Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[C:7](=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[N:13]([CH3:15])[N:14]=2)[N:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH3:3].[OH-].[K+].Br[CH2:28][CH2:29][CH3:30]>CS(C)=O>[CH2:1]([N:4]([CH2:28][CH2:29][CH3:30])[C:5]1[C:6]2[C:7](=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[N:13]([CH3:15])[N:14]=2)[N:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH3:3]
Reactant: CCCBr
Reactant: CCCNc1nc(C)nc2c(-c3c(C)cc(C)cc3C)n(C)nc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCN(CCC)c1nc(C)nc2c(-c3c(C)cc(C)cc3C)n(C)nc12
Temperature: 60 °C

Procedure:
A mixture of the product of step F (400 mg, 1.2 mmol), powder KOH (1.0 g) and 1-bromopropane (1 mL) in 2 mL of DMSO was heated at 60° C. for 8 hours. The excess bromopropane was then evaporated. The mixture was partitioned between water and ether. The aqueous layer was separated and extracted with ether. The combined ether extracts were washed with water and brine, dried over Na2SO4 and concentrated to an oil. The oil was purified through silica gel column chromatography to give 260 mg of the title compound as an oil. 1H NMR (CDCl3): d 0.97 (t, 6H), 1.76 (m, 4H), 1.96 (s, 6H), 2.32 (s, 3H), 2.45 (s, 3H), 3.77 (s, 3H), 3.40-4.30 (br, 4H), 6.95 (s, 2H)ppm. The hydrochloride salt prepared in Ether/HCl melted at 210°-13° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:47][CH:48]([CH2:51][CH3:52])[CH2:49][CH3:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:47][CH:48]([CH2:51][CH3:52])[CH2:49][CH3:50])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCC(N)CC
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NC(CC)CC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-aminopentane (Alfa) to give the title product. LC-MS (ES+) 734 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.BrC1C=CN=C(N)C=1.[CH3:19][N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.O.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:19][N:20]1[C:24]([C:2]2[CH:7]=[CH:6][N:5]3[CH:8]=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:23][CH:22]=[N:21]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccn2ccnc2c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Nc1cc(Br)ccn1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1nccc1-c1ccn2ccnc2c1
Temperature: 75 °C
Yield: 70 %

Procedure:
A solution of 7-Bromo-imidazol[1,2-a]pyridine (0.5 g, 2.54 mmol, 1 equivalent, made according to general procedure A1 using 4-bromo-pyridin-2-ylamine instead of 4-chloro-pyridin-2-ylamine), 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 5.08 mmol, 2 equivalents), bis(tri-t-butylphosphine) palladium (0) (66 mg, 0.13 mmol, 0.05 equivalents) and potassium carbonate (2.1 g, 15.24 mmol, 6 equivalents) in ethanol (10 ml), toluene (10 ml) and water (10 ml) was heated at 75° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was then washed with a saturated brine solution, dried (MgSO4), filtered and the solvent removed by evaporation in vacuo. The residue was purified by column chromatography (Biotage SP4, 25S, flow rate 25 ml/min, gradient 0% to 20% methanol in ethyl acetate) to give 7-(2-methyl-2H-pyrazol-3-yl)-imidazo[1,2,a]pyridine as a colourless oil (350 mg, 70%). MS: [M+H]+ 199.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:13][C:12]=3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[CH3:24][C@H:25]1[CH2:30][N:29]([CH:31]2[CH2:34][O:33][CH2:32]2)[C@H:28]([CH3:35])[CH2:27][N:26]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)=[N:40][CH:41]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:24][CH:25]1[CH2:30][N:29]([CH:31]2[CH2:34][O:33][CH2:32]2)[CH:28]([CH3:35])[CH2:27][N:26]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47]([C:2]3[C:7]([CH:8]=[O:9])=[C:6]([N:10]4[CH2:22][CH2:21][C:20]5[N:19]6[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]6)=[CH:13][C:12]=5[C:11]4=[O:23])[N:5]=[CH:4][CH:3]=3)[CH:48]=2)=[N:40][CH:41]=1
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC1CN(C2COC2)C(C)CN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 139a (133 mg, 0.40 mmol), 155a (198 mg, 0.40 mmol), Pd(dppf)Cl2 (17 mg, 0.020 mmol), K3PO4 (254 mg, 1.2 mmol), sodium acetate (98 mg, 1.2 mmol), water (5 drops), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 3 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 155b as white solid (80 mg, 30%). MS-ESI: [M+H]+ 663.3.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[C:9]([NH:28][C:29]1[S:30][CH:31]=[C:32](/[C:34](=[N:40]/O)/[C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:33]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O.[K+].[Br-]>C1C=CC=CC=1>[C:9]([NH:28][C:29]1[S:30][CH:31]=[C:32](/[C:34](=[N:40]/[O:8][CH:5]2[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]2)/[C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:33]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(O)CC1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: COC(=O)N=NC(=O)OC
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)/C(=N\OC1CCC(=O)CC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 336 h

