Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7].Cl.Cl[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>COCCOCCOC>[F:1][C:2]([F:12])([F:13])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[N:7]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: ClCCNCCCl
Reactant: Nc1ccccc1OCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOCCOC
Product: FC(F)(F)COc1ccccc1N1CCNCC1
Yield: 52 %

Procedure:
A mixture of 2-(2,2,2-trifluoroethoxy)aniline (3.89 g, 20.4 mmol), bis(2-chloroethyl)amine hydrochloride (3.64 g, 20.4 mmol), potassium carbonate (2.82 g, 20.4 mmol) and sodium iodide (0.6 g, 4.1 mmol) in 10 mL of 2-methoxyethyl ether was heated at reflux for 4.5 hours. The mixture was cooled and 20 mL of an aqueous solution at pH 9 was added. The mixture was extracted with ethyl acetate (4×50 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with 5% methanol/methylene chloride to give 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine (2.74 g, 10.6 mmol). The free base was recrystallized from hydrochloric acid in alcohol to give 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine hydrochloride, m.p. 172°-173° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[K+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([CH3:21])[N:15]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:13][C:14]1[N:15]=[C:16]([CH3:21])[N:17]=[C:18]([NH:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:19]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Cl)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(4-methoxyphenyl)methanamine (1.51 g, 11 mmol) was added in DMF (15 mL), potassium hydroxide was added and stirred at room temperature for 10 minutes. The reaction was cooled to −2° C., 4,6-dichloro-2-methylpyrimidine (1.63 g, 10 mmol) in DMF (5 mL) was added drop-wise at a speed the internal temperature was controlled <0° C. After 30 minutes, the reaction was added ethyl acetate (50 mL), washed with brine (20 mL×2). The organic phase was dried by magnesium sulfate, filter, concentrated and purified by column chromatography through a 110 gram AnaLogix™ silica gel cartridge eluting with 30% ethyl acetate/hexanes to give the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.Cl[C:11]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.B.S(C)C.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:11]3[N:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:12]=3[CH2:13][NH:8][C:6]=2[N:7]=1
Reactant: Cc1ccc(N)c(N)n1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)NCc1ccc(C(F)(F)F)nc1N2
Temperature: 160 °C
Reaction time: 8 h

Procedure:
A mixture of 6-methyl-2,3-pyridinediamine (2.1 g, 17 mmol), 2-chloro-6-(trifluoromethyl)nicotinic acid (3.8 g, 17 mmol) and Cu (1 g, 17 mmol) in HOC2H5OBu was stirred at 160° C. overnight. When LCMS showed the reaction was complete, the mixture was filtered and concentrated to give a crude product, which was dissolved in THF (100 ml) in a flask equipped with a condenser and a nitrogen balloon. A solution of borane-Me2S (10 M, 10 ml, 0.1 mol) was added dropwise, and the resulting mixture was refluxed for 20 h before it was cooled, acidified to pH=1 with concentrated HCl, and refluxed for another 3 hours. The mixture was neutralized to pH=8 with saturated aqueous sodium bicarbonate, and the product was extracted with ethyl acetate (200 ml×3). The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on silica gel eluting with pet ether:ethyl acetate (10:1) to afford the product 2-methyl-7-(trifluoromethyl)-10,11-dihydro-5H-dipyrido[2,3-b:2′,3′-e][1,4]diazepine. 1H-NMR A27111 H02393-117-1 (400 MHz, DMSO) δ 10.83 (br, 1H, NH), 7.45 (d, J=7.6 Hz, 1H, Ar—H), 7.40 (d, J=8 Hz, 1H, Ar—H), 7.16 (d, J=7.6 Hz, 1H, Ar—H), 6.61 (t, J=7.6 Hz, 1H, Ar—H), 4.23 (s, 2H, CH2), 2.51 (s, 3H, CH3).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]5[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:22])[CH2:16][C:15]=4[CH:35]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1>C(O)C.CO>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]5[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:22])[CH2:16][C:15]=4[CH:35]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCCCC3c3ccccc3)CCO4)cc2[nH]1
Solvent: CO
Solvent: CCO
Product: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCCC[C@H]3c3ccccc3)CCO4)cc2[nH]1

