Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.P(Cl)(Cl)([Cl:17])=O.Cl.[C:21]1([C@H:27]2[CH2:31][CH2:30][CH2:29][C@H:28]2[NH2:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC=CC=1>[ClH:17].[C:21]1([C@H:27]2[CH2:31][CH2:30][CH2:29][C@H:28]2[N:32]=[C:1]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCCCCCCCCCN1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Solvent: c1ccccc1
Product: c1ccc([C@H]2CCC[C@H]2N=C2CCCCCCCCCCCN2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 21.7 g of 2-azacyclotridecanone in 200 ml of dry benzene was added dropwise 15.3 g of phosphorus oxychloride. The mixture was stirred at room temperature for 4 hours after which 19.8 g of cis-2-phenylcyclopentylamine hydrochloride was added. The reaction mixture was stirred at room temperature for 2 hours and refluxed for 24 hours. The resulting homogeneous solution was washed with 2 N NaOH, 2 N HCl and saturated NaCl solution, dried over sodium sulfate and the solvent evaporated. The resulting oily product crystallized from acetone and was recrystallized from methanol-acetone to give the desired product, M.P. 156°-159° C.
Reaction SMILES: C([CH:8]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]1=[O:10])(OC(C)(C)C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O1CCOCC1>[Cl:26][CH:15]1[CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8]1
Reactant: CC(C)(C)OC(=O)C1CCCCNC1=O
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C1CC(Cl)CCCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 129.7 %

Procedure:
Example 228 B) To a solution of 1 g (0.0047 mol) of this Boc-caprolactam product of Example 228 A in 10 mL of anhydrous THF at -78° C. was added 0.005 mol of LiHMDS. After stirring for 30 minutes, 1.2 g (0.005 mol) of hexachloroethane in 5 ml of anhydrous THF was added. The mixture was allowed to warm to 0° C. and was quenched with dilute HCl. The mixture was extracted with EtOAc and the organic layer was washed with 5% HCl, dried (MgSO4), filtered and concentrated to afford a yellow oil. The residue oil was dissolved in 40 mL of 1,4-dioxane (satd. with anhydrous HCl), stirred for 40 minutes, concentrated to afford 0.9 g of 3-chlorocaprolactam as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH2:15][Cl:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:9]=[C:10]([CH2:15][Cl:16])[CH:11]=[C:12]([OH:14])[N:13]=2)=[CH:4][CH:3]=1)=[O:27]
Reactant: Nc1ccc(-c2nc(O)cc(CCl)n2)nc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(-c2nc(O)cc(CCl)n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 49 (0.40 g, 0.16 mmol) in THF (4 mL) at 0° C. was added triethylamine (0.025 g, 0.25 mmol) and chloroacetylchloride (0.0285 g, 0.25 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH3:35])=[CH:29][CH:28]=3)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:35][O:34][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]([S:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][CH:15]([NH2:14])[CH2:16][CH2:17]1)=[CH:33]2
Reactant: COc1ccc2ncc(SCCN3CCC(NC(=O)OC(C)(C)C)CC3)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(SCCN3CCC(N)CC3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 106.4 %