Procedure:
4-Hydroxycyclohexanone (570 mg; J. B. Aldersley, G. N. Burkhardt, A. E. Gillam, and N. C. Hindley, J. Chem. Soc., 1940, 10) ethyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate (1.37 g) and triphenyl-phosphine (860 mg) in anhydrous benzene (9 ml) were allowed to react with dimethyl azodicarboxylate (0.40 ml) as described in Example 67c except the reaction time was 14 days. Workup and chromatography gave the title compound (158 mg), νmax (KBr) 3390, 1737, 1710, 1596, 1585, 1529, and 1491cm-1 ; δH (CDCl3) 1.33 (3H, t, J 7Hz), 2.01, 2.31, and 2.55 (8H, 3m), 4.36 (2H, q, J 7z), 4.73 (1H, m), 6.52 (1H, s), 6.97 (1H, brs, D2O exch.), and 7.30 (15H, br s).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O[Li].O.C(OCC)(=O)C>O1CCCC1.O.CCCCCC>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 87.3 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (436) (1.2 g, 2.60 mmol) in tetrahydrofuran-water (2:1; 24 mL), LiOH.H2O (1.09 g, 26.03 mmol) was added, refluxed for 16 h while silica thin layer chromatography was performed (50% ethyl acetate in hexane, Rf=0.1). From the reaction mixture volatiles were removed and the residue was diluted with water (20 mL). Thereafter, the pH of this mixture was adjusted to 7 with 1N aqueous HCl. The resulting precipitate was filtered and dried. The obtained solid was triturated with ether to get 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (437) (920 mg, 87%) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[C:14]([CH3:16])[N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([Br:25])[CH:31]=4)[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cc(-c2ccc3c(c2)OCO3)cc(OS(=O)(=O)C(F)(F)F)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc3c(c2)OCO3)cc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 4-benzo[1,3]dioxol-5-yl-6-methyl-pyridin-2-yl ester (example A.56) (1.1 g, 3.04 mmol) and commercially available 3-bromobenzeneboronic acid (0.611 g, 3.04 mmol) according to the general procedure IVb. Obtained as a colorless gum (0.44 g, 39%). MS (ISP) 368.0 [(M+H)+] and 370.0 [(M+2+H)+].
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:20][OH:21])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:23]=[O:24])=[CH:5][NH:6]2.Cl([O-])=[O:26].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.CC(=CC)C.O>[F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3([CH2:20][OH:21])[CH2:18][CH2:19]3)=[CH:15][CH:16]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([C:23]([OH:26])=[O:24])=[CH:5][NH:6]2
Reactant: O=Cc1c[nH]c2cc(F)c(-c3ccc(C4(CO)CC4)cc3)c(F)c12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: O=C(O)c1c[nH]c2cc(F)c(-c3ccc(C4(CO)CC4)cc3)c(F)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.7 %