Procedure:
Prepared by chiral preparative HPLC separation of racemic 7-(2-methyl-1H-benzimidazol-6-yl)-4-[(2-phenylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine (example 1) using a SHIMADZU LC-20AD apparatus equipped with a Chiralpak AD-H, 25 cm×4.6 mm column using a mobile phase of ethanol:methanol 1:1 and flow rate of 18.0 mL/min and detection at 220 nm. The isomer with retention time 11.20 min. was assigned as the (5)-enantiomer. Chiral analytical HPLC was carried out using a SHIMADZU LC-20AD apparatus equipped with a Chiralpak AD-H, 25 cm×4.6 mm column using a mobile phase of ethanol:methanol 1:1 and flow rate of 0.7 mL/min with detection at 254/220 nm. This isomer gave a retention time 13.30 min and ee>99%. MS (EI) C29H30N4O2: 467 (MH+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[N:21]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:22]3[CH:23]=[CH:24][NH:20][N:21]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc[nH]n1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1cc[nH]n1
Yield: 57 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 57% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1Cl
Reactant: Fc1cccnc1Br
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2ncccc2F)c(F)cc1Cl
Temperature: 80 °C
Yield: 16 %

Procedure:
To a solution of methyl 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.67 g, 5.30 mmol) in THF (10 mL) was added 2-bromo-3-fluoropyridine (933 mg, 5.30 mmol), tri(o-tolyl)phosphine (67 mg, 0.22 mmol), Na2CO3 (2.25 g, 21.2 mmol) and water (1.6 mL) and the reaction was purged with nitrogen for 15 minutes. Bis(dibenzylidene acetone)palladium (63 mg, 0.11 mmol) was added with further purging with nitrogen for 10 minutes before heating at 80° C. for 1 hour. The reaction was cooled to room temperature and filtered through a pad of arbocel, washing through with EtOAc (50 mL). The filtrate was washed with water (50 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10-20% EtOAc in heptanes to afford the title compound (240 mg, 21%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[O:14][C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[O:14][C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)c2ccccc2Oc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1c2ccccc2Oc2ccccc2N1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Title compound 461 (4.29 g, 11.6 mmol) was dissolved in THF (30.0 mL) and tetrabutylammonium fluoride (1M in THF, 13.4 mL, 13.4 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was evaporated to ⅓ of the volume and then poured in ether. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (50-70% ethyl acetate in hexanes) to afford title compound 462 (2.51 g, 85%) as a white solid. MS (m/z): 256.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16](=[O:20])[N:17]([CH3:19])[NH:18][C:11]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:40][CH2:41][CH2:42][CH:43](O)[CH2:44][CH2:45][CH3:46].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([O:20][CH:43]([CH2:44][CH2:45][CH3:46])[CH2:42][CH2:41][CH3:40])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: CCCC(O)CCC
Reactant: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CCC)Oc1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
A mixture of 200 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydro-pyrazolo[3,4-b]pyridin-3-one (Example 1, step 5) and 337 mg of triphenylphosphine in 15 mL of dry tetrahydrofuran was treated with 124 mg of 4-heptanol and 224 mg of diethylazodicarboxylate. The mixture was stirred under an atmosphere of nitrogen at room temperature for 16 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel eluting with 15% ethyl acetate/hexane to afford 84 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutoxy)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine as a colorless oil: ms (MH+)=390.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]2[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]3[O:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[N:8][C:9]=2[CH:10]=[CH:11][CH:12]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:2]([CH3:1])[C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[N:8]3)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNc1cccc2nc(NCc3ccc(C)o3)ccc12
Product: Cc1ccc(CNc2ccc3c(N(C)S(=O)(=O)c4ccc(F)cc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=426.1 (M+H+), was prepared from N5-methyl-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,5-diamine and 4-fluorobenzene sulphonylchloride as described in example 39.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1([F:30])[CH2:29][NH:28][CH2:27]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:28]3[CH2:29][C:26]([F:30])([F:25])[CH2:27]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)CNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(F)(F)C3)ccc2n1CC1CCOCC1
