfonic acid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH2:7]=[CH:8][CH:9]=[CH2:10]>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>[CH2:2]([O:1][CH:7]=[CH:8][CH:9]=[CH:10][CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]([CH2:5][OH:6])[OH:4]
Reactant: C=CC=C
Reactant: OCC(O)CO
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: O
Product: CCCCC=CC=COCC(O)CO
Temperature: 80 °C
Yield: 72.9 %

Procedure:
In a 500-mL autoclave, charged were 70 g (0.76 mol) of glycerin, 0.7 g (2.3 mmol) of bis(acetylacetonato)palladium (II), 3.0 g (5.3 mmol) of triphenylphosphine-3,3′,3″-trisulfonic acid trisodium salt and 35 g of water. The mixture was heated to 80° C., whereby a water-soluble liquid phase was obtained. After cooling, 180 g (3.3 mol) of 1,3-butadiene was introduced at a time into the autoclave as a hydrocarbon solvent phase. While stirring, the mixture was heated to 80° C. again. The initial pressure in the autoclave showed 1.0 MPa. After stirring at 80° C. for 10 hours, the water phase and unreacted butadiene were removed, followed by washing with water, whereby 111 g of octadienyl glyceryl ether was obtained as a pale yellow transparent oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:9])[CH3:8].[C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)#[N:23]>CN(C)C=O.CC(C)([O-])C.[K+]>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([C:22]#[N:23])=[CH:25][CH:26]=1)[NH:10][C:7](=[O:9])[CH3:8])[CH3:16]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: N#Cc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(C#N)cc1)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
To 50 ml of dimethylformamide is added 5.7 g (51 mmoles) of potassium tert-butoxide and 11.1 g (51 mmoles) of diethyl acetamidomalonate and the resulting mixture stirred at 25° for 15 minutes. The solution is then cooled to 10° and a solution of 10.0 g (51 mmoles) of 4-cyanobenzyl bromide, Case, J. Am. Chem. Soc., 47, 1143, (1925) in 40 ml of dimethylformamide is added dropwise over 20 minutes. The mixture is then stirred at 25° for 1 hour after which a further 0.285 g (2.5 mmoles) of potassium tert-butoxide and 0.55 (2.5 mmoles) of diethyl acetamidomalonate are added and stirring continued for 1 hour at 25°. The reaction mixture is then poured into 300 ml of ice water, causing the product to precipitate. Filtration, washing with water and drying yields 10.3 g (31 mmoles, 61%) of N-acetyl-4-cyano-α-(ethoxycarbonyl)phenylalanine ethyl ester, m.p. 160°-163°.
Reaction SMILES: [PH2](=O)[O-].[NH4+].C[Si](C)(C)N[Si](C)(C)C.C[Si](P([Si](C)(C)C)(=O)[O-])(C)C.[CH3:25][O:26][C:27]1[CH:68]=[CH:67][C:30]([C:31]([O:44][CH2:45][C@H:46]2[O:50][C@@H:49]([N:51]3[CH:58]=[C:57]([CH3:59])[C:55](=[O:56])[NH:54][C:52]3=[O:53])[C@H:48]([O:60][CH2:61][CH2:62][O:63][CH3:64])[C@@H:47]2[CH2:65]I)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>ClCCl.C1COCC1.CO.CCN(CC)CC>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([O:44][CH2:45][C@H:46]2[O:50][C@@H:49]([N:51]3[CH:58]=[C:57]([CH3:59])[C:55](=[O:56])[NH:54][C:52]3=[O:53])[C@H:48]([O:60][CH2:61][CH2:62][O:63][CH3:64])[C@@H:47]2[CH3:65])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:67][CH:68]=1
Reactant: COCCO[C@@H]1[C@H](CI)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)P(=O)([O-])[Si](C)(C)C
Agent: O=[PH2][O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COCCO[C@@H]1[C@H](C)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A mixture of ammonium phosphinate (410 mg, 5.1 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (1.18 mL, 0.90 g, 5.59 mmol) was heated at 100–110° C. for 2 h under nitrogen atmosphere with condenser. The intermediate BTSP (bis[trimethylsilyl]phosphinate) was cooled to 0° C. and 5 mL of dichloromethane was injected. To this mixture was injected a solution of 3′-deoxy-5′-O-(4-methoxytrityl)-3′-(iodomethyl)-2′-O-(2-methoxyethyl)-5-methyluridine (0.78 g, 1.1 mmol) and diisopropylethylamine (0.39 mL, 287 mg, 2.23 mmol) in 7 mL of dichloromethane. After the reaction mixture was stirred at rt overnight, a mixture of THF-MeOH—NEt3 (3/6/0.3 mL) was added and continued to stir for 1 h. The reaction mixture was filtered through a pad of celite and washed with dichloromethane. The solvent was evaporated and the residue was purified by flash chromatography on a silica gel column using 2:1, 1:1, and then 1:2 hexanes-EtOAc as eluent providing 380 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[C:14](=O)[NH:13][C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:11][C:5]=1[NH:6]2.O=P(Cl)(Cl)[Cl:25].C(Cl)(Cl)Cl.CO.CCOCC>C(Cl)(Cl)Cl.CO>[Cl:25][C:14]1[C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][C:5]=2[N:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=1
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1cccc(Cl)c12
Temperature: 115 °C
Yield: 70 %