Procedure:
Trifluoroacetic acid (1.88 mL, 24.2 mmol, 15.0 eq) is added at 0° C. to a stirred solution of {1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (724 mg, 1.61 mmol, 1.0 eq) in dichloromethane (75 mL). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×50 mL) and water (50 mL) and the pH value adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine as a brown oil (544 mg, 99% yield).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[CH2:44]([CH2:46][NH2:47])[OH:45]>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:23]=[C:20]([CH2:21][NH:47][CH2:46][CH2:44][OH:45])[CH:19]=[N:18][C:17]=2[NH:24][C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:10]=1
Reactant: NCCO
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(CNCCO)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.200 g, 0.346 mmol) and ethanolamine (Aldrich, St. Louis, Mo.) (0.031 mL, 0.519 mmol). 1H NMR (400 MHz, d6-DMSO) δ 11.79 (s, 1H); 8.89 (d, J=2.35 Hz, 1H); 8.55 (d, J=2.54 Hz, 1H); 8.34 (d, J=2.35 Hz, 1H); 8.13 (dd, J=8.90, 2.64 Hz, 1H); 7.74-7.93 (m, 1H); 6.84 (d, J=9.00 Hz, 1H); 5.08 (br. s., 1H); 4.08 (s, 2H); 3.82-3.88 (m, 3H); 3.63 (q, J=4.96 Hz, 2H); 2.95 (t, J=5.09 Hz, 2H); 2.44 (s, 3H). m/z (ESI, +ve ion) 383.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[N:23][N:24]([CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2C(OC(C)(C)C)=O)[CH:25]=1.Cl.O1CCOCC1>CC(O)C>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[CH:25]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1cc(N)cn1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1[C@H](Nc2nc(Nc3cnn(C[C@H]4CCCN4)c3)ncc2Cl)[C@H]2C=C[C@@H]1C2
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
(1S,2S,3R,4R)-3-(2,5-Dichloropyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (100 mg, 0.334 mmol) and (R)-tert-butyl 2-((4-amino-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate (116 mg, 0.435 mmol) were combined with 2-propanol (2 ml) and 4N HCl in dioxane (0.084 ml, 0.334 mmol) in a sealed tube and the reaction was heated to 85° C. for 4 hours. The reaction mixture was concentrated to dryness, and the residue was treated with trifluoroacetic acid (3 mL). After stirring at room temperature for 30 minutes, the reaction mixture was again concentrated to dryness and the residue was suspended in saturated aqueous NaHCO3 (5 mL). The resulting mixture was extracted with CH2Cl2 (2×10 mL) and ethyl acetate (2×10 mL). The organic extracts were combined, dried (Na2SO4) filtered, and concentrated. The residue was purified by flash chromotography (Analogix, 4 g column, 15 mL/minutes, 0 to 20% methanol (containing 5% NH4OH)/CH2Cl2 over 25 minutes) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.30-1.44 (m, 2H) 1.53-1.81 (m, 3H) 2.11 (d, J=8.82 Hz, 1H) 2.51-2.56 (m, 1H) 2.75-2.85 (m, 3H) 2.86-2.89 (m, 1H) 3.37-3.47 (m, 1H) 3.93-4.01 (m, 2H) 4.12 (t, J=7.12 Hz, 1H) 6.31-6.39 (m, 2H) 7.25 (s, 1H) 7.52 (s, 1H) 7.65-7.83 (m, 3H) 7.89 (s, 1H) 9.10 (s, 1H); MS (ESI(+)) m/e 429 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13]CN(C(C)C)C(C)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl>[CH2:26]([O:25][C:23]([NH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C

Procedure:
To a solution of methyl (3-aminophenyl)acetate (25 g, 140 mmol) in 250 mL anhydrous DCM was added DIEA (28.5 mL, 155 mmol) and the resulting solution cooled to 0° C. and set under nitrogen atmosphere. To this cooled solution was then added benzyl chloroformate (21.1 mL, 148 mmol) and the resulting mixture stirred overnight allowing to warm to room temperature. The reaction was washed with 1 M HCl, water, and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. No further purification was necessary and the material (44 g, 99%) was used as is for the next step reaction. LC-MS: m/z (ES) 314 (MH)+, 336 (MNa)+.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][C:13]=1[CH3:41]>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[C:13]([CH3:41])[CH:14]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: Cc1cc(Oc2ccc(NC(=O)[C@@H]3C[C@@H](Cc4ccc(F)cc4)CN3)cc2)ccc1F
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: Cc1cc(Oc2ccc(NC(=O)[C@@H]3C[C@@H](Cc4ccc(F)cc4)CN3C(=O)Cn3cncn3)cc2)ccc1F
Yield: 84 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluoro-3-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide, gave Compound 73, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluoro-3-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (149 mg, 84%). 1H-NMR (400 MHz, CDCl3): σ 8.90 (s, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.40 (d, 2H), 7.17-7.14 (m, 2H), 7.00 (t, 2H), 6.95-6.88 (m, 3H), 6.79-6.72 (m, 2H), 5.03 (d, 1H), 4.95 (d, 1H), 4.80 (d, 1H), 3.64 (t, 1H), 3.23 (t, 1H), 3.05-2.85 (2H), 2.69-2.61 (m, 2H), 2.22 (s, 3H), 1.72-1.67 (m, 1H). MS (EI) for C29H27F2N5O3. found 530.2 (MH−).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.[CH:14](N(CC)C(C)C)(C)[CH3:15].[C:23]1([CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:27]1[C:26]2([CH2:25][CH2:24][N:1]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=3)[CH2:15][CH2:14]2)[CH2:29][CH2:23][CH2:28]1
Reactant: Cc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1ccc(N)c2ccccc12
Solvent: O
Product: N#Cc1ccc(N2CCC3(CCCC3)CC2)c2ccccc12
Yield: 5 %

