Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:22]=[CH:21][C:17]4[CH2:18][CH2:19][O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.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:20]1[C:16]2[CH:15]=[C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:30]5[CH:29]=[CH:28][N:27]=[C:26]([O:25][CH3:24])[CH:31]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)[CH:22]=[CH:21][C:17]=2[CH2:18][CH2:19]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCC4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OCC5)CC3)ccc2C)ccn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
A mixture of N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-6-yl)cyclopropanecarboxamide (50.0 mg, 0.15 mmol), 2-methoxypyridine-5-boronic acid (23.26 mg, 0.15 mmol), and tetrakis(triphenylphosphine)palladium (0) (9.0 mg, 0.0076 mmol) in 1,2-dimethoxyethane (1.5 mL) and 2 M Na2CO3 (0.3 mL) was stirred at 80° C. for 16 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 30 mg (49%) of 1-(2,3-dihydrobenzofuran-6-yl)-N-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 401.2. found 402.0 (M+1)+. Retention time 1.83 minutes.
Reaction SMILES: [SiH3]Cl.[C:3]([C:7]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=1[O:9][Si:10]([CH3:13])([CH3:12])Cl)([CH3:6])([CH3:5])[CH3:4].[S-:23][C:24]#[N:25].[NH4+]>C1(C)C=CC=CC=1>[C:3]([C:7]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=1[O:9][Si:10]([N:25]=[C:24]=[S:23])([CH3:13])[CH3:12])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cc(C(C)(C)C)c(O[Si](C)(C)Cl)c(C(C)(C)C)c1
Reactant: N#C[S-]
Agent: [NH4+]
Agent: [SiH3]Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(C)C)c(O[Si](C)(C)N=C=S)c(C(C)(C)C)c1
Yield: 48 %

Procedure:
A mixture of the silyl chloride prepared in (a) above (78 g, 0.25M), ammonium thiocyanate(26 g,0.28M) and toluene was refluxed for 48 hours. The mixture was filtered and the filtrate evaporated; recrystallisation of the residue from acetonitrile gave the title compound (40 g, 48%) m.p. 83°-4°. (Found: C, 64.8; H, 9.0; N, 4.05. C18H29
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:32][C:33]1[CH:34]=[N:35][N:36]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH:37]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)[CH2:32][C:33]1[CH:34]=[N:35][N:36]([CH2:38][C:39]([F:42])([F:40])[F:41])[CH:37]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)Cn1cc(CCl)cn1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: CC(C)c1ccc(N(Cc2cnn(CC(F)(F)F)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 59 %

Procedure:
By the reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.05 g) and 4-chloromethyl-1-(2,2,2-trifluoroethyl)pyrazole (1.02 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.70 g) was obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]([N:49]3[CH:53]=[CH:52][CH:51]=[N:50]3)[CH:46]=[CH:47][CH:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:49]1([C:45]2[CH:44]=[C:43]([C:19]([C:11]3[N:10]([S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:9])=[O:8])[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:48]=[CH:47][CH:46]=2)[CH:53]=[CH:52][CH:51]=[N:50]1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC1(C)OB(c2cccc(-n3cccn3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)C=C(c1cccc(-n2cccn2)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 120.1 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.04 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (4.08 g, 15.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.5 g, 0.71 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated at 100° C. in a microwave for 2 h. At this time, the reaction mixture was cooled to 25° C., diluted with ethyl acetate (350 mL) and washed with a saturated aqueous sodium carbonate solution (2×75 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (300-400 mesh, 50% ethyl acetate/petroleum ether) afforded 2-(1-(3-(1H-pyrazol-1-yl)phenyl)-3-methylbut-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.4 g, 60.1%) as a gray solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.49 (d, 1H, J=2.1 Hz), 8.40 (dd, 1H, J1=4.8 Hz, J2=1.8 Hz), 8.10 (dd, 2H, J1=7.8 Hz, J2=1.8 Hz), 7.44 (dd, 1H, J1=7.8 Hz, J2=1.2 Hz), 7.68-7.61 (m, 4H), 7.55 (t, 1H, J=8.1 Hz), 7.42-7.33 (m, 4H), 7.06 (d, 1H, J=7.8 Hz), 6.89 (s, 1H), 6.52 (t, 1H, J=1.8 Hz), 6.35 (d, 1H, J=9.6 Hz), 1.14 (d, 3H, J=5.1 Hz), 1.12 (d, 3H, J=4.8 Hz).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9](=[O:22])[N:8]2CC2C=CC(OC)=CC=2OC)[CH:5]=[N:4][CH:3]=[N:2]1.OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O.C(#N)C>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9](=[O:22])[NH:8]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2cncn2)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1cncn1)OCc1ccccc1
Temperature: 90 °C
Yield: 56.3 %