Procedure:
To 9 (2 g, 6.274 mmol) was added 30 mL of POCl3 in a 250 mL round bottom flask. The reaction mixture was refluxed at 110-120° C. for 4 hours. After this the POCl3 was evaporated and the mixture was neutralized using NH4OH. The aqueous mixture was filtered (the ppt being the compound). The filtrate too contained some compound. Therefore it was extracted using chloroform and ethyl acetate. The ppt. obtained was dissolved in chloroform and methanol. Both the dissolved ppt. and extracted filtrate were dried using sodium sulfate overnight. To the solution was added silica and solvent was removed under reduced pressure to provide a silica gel plug. The plug was transferred on top of a column packed with silica gel, twenty times the weight of plug, eluted with chloroform, 1% methanol in chloroform and 5% methanol in chloroform. Fractions containing the product 10 (TLC) were pooled and evaporated to give a solid. The overall yield was 70%. TLC Rf 0.86 (chloroform-methanol 5:1), m.p. 245.6-246.1° C., 1H NMR: δ 1.24 (s, 9H, pivaloyl); 7.37-7.63 (m, 3H, phenyl); 10.32 (s, 1H, 9-NH, exch); 12.96 (s, 1H, 2-NH, exch). Anal. Calculated (C15H14Cl2N4O. 0.25 (C2H5)2O): C, 54.02; H, 4.67; N, 15.74. Found: C, 54.14; H, 4.56; N, 15.69.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]2)[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.[F-].[Cs+]>COCCOC.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>[Cl:14][C:6]1[CH:5]=[C:4]([C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]2)[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(Br)c2)CCC1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C)cc3)c2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A mixture of compound ethyl 1-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (500 mg, 1.2 mmol), 4-methyl phenylboronic acid (0.237 g, 1.68 mmol), Palladium Tetrakis (triphenylphosphine) (0.134 g, 0.116 mmol), Cesium fluoride (0.354 g, 2.23 mmol) in DME (30 ml) was stirred for overnight at 100° C. After completion of the reaction, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield ethyl 1-(5-chloro-4′-methyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutanecarboxylate (325 mg) as thick oil.
Reaction SMILES: C([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:6]1=[O:25])C=C>C(Cl)Cl.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>[OH:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:6]1=[O:25]
Reactant: C=CCON1C(=O)c2ccc(N3CCCC3)c3cc(C)cc(c23)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc2c3c(ccc(N4CCCC4)c3c1)C(=O)N(O)C2=O
Yield: 65.6 %