Procedure:
4-Amino-1-naphthalenecarbonitrile (168.20 mg), 3,3-tetramethylene-1,5-dibromopentane (284 mg, 1.0 mmol, Klitgaard, N. et al., Acta Chem. Scand. 1970, 24, 33-42), N,N-diisopropylethylamine (323 mg, 2.5 mmol) and toluene (15 mL) were heated to 120° C. for 16 h. The crude product was poured in water (100 mL), extracted with ethyl acetate (3×100 mL), the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparative TLC (dichloromethane, 3× eluted) afforded the title compound (14 mg, 5.0%) as an off-white solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=O)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[CH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Solvent: CC#N
Product: CCCCc1nc(=O)c2cc(C=CC(=O)OCC)ccc2[nH]1
Yield: 46.4 %

Procedure:
A mixture of 3.202 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde and 5.093 g of (carbethoxymethylene)triphenylphosphorane in 50 ml of acetonitrile is heated at reflux for 18 hours. The reaction mixture is cooled and the resulting solid washed with ether and dried to give 1.94 g of the desired product. CI MASS SPEC 301 (MH+)
Reaction SMILES: [Zn:1].[C:2]([OH:7])(=[O:6])[C:3]([CH3:5])=[CH2:4].[O-2].[Zn+2]>>[C:2]([O-:7])(=[O:6])[C:3]([CH3:5])=[CH2:4].[C:2]([O-:7])(=[O:6])[C:3]([CH3:5])=[CH2:4].[Zn+2:1]
Reactant: C=C(C)C(=O)O
Reactant: [Zn]
Agent: [O-2]
Agent: [Zn+2]
Product: C=C(C)C(=O)[O-]

Procedure:
One hundred parts of cis-polybutadiene were blended on a mill with 17 parts of zinc oxice. 22.2 parts of methacryalic acid was slowly added and blended until thoroughly dispersed. After a few minutes there was very little odor of methacrylic acid from the stock, indicating that the acid had thoroughly reacted with the zinc oxide to form zinc dimethacrylate. 6.3 parts of Di-Cup 40-C was then blended into the rubber. Golf balls were molded as in Example 3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:34](Cl)=[O:35]>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:39]([Cl:40])=[C:31]([Cl:30])[CH:32]=2)[N:13]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.28 ml triethylamine and 251 mg of 3,4-dichlorobenzoyl chloride are mixed together then the reaction medium is agitated at ambient temperature for 1 hour. Then 2 ml of water is added, followed by extracting with methylene chloride, drying and evaporating the solvents. In this way 237 mg of expected product is obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]([CH3:7])[CH3:6].C(O)(C)C.C(=O)=O.C([Li])CCC.[B:24](OC)([O:27][CH3:28])[O:25][CH3:26]>O1CCCC1>[CH3:6][N:5]([CH2:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[B:24]([O:27][CH3:28])[O:25][CH3:26])[CH3:7]
Reactant: CN(C)Cc1ccccc1Br
Reactant: COB(OC)OC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COB(OC)c1ccccc1CN(C)C
Temperature: -70 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
20.2 g (94.2 mmol) of the (2-bromobenzyl)dimethylamine prepared according to example 1 (2nd stage) were dissolved in 350 ml tetrahydrofuran and the solution was cooled to −70° C. in a cooling bath (isopropanol/dry ice). 68 ml (108 mmol) butyllithium solution (1.6 M in hexane) were added dropwise under nitrogen such that the temperature did not rise above −60° C. After the mixture had been stirred at −70° C. for two hours, 32 ml (282 mmol) trimethyl borate were also added dropwise such that the temperature did not rise above −60° C. The mixture was warmed to 25° C. in the course of 15 hours and the solution was concentrated on a rotary evaporator (500-10 mbar) without heat being supplied. The residue was taken up in 200 ml n-hexane, the mixture was stirred for one hour and filtered over an inert gas frit under nitrogen and the filtrate was concentrated on a rotary evaporator (500-10 mbar) without heat being supplied. 12.0 g dimethyl 2-(dimethylaminomethyl)benzeneboronate (61.5% of theory) were obtained in this manner.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:41]=[CH:40][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:24]([C:36]([F:39])([F:38])[F:37])[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:24]([C:36]([F:38])([F:37])[F:39])[CH:23]=2)=[O:20])=[CH:40][C:41]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)CC1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc2C(F)(F)F)CC1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 132-133° C.; 1H NMR (300 MHz, CDCl3) δ: 9.53 (1H, s), 8.10 (1H, s), 8.00 (2H, m), 7.85-7.87 (1H, d, J=6.0 Hz), 7.66-7.69 (1H, d, J=9.0 Hz), 7.43-7.45 (1H, d, J=6.0 Hz), 7.33-7.36 (1H, d, J=9.0 Hz), 6.58-6.61 (1H, d, J=9.0 Hz), 5.56 (1H, s), 4.23-4.25 (1H, m), 3.64 (2H, s), 2.61 (8H, brs), 2.44 (3H, s), 2.43 (2H, m), 1.91-1.97 (2H, m), 1.81-1.86 (1H, brs). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C30H31ClF3N6O: 583.2194. found: 583.2174.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:13]1[N:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1.C1(C)C=CC=CC=1.CC([O-])(C)C.[Na+]>CCOC(C)=O.O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:13]2[N:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(OC)nn2)CC1
Temperature: 95 °C
Yield: 40.2 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid ethyl ester (5.66 g, 36.0 mmol) and 3-chloro-6-methoxy-pyridazine (4.34 g, 30 mmol) in toluene (60 mol) was added NaOtBu (3.46 g, 36 mol), BINAP (560 mg, 0.90 mmol) and tris(dibenilideneacetone)dipalladium(0) (549 mg, 0.60 mmol). The reaction mixture was heated at 95° C. for 1 hours, cooled down to RT, and diluted with AcOEt (500 mL) and H2O (50 mL). The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/heptane, 1:9 to 1:1) yielded 3.20 g (34%) of 1-(6-methoxy-pyridazin-3-yl)-piperidine-4-carboxylic acid ethyl ester as a yellow oil. ES-MS m/e: 266.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13](I)=[C:12]([Cl:23])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].CCOC(C)=O>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.O>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)=[C:12]([Cl:23])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(I)c(OCC(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)c(OCC(F)(F)F)c1
Yield: 51.3 %