Procedure:
Prepared in an analogous manner to example 4, step 2 using benzyl ((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)carbamate (101 mg, 0.224 mmol), K2S2O8 (85 mg, 0.313 mmol) and K2HPO4 (50.7 mg, 0.291 mmol) in ACN:water (2:1, 61.5 mL) while heating for 2 h at 90° C. More K2S2O8 (18.1 mg, 0.067 mmol) and K2HPO4 (10.1 mg, 0.058 mmol) were added and heated for another 1.5 h. More K2S2O8 (18.1 mg, 0.067 mmol) and K2HPO4 (10.1 mg, 0.058 mmol) were added and heated for another hour. It was diluted with ACN and concentrated in vacuo, removing most of the ACN. The mixture was diluted with water/DCM then added EtOAc and the layers separated. The aqueous layer was extracted with EtOAc (5×) and the combined organic layers were dried over Na2SO4. The crude residue was purified via silica gel chromatography (MeOH-DCM, 10%) to afford the title compound (38 mg, 56%). LCMS: Rt=0.50 min, m/z=302.2 (M+1) Method 2m_acidic; 1H NMR (500 MHz, ACN-d3) δ 8.17 (s, 1H), 7.92 (s, 1H), 7.49-7.31 (m, 4H), 6.82-6.74 (m, 1H), 6.67 (br s, 1H), 5.18-5.01 (m, 3H), 4.49-4.42 (m, 1H), 4.37-4.30 (m, 1H), 4.21 (q, J=5.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].C(CN)O.Cl>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:16]1[NH:10][C:11](=[O:12])[NH:13][C:14]1=[O:15]
Reactant: O=Cc1ccccc1Cl
Reactant: O=C1CNC(=O)N1
Agent: Cl
Solvent: O
Solvent: NCCO
Product: O=C1NC(=O)C(=Cc2ccccc2Cl)N1
Reaction time: 4.25 h