Procedure:
Following the procedure of Example 59, 2-allyloxy-5-methyl-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.55 g, 1.8 mmol, from Example J2), phenylsiliane (0.29 g, 2.6 mmol), Pd(PPh3)4 (0.81 g, 0.070 mmol) in CH2Cl2 (40 mL) were reacted to give 0.35 g of the title compound, mp 236-237° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]#[N:13])[N:9]=[CH:8]1.C[Si](C)(C)CCOCN1C(C#N)=CN=C1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1])[CH:11]=[C:10]([C:12]#[N:13])[N:9]=1
Reactant: C[Si](C)(C)CCOCn1cnc(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)CCOCn1cncc1C#N
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1Br
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A 22-L, four-neck, round-bottom flask equipped with a mechanical stirrer, a temperature probe, and a condenser with a nitrogen inlet was charged with a mixture of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile and 3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carbonitrile [600 g, 2.69 mol, as prepared in the previous step) and carbon tetrachloride (1.8 L). Agitation was initiated and the mixture was heated to 60° C. At this point N-bromosuccinimide (502 g, 2.82 mol) was added in several portions over 30 min, which resulted in an exotherm to 74° C. The reaction was allowed to cool to 60° C. and further stirred at 60° C. for 1 h. The reaction was allowed to cool slowly to ambient temperature and the resulting slurry was filtered and the filtrate washed with satd NaHCO3 solution (4.0 L). The organics were passed through a plug of silica gel (8×15 cm, silica gel; 600 g) using 2:1 heptane/ethyl acetate (6.0 L) as eluent. The fractions containing the product (based on TLC analysis) were combined and concentrated under reduced pressure to give a crystalline light yellow solid, which was then filtered and washed with heptane (500 mL) to give the title compound as a crystalline white solid [593 g, 73%). The 1H and 13C NMR spectra were consistent with the assigned structure and showed no evidence of the minor regioisomers.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=1>N1C=CC=CC=1>[CH3:20][O:19][C:18]1[C:13]([NH:12][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])(=[O:10])=[O:9])=[N:14][CH:15]=[C:16]([CH3:21])[N:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1I
Reactant: COc1nc(C)cnc1N
Solvent: c1ccncc1
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1I
Temperature: 70 °C
Yield: 44.4 %

Procedure:
2-Iodobenzenesulphonyl chloride (obtained as described in J Org Chem, 1977, 42, 3265) (12.1 g) was added to a solution of 2-amino-3-methoxy-5-methylpyrazine (5.6 g) in pyridine (100 ml) and the solution was heated at 70° C. for 8 hours. Volatile material was removed by evaporation and water (200 ml) was added to the residue. The mixture was extracted with ethyl acetate (2×200 ml) and the extracts were washed with 2M hydrochloric acid (200 ml) and water (200 ml). The extracts were dried (MgSO4) and the solvent was removed by evaporation. The residue was triturated with ether to give N-(3-methoxy-5-methyl-2-pyrazinyl)-2-iodobenzenesulphonamide (7.2 g), m.p. 136°-138° C.; 1H NMR (d6 -DMSO): 2.3 (s,3H), 3.9 (s,3H), 7.3 (dt,1H), 7.5-7.65 (m,2H), 8.05-8.15 (m,2H), 10.7-10.8 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.[ClH:22]>O1CCOCC1>[ClH:22].[CH3:19][C:4]([CH3:20])([CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[C:3]([O:2][CH3:1])=[O:21]
Reactant: COC(=O)C(C)(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)CC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(3-methoxy-2,2-dimethyl-3-oxopropyl)piperidine-1-carboxylate (1.40 g, 4.67 mmol) was dissolved in anhydrous 4N HCl in dioxane (10 mL) and the resulting solution was stirred at rt for 1 h. The reaction mixture was concentrated to afford methyl 2,2-dimethyl-3-piperidin-4-ylpropanoate hydrochloride.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:17][C:18]([F:21])([F:20])[F:19])C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Cl:15][C:13]1[C:12]([Cl:16])=[CH:11][C:10]2[N:6]([CH2:5][CH2:4][OH:3])[C:7]([CH2:17][C:18]([F:19])([F:20])[F:21])=[N:8][C:9]=2[CH:14]=1
Reactant: CCOC(=O)Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCCn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Reaction time: 1 h

Procedure:
To [5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzimidazol-1-yl]-acetic acid ethyl ester (915 mg) in toluene (20 mL) at −78° C. was added DiBAl—H (3.43 mls of 1.5 M in toluene). The resulting mixture was stirred for 1 hour. The reaction mixture was quenched with Rochelle's salt (aq), extracted with EtOAc, and dried over Na2SO4. The extracts were concentrated to a toluene solution and ethanol (10 mL) was added. To the resulting solution was added NaBH4 (533 mg). The resulting mixture was stirred for 5 hour. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (15%-60% EtOAc/hexanes) to yield the title compound as a yellow solid.