Yield: 66.3 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (90 mg, 0.24 mmol), 3,3-difluoroazetidine (45 mg, 0.49 mmol) and DMAP (59 mg, 0.49 mmol) in MeCN (10 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 68 mg (66%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.46-1.63 (m, 4 H), 1.65 (s, 9 H), 2.27-2.44 (m, 1 H), 3.30-3.39 (m, 2 H), 3.89-3.98 (m, 2 H), 4.20 (t, J=12.30 Hz, 4 H), 4.51 (d, J=7.62 Hz, 2 H), 7.93 (dd, J=8.69, 1.66 Hz, 1 H), 8.05 (d, J=8.79 Hz, 1 H), 8.19 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=427.8; Anal. Calcd for C20H27F2N3O3S+1.10 TFA+0.3 CH3CN (565.26): C, 48.45; H, 5.17; N, 8.18. Found: C, 48.42; H, 4.86; N, 8.20.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:22]=O)[CH:18]=3)[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:18]=3)[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3n2)CC1
Reactant: NCCC(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(=O)O)ccc3n2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-(4-tert-butyl-cyclohexyloxy)-quinoline-6-carbaldehyde (30.6 mg, 0.0983 mmol) and Beta-alanine (8.75 mg, 0.0983 mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 h. The yellow solution was cooled to rt and sodium cyanoborohydride (7.41 mg, 0.118 mmol) was added and was heated to reflux for 1 h. After cooled down to rt, citric acid was added and concentrated down. The solid was suspended in water and filtrate, and the collected solid was washed thoroughly with water. HPLC purification of the solid give the product (7.5 mg, 15%). LCMS Rt=1.60 min m/z=385.49 [M+1]. 1H NMR (400 MHz, MeOD) δ=8.14 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.72 (d, J=10.7 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 5.29-5.09 (m, 1H), 4.40 (s, 2H), 3.36 (t, J=5.8 Hz, 2H), 2.79 (t, J=6.7 Hz, 2H), 2.30 (d, J=10.9 Hz, 2H), 1.94 (d, J=12.9 Hz, 2H), 1.55-1.06 (m, 5H), 0.94 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].S([O-])(O[O-])(=O)=[O:16].[K+].[K+].[OH-].[Na+].Cl>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1)[C:5]([OH:16])=[O:6]
Reactant: O=Cc1cc(C(F)(F)F)cc(Cl)c1F
Reactant: O=S(=O)([O-])O[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 3-chloro-2-fluoro-5-trifluoromethyl-benzaldehyde (4.2 g, 18.5 mmol) in DMF (21 ml) and CH2Cl2 (21 ml) was added potassium peroxomonosulfate (11.4 g, 18.5 mmol, 1.0 equiv.) whereupon the temperature rose from 25 to 34° C. The white suspension was stirred for 2 h, the white solid was filtered off, the filter cake was washed with CH2Cl2 (25 ml) and the solvent was removed under vacuum. The obtained residue was dissolved in TBME (50 ml) and the pH was adjusted to 14 upon addition of NaOH (2M, 22.7 ml, 45.4 mmol, 2.45 equiv.). The aqueous phase was separated, washed with TBME (25 ml), whereas the organic phases were washed with water (25 ml). The combined aqueous phases were acidified upon addition of HCl (37%, 8.4 ml, 5.35 equiv.) and extracted with TBME (50 ml). The organic phase was washed three times with brine (75 ml), whereas the aqueous phases were washed with TBME (25 ml). The combined organic phases were dried over sodium sulfate, which was filtered off, washed with TBME (20 ml) and the solvents were removed under vacuum to yield the 3-chloro-2-fluoro-5-trifluoromethyl benzoic acid as white solid (4.2 g of crude product, 93.4% yield). The crude product was dissolved in hot methyl cyclohexane (20 ml), the oil bath was removed and the suspension was slowly cooled to ambient temperature, whereupon white crystals precipitated. The white suspension was stirred in an ice bath for 2 h, the crystals were filtered off, washed with methyl cyclohexane (5 ml) and dried under vacuum until weight constancy to yield the title compound as white crystals (3.1 g, 68.9% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13](=[C:16]([CH3:18])[CH3:17])[O:12][C:11]1=[O:19].[C:20]1(C)[CH:25]=CC(S(OC(C)C#C)(=O)=O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:21]([CH3:22])[C:20]#[CH:25])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13](=[C:16]([CH3:17])[CH3:18])[O:12][C:11]1=[O:19]
Reactant: C#CC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)=C1OC(=O)N(c2cc(O)c(Cl)cc2F)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CC(C)Oc1cc(N2C(=O)OC(=C(C)C)C2=O)c(F)cc1Cl