Procedure:
A mixture of o-chlorobenzaldehyde (2.50 g.) and hydantoin (1.78 g., 1 molar ratio) was treated with water (15 ml) and heated to 70°. Monoethanolamine (1.63 g., 1.5 molar ratio) was added and the mixture was stirred magnetically at 90°-92° (bath temperature) for 4.25 hours. The mixture was cooled in an ice-bath, acidified with concentrated HCl, refrigerated overnight, filtered, washed with water and dried at 55°/10 mm. The title compound was obtained as a pinkish solid (2.63 g.), m.p. 266°-270° decomp.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=1O>N1C=CC=CC=1>[CH3:18][C:14]1[CH:13]=[CH:12][C:11]2[N:10]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8][C:16]=2[CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(N)c(O)c1
Solvent: c1ccncc1
Product: Cc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
Benzoyl chloride (79 ml) was slowly added to a stirred suspension of 6-amino-m-cresol (83 gm) in pyridine (600 ml). The temperature was kept below 5° C. The solution was heated under reflux for 2 hr., then was evaporated to dryness to give an oil. This oil was extracted with aqueous 2N sodium hydroxide solution. The aqueous layer was made acid with concentrated hydrochloric acid. The solid, N-(2'-hydroxy-4'-methyl-benzanilide), m.p. 170° C, was filtered off. This product was heated until no more water was evolved. The resulting liquid was allowed to cool and the solid produced was powdered and taken up in petroleum ether. The solution was treated with carbon and the filtrate evaporated to dryness to yield 6-methyl-2-phenyl-benzoxazole, m.p. 93° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.C(O[C:14](=[O:16])[CH3:15])(=O)C.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([NH:36][C:37]4[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][N:38]=4)[N:30]=3)=[CH:25][CH:24]=2)[CH2:19]1>C1COCC1>[CH3:35][C:33]1[CH:32]=[C:31]([NH:36][C:37]2[CH:42]=[C:41]([C:43]([F:44])([F:46])[F:45])[CH:40]=[CH:39][N:38]=2)[N:30]=[C:29]([C:26]2[CH:27]=[N:28][C:23]([N:20]3[CH2:21][CH2:22][C@H:18]([NH:17][C:14](=[O:16])[CH3:15])[CH2:19]3)=[CH:24][CH:25]=2)[CH:34]=1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(N3CC[C@H](N)C3)nc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CCN(c2ccc(-c3cc(C)cc(Nc4cc(C(F)(F)F)ccn4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N-Diisopropylethylamine (0.032 mL, 0.181 mmol), acetic anhydride (6.26 μL, 0.066 mmol), 6′-[(3S)-3-aminopyrrolidin-1-yl]-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]-2,3′-bipyridin-6-amine (Example 5, 25 mg, 0.060 mmol), and THF (1 mL) were added to a flask and stirred at room temperature for 16 hours. The crude solution was purified via reverse phase high pressure liquid chromatography to afford N-[(3S)-1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)pyrrolidin-3-yl]acetamide. MS ESI calcd. for C23H24F3N6O [M+H]+ 457. found 457. 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.76 (s, 1H), 8.60 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.11 (m, 1H), 7.24 (s, 1H), 7.17 (d, J=5.0 Hz, 1H) 7.12 (s, 1H), 6.46 (d, J=8.8 Hz, 1H), 3.52-3.60 (m, 3H), 3.43 (m, 1H), 3.12 (m, 1H), 2.30 (s, 3H), 2.05 (s, 1H), 1.87-1.80 (m, 2H), 1.72 (s, 1H). rhSyk IC50=17 nM.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[O:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O>O1CCOCC1.O>[C:25]([O:24][C:22]([N:10]1[CH2:9][CH2:8][CH:7]([O:6][C:5]2[CH:13]=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1)=[O:21])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Brc1ccc(OC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Reaction time: 48 h
Yield: 86.4 %

Procedure:
To a solution of 4-(4-Bromo-phenoxy)-piperidine (1 g, 3.9 mmol) in dioxane (20 ml), water (20 ml) added Na2CO3 (1.6 g, 18.9 mmol) and (BOC)2O (1.3 g, 5.9 mmol). Reaction stirred at ambient for 48 hours, solvent was removed under reduced pressure and residue partitioned between EtOAc and water the layers were separated. The organic layer was washed with brine, dried (MgSO4), and concentrated under reduced pressure to give (1.2 g) of product.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7](Cl)=[O:8].[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>>[F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1)=[O:8]
Reactant: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: NCC1CCCCN1
Product: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
contacting the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride with 2-aminomethylpiperidine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9](Cl)[CH:8]=[C:7]([CH3:12])[N:6]=1)[CH2:2][CH2:3][CH3:4].[NH3:13]>>[NH2:13][C:9]1[CH:8]=[C:7]([CH3:12])[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:10]=1
Reactant: CCCCc1nc(C)cc(Cl)n1
Reactant: N
Product: CCCCc1nc(C)cc(N)n1