Procedure:
A mixture of ethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.5, 1.04 mmol), 4-trifluoromethylphenylboronic acid (0.96 g, 2.09 mmol), CsF (0.395 g, 2.6 mmol) and Pd (PPh3)4 (0.121 g, 0.104 mmol) in 50 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 25 mL of EtOAc and 25 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoate (0.265 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O>C1COCC1>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1cccs1
Reactant: COc1cc(OC)c(C=O)cc1Br
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cccs2)cc1C=O
Temperature: 60 °C
Yield: 93.9 %

Procedure:
Ex-6A: 5-bromo-2,4-dimethoxybenzaldehyde (20.3 g), thiophene-2-boronic acid (11.6 g) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10.1 g), and Pd(tBu3P)2 (0.424 g). The solution was immediately heated to 60° C. and aged for 1.5 h. The reaction was diluted with H2O (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H2O (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floc (5 g). The pad of solka floc and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was concentrated to dryness. The crude product was dissolved in THF (38 mL) and crystallized upon heptane (152 mL) addition. The product was filtered and then dried to a constant weight in the vacuum oven (38° C., 20 inHg) affording 19.32 g (94% yield) of desired 2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde as a light off-white solid, m.p. 125–126° C. 1H-NMR (300 MHz, CDCl3): 10.34 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H, J=3.5 and 1.5 Hz), 7.31 (dd, 1H, J=5.2 and 1.5 Hz), 7.07 (dd, 1H, J=5.2 and 3.5 Hz), 6.51 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[Cl:15].[Cu][C:20]#[N:21]>N1C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[C:20]([C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[Cl:15])#[N:21]
Reactant: N#C[Cu]
Reactant: CC(=O)c1cc(Br)c(Sc2ccc(Cl)cc2Cl)s1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: CC(=O)c1cc(C#N)c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a CEM microwave tube, was charged with 1-[4-bromo-5-(2,4-dichlorophenyl)sulfanyl-2-thienyl]ethanone as prepared in example 21 (0.6 g, 1.6 mmol), copper(I) cyanide (0.85 g, 9.4 mmol), and pyridine (5 mL) as solvent. The mixture was subjected to microwave irradiation (200 W) on a CEM Discovery™ microwave machine at 150° C. for 30 minutes. After the irradiation, the mixture was cooled to ambient temperature and treated with 20 mL of saturated copper(II) sulfate aqueous solution and extracted with ethyl acetate. The combined organic layer was separated, washed with water, dried (Na2SO4) and concentrated. The crude was purified by silica gel chromatography using a 96:4 mixture of hexane and ethyl acetate as eluent to afford the title product (0.515 g, 78% yield). 1H NMR (400 MHz, CDCl3) δ: 7.69 (1H, s), 7.56 (1H, m), 7.53 (1H, m), 7.33 (1H, m), 2.51 (3H, s). MS m/z: 326.2 [M+H]+.