Procedure:
Acetonitrile (50 ml) was added to a mixture comprising 3N-(2-fluoro-4-chloro-5-hydroxyphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (5.0 g, 15.7 mmol), 1-butyn-3-yl p-toluenesulfonate (4.0 g, 17.8 mmol) and potassium carbonate (1.5 g, 10.9 mmol), and the reaction mixture was heated for 4 hours under reflux. After reaction, acetonitrile was removed by distillation under reduced pressure, and 1N hydrochloric acid (100 ml) was added to the residue, which was then extracted with ether (50 ml×2). After dried, ether was removed by distillation under reduced pressure, and an oily product of 3N-{2-fluoro-4-chloro-5-(1-butyn-3-yl)oxyphenyl}-5-isopropylidene-1,3-oxazolidine-2,4-dione was obtained. This was recrystallized from ether/hexane, and a pure product (4.94 g, 14.6 mmol) was obtained. Yield: 83.6%. Spectral and other data of the product are those as shown in Example 30.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23]([C:25]2[C:26](=[O:38])[N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]([CH3:31])[C:29]=2[CH3:30])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:44][CH2:45][CH2:46][N:47]1[CH2:53][CH:52]([OH:54])[C:49]2([CH2:51][CH2:50]2)[CH2:48]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:54][CH:52]1[C:49]2([CH2:51][CH2:50]2)[CH2:48][N:47]([CH2:46][CH2:45][CH2:44][O:21][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:22][C:23]([C:25]5[C:26](=[O:38])[N:27]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:28]([CH3:31])[C:29]=5[CH3:30])=[O:24])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][C:16]=2[O:19][CH3:20])[CH2:53]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 65.8 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (200 mg, 0.389 mmol) in DMA (2 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (193 mg, 0.778 mmol) and Cs2CO3 (379 mg, 1.167 mmol). The reaction was then stirred at rt for 40 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (10 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as a pale yellow solid (171 mg, 66%).
Reaction SMILES: O1CCOCC1.C(=O)(O)[O-].[Na+].[NH2:12][C:13]1[N:17]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23]([CH3:25])=[N:24][C:20]=3[CH:19]=2)[N:16]=[CH:15][C:14]=1[C:28]([C:30]1[N:31]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:32]=[C:33](Br)[CH:34]=1)=[O:29].[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O>[NH2:12][C:13]1[N:17]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23]([CH3:25])=[N:24][C:20]=3[CH:19]=2)[N:16]=[CH:15][C:14]=1[C:28]([C:30]1[N:31]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:32]=[C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:34]=1)=[O:29]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)cc2C(=O)c2cnn(-c3ccc4[nH]c(C)nc4c3)c2N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3)cc2C(=O)c2cnn(-c3ccc4[nH]c(C)nc4c3)c2N)cc1

Procedure:
Dioxane (1.5 ml) and an aqueous solution (1.5 ml) of 1 M sodium bicarbonate were added to [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[4-bromo-1-(toluene-4-sulfonyl)-1H-pyrrol-2-yl]-methanone (57 mg), palladium chloride bis-triphenylphosphine complex (10 mg), and phenylboronic acid (37 mg). The mixture was reacted at 140° C. in a microwave reactor for ten minutes. The reaction mixture was diluted with water (5 ml), and then extracted with ethyl acetate. The organic layers were combined, and concentrated under reduced pressure. After HPLC purification, the eluate was desalted using PLHCO3 cartridge (PolymerLabs), and then concentrated under reduced pressure. Thus, [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[4-phenyl-1-(toluene-4-sulfonyl)-1H-pyrrol-2-yl]-methanone was obtained as a yellow powder (15 mg, 26%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[CH3:21])[N:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[N:31][C:30]2[CH:32]=[CH:33][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)[CH3:21])[N:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=Nc2ccccc2C(C)(C)C)n1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(C(C)(C)C)cc1)c1cccc(C(C)=Nc2ccccc2C(C)(C)C)n1
Reaction time: 60 h

Procedure:
Monoimine (9,1.06 g, 3.6 mmol) and 4-tert-butylaniline (0.56 g, 3.75 mmol) were dissolved in 25 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 60 hours the mixture was filtered. The solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 0.81 g (53%) of mixed diimine (10). 1H-NMR (CDCl3) δ 8.36 (d, 1H, Py-Hm), 8.34 (d, 1H, Py-Hm), 7.88 (t, 1H, Py-Hp), 7.4 (m, 3H, ArH), 7.18 (t, 1H, ArH), 7.07 (t, 1H, ArH), 6.78 (d, 2H, ArH), 6.54 (d, 1H, ArH), 2.42 (s, 3H, Me), 2.38 (s, 3H, Me), 1.35 (s, 9H, But),1.34 (s, 9H, But).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][C:5]=12.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:7]2[CH:8]=[CH:9][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccn2ccnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccn2ccnc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 18 %

Procedure:
The title compound is prepared from imidazo[1,2-a]pyridine-7-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 18% of theory; LC (method 4): tR=1.56 min; Mass spectrum (ESI+): m/z=318 [M+H]+.