Procedure:
The title compound is prepared from 2-n-butyl-4-chloro-6-methylpyrimidine (from Example 26) upon treatment with alcoholic ammonia as described by Marshall and Walker (J. Chem. Soc., 1951, 1004).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:30])[CH2:15][N:16]2[C:21](=[O:22])[C:20]3[C:23]([CH3:29])=[C:24]([C:26]([OH:28])=O)[S:25][C:19]=3[N:18]=[CH:17]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[F:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([NH:13][C:14](=[O:30])[CH2:15][N:16]2[C:21](=[O:22])[C:20]3[C:23]([CH3:29])=[C:24]([C:26]([N:52]4[CH2:51][CH2:50][N:49]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=5[F:42])[CH2:54][CH2:53]4)=[O:28])[S:25][C:19]=3[N:18]=[CH:17]2)[CH:4]=[C:3]([C:2]([F:32])([F:31])[F:1])[CH:8]=1
Reactant: Cc1c(C(=O)O)sc2ncn(CC(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(=O)c12
Reactant: Fc1ccccc1N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N2CCN(c3ccccc3F)CC2)sc2ncn(CC(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 3-(2-(3,5-bis(trifluoromethyl)phenylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid (0.24 g, 0.5 mmol) in DCM (5 mL) was added DIEA (0.3 mL, 1.5 mmol), 2-fluorophenylpiperazine (0.060 mL, 0.5 mmol), and HATU (0.25 g, 0.65 mmol). The reaction mixture was stirred at RT overnight. The organic layer was washed with sat. NaHCO3 aq. (20 mL), dried over Na2SO4, and concentrated to give crude product as a gummy solid. Purification by flash column chromatography using a mixture of Et2O:DCM (1:1) as the eluant afforded the 0.19 g of the desired product N-(3,5-bis(trifluoromethyl)phenyl)-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxo thieno[2,3-d]pyrimidin-3(4H)-yl)acetamide, (yield: 60%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:36][C:37]1[CH:46]=[C:45]2[CH:40]([CH2:41][CH2:42][N:43]([C:47](=[O:52])[C:48]([F:51])([F:50])[F:49])[CH2:44]2)[CH2:39][CH:38]=1.Cl>O1CCOCC1.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:21]1[CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C:37]4[CH:46]=[C:45]5[C:40]([CH2:41][CH2:42][N:43]([C:47](=[O:52])[C:48]([F:51])([F:49])[F:50])[CH2:44]5)=[CH:39][CH:38]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35])=[O:33]
Reactant: NC1=CCC2CCN(C(=O)C(F)(F)F)CC2=C1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)c1c(F)cccc1F
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C(=O)C(F)(F)F)CC4)n2)cc1NC(=O)c1c(F)cccc1F
Temperature: 80 °C
Yield: 44.7 %

Procedure:
To a solution of N-[5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzamide (158 mg, 0.32 mmol) in 1,4-dioxane (6 mL) and 2-propanol (2 mL) was added 7-amino-N-trifluoroacetyl tetrahydroisoquinoline (158 mg, 0.64 mmol) followed by catalytic 12M HCl. After heating overnight at 80° C., reaction was quenched with saturated NaHCO3 (25 mL), solvent removed by rotary evaporation, aqueous layer extracted with DCM (25 mL), the organic layer was concentrated and purified by column chromatography (5-50% EtOAc in hexanes) to provide the product (100 mg, 44%) as an off-white solid. ESIMS (M+H)+=700.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([Cl:36])[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:33])=[O:34])=[C:28]([Cl:36])[CH:27]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.20 g, 5.09 mmol) in dichloromethane (35 ml) was treated with morpholinomethyl-polystyrene HL resin (2.43 g, 4.2 mmol/g loading, 10.21 mmol) and then the 4-bromo-2-chlorobenzenesulfonyl chloride (2.96 g, 10.21 mmol). The resulting solution was stirred at room temperature overnight. The resin and was filtered, washed with methanol, and the solvent evaporated in vacuo. The residue was then passed through an SCX column eluting first with methanol followed by 2M ammonia in methanol. The basic fractions were collectedand solvent evaporated in vacuo to afford a crude product which was purified further by chromatography using a Flashmaster using an elution gradient of 0 to 5% methanol in dichloromethane. The relevant fractions were collected, combined and the solvent evaporated in vacuo to afford the title compound (E104). MS (ES+) m/e 488/490/492 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[CH:30]=[CH:31]/[CH2:32]O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C(Br)(Br)(Br)[Br:35]>C1C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[CH:30]=[CH:31]/[CH2:32][Br:35])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(/C=C/CO)cc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1ccc(/C=C/CBr)cc1OC
Reaction time: 1 h

Procedure:
3.67 g of triphenylphosphine was added to a solution of 1.94 g of (E)-3-(3,4-dimethoxyphenyl)allyl alcohol and 3.98 g of carbon tetrabromide dissolved in 20 ml of benzene, with ice-cooling in a nitrogen atmosphere. The mixture was stirred for 1 hour at the same temperature to obtain a benzene solution of (E)-3-(3,4-dimethoxyphenyl)allyl bromide. To this solution were added 1.11 g of triethylamine and a solution of 3.15 g of 5-(piperazin-1-yl)-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine dihydrate dissolved in 12 ml of benzene, with ice-cooling. The mixture was stirred for 2 hours at room temperature. To the reaction mixture was added 30 ml of water. The resulting insolubles were removed by filtration. An organic layer was separated and to the layer was added 30 ml of water. The mixture was adjusted to pH 1.0 with dilute hydrochloric acid. The aqueous layer was separated and 30 ml of ethyl acetate was added thereto. The mixture was adjusted to pH 8.0 with a 10% aqueous sodium hydroxide solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/acetone=2/1) to obtain 2.52 g of 5-[4-{(E)-3-(3,4-dimethoxyphenyl)allyl}piperazin-1-yl]-10,11-dihydo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine. It was recrystallized from a mixed solvent of ethyl acetate and n-hexane to obtain 2.13 g of colorless crystals having a melting point of 135°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:5](=[CH:7][C:8]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][CH:10]=1)[OH:6].[CH2:17]([NH:24][CH:25]([CH3:38])[CH2:26][O:27][C:28]1[CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]([OH:37])=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[C:33]([C:32]1[CH:36]=[C:28]([CH:29]=[CH:30][C:31]=1[OH:37])[O:27][CH2:26][CH:25]([N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:14][CH:13]([OH:15])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]([C:3]([O:2][CH3:1])=[O:16])=[C:5]([OH:6])[CH:7]=1)[CH3:38])(=[O:34])[NH2:35]
Reactant: COC(=O)c1ccc(OCC2CO2)cc1O
Reactant: CC(COc1ccc(O)c(C(N)=O)c1)NCc1ccccc1
Solvent: CC(C)O
Product: COC(=O)c1ccc(OCC(O)CN(Cc2ccccc2)C(C)COc2ccc(O)c(C(N)=O)c2)cc1O
Reaction time: 40 h

Procedure:
After 40 hours' boiling and working up analogously to Example 4a), 22.4 g of 4-(2,3-epoxypropoxy)salicylic acid methyl ester and 30 g of 5-(2-benzylaminopropoxy)salicylamide in 200 ml of isopropanol yield crude 1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-(3-hydroxy-4-methoxycarbonylphenoxy)propan-2-ol as a light-coloured foam which is further processed as a crude product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH:3]=1.[CH:24](=O)[CH2:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH3:26])[CH2:10][CH2:9]2)=[C:4]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH:3]=1
Reactant: CCC=O
Reactant: Cc1ccc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN1CCN(c2ccc(C)cc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To a mixture of 1-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (55 mg, 0.175 mmol) produced in Example (70b), propionaldehyde (20 mg, 0.350 mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride (75 mg, 0.350 mmol), followed by stirring for 1 hour and 15 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 56 mg of 1-[4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazine as a colorless solid.