Procedure:
To a solution of 4,6-difluoro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carbaldehyde (70 mg, 0.214 mmol) in acetonitrile (4.6 mL), t-Butanol (4.6 mL) and 2-methyl-2-butene (3.0 mL) was added a solution of sodium chlorite (289 mg, 4.28 mmol) and NaH2PO4 (590 mg, 4.28 mmol) in water (4.6 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with a solution of sodium sulfate (674 mg, 5.35 mmol) in water (5.0 mL), and extracted with ethyl acetate (20 mL×3). The organic layers were washed with brine (20 mL×1) and dried over sodium sulfate, filtered, concentrated, and purified which was purified by preparative HPLC to give the title compound (17.4 mg, 24%) as a white solid. MS (AP+) 343.9 (M+1)+. 1H NMR (400 MHz, CD3OD) δ 8.00 (s, 1H), 7.48 (d, 2H), 7.39 (d, 2H), 7.11 (d, 1H), 3.71 (s, 2H), 0.91 (s, 4H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:4](=[S:23])[N:3]1[C:24]1[CH:25]=[C:26]([C:32]([F:35])([F:34])[F:33])[C:27]([C:30]#[N:31])=[N:28][CH:29]=1.[N:36]([Si](C)(C)C)=[C:37]=[O:38].O>C(Cl)Cl>[C:30]([C:27]1[N:28]=[CH:29][C:24]([N:3]2[C:2](=[O:1])[C:6]3([CH2:9][CH2:8][CH2:7]3)[N:5]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([C:37]([NH2:36])=[O:38])[CH2:19][CH2:18]4)=[CH:12][CH:11]=3)[C:4]2=[S:23])=[CH:25][C:26]=1[C:32]([F:34])([F:33])[F:35])#[N:31]
Reactant: C[Si](C)(C)N=C=O
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OC4CCNCC4)cc3)C2=S)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OC4CCN(C(N)=O)CC4)cc3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A mixture of 5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (70 mg, 0.14 mmol) and isocyanatotrimethylsilane (23 μL, 0.17 mmol) in DCM (3 mL) was stirred at room temperature overnight. Water was added and the mixture was stirred vigorously for 1 h. The aqueous layer was extracted with DCM (3×), the organics were combined, dried over sodium sulfate, and evaporated to dryness. Column chromatography on silica gel (0 to 20% MeOH/DCM) afforded 55 mg of 4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidine-1-carboxamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.69 (s, 1H), 7.23 (d, 2H), 7.12 (d, 2H), 5.92 (s, 2H), 4.53 (m, 1H), 3.67-3.63 (m, 2H), 3.08-3.04 (m, 2H), 2.44 (m, 2H), 2.39 (m, 2H), 1.88 (m, 3H), 1.46 (m, 3H). LCMS [M+1]+ 545.2
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[C:1]1([CH2:11][NH:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccc2ccccc12
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1cccc2ccccc12
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield from 1-naphthylmethylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.39 (br s, 1H), 8.25 (s, 1H), 8.15 (d, 1H, J=7.9 Hz), 7.98 (d, 1H, J=7.5 Hz), 7.84-7.89 (m, 2H), 7.45-7.62 (m, 5H), 5.03 (s, 2H). [M+H] calc'd for C17H14N2O2, 279. found 279.
Reaction SMILES: C1([CH:7]2[C:12](=S(=O)=O)[CH:11]=[CH:10][CH:9]=[C:8]2[C:16](=[CH2:21])[C:17]([O:19][CH3:20])=[O:18])C=CC=CC=1.[CH2:22]([SnH:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].N(C(C)(C)C#N)=NC(C)(C)C#N>C1CCCCC1>[C:8]1([C:16](=[CH:21][Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])[C:17]([O:19][CH3:20])=[O:18])[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C(C(=O)OC)C1=CC=CC(=S(=O)=O)C1c1ccccc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCCCC1
Product: CCCC[Sn](C=C(C(=O)OC)c1ccccc1)(CCCC)CCCC
Temperature: 25 °C

Procedure:
Combine 2-phenyl-3-sulfonlyphenyl-propenoic acid, methyl ester (41.0 g, 136 mmol) and tri-n-butyltin hydride (79.0 g, 271 mmol) in cyclohexane (900 mL). Add 2,2'-azobisisobutyronitrile (AIBN) (0.7 g, 4.3 mmol) and heat to reflux for 3 hours. Cool to ambient temperature and evaporate in vacuo. Chromatograph on silica gel eluting with 20% ethyl acetate/hexane. Evaporate the product containing fractions and chromatograph on silica gel eluting sequentially with 5% ethyl acetate/hexane and 10% ethyl acetate/hexane to give the title compound and a clear oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:32]=[CH:31][C:22]([C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].CN1CCOCC1.[CH:40]1(Br)[CH2:44][CH2:43][CH2:42][CH2:41]1>C(#N)C>[CH:40]1([N:28]2[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([C:17]([N:14]4[CH2:15][CH2:16][N:11]([C:6]5[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=5)[CH2:12][CH2:13]4)=[O:18])=[CH:32][CH:31]=3)[CH2:30][CH2:29]2)[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Reactant: BrC1CCCC1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCN(C4CCCC4)CC3)cc2)CC1
Reaction time: 20 h
Yield: 71 %

Procedure:
1-[4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoyl]piperazine (0.5 g) was dissolved in acetonitrile (25 ml) and then, N-methylmorpholine (0.17 ml) and cyclopentyl bromide (0.3 ml) were added. The solution was heated to 65~75° C. and stirred for 20 hours. The solvent was concentrated under reduced pressure and then, the residue was dissolved in chloroform (40 ml). The solution was washed with water twice and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether and hexane, and further recrystallized using ethanol and isopropyl ether. The recrystallized product was filtered and dried to give 0.41 g (yield: 71%) of the desired compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([C:38]1[C:39]([N:47]2[CH2:52][CH2:51][CH:50]([N:53]3[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]3)[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43])[CH3:37].Cl>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH2:36][CH3:37])[C:39]([N:47]4[CH2:48][CH2:49][CH:50]([N:53]5[CH2:54][CH2:55][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:57][CH2:58]5)[CH2:51][CH2:52]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCc1cc(N)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCc1cc(Nc2nccc(-c3c(-c4ccc(OC)c(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 170 °C
Yield: 58.7 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.60 g, 1.22 mmol), 5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 206, Step B) (0.48 g, 1.22 mmol) and HCl (4N,1,4-Dioxane, 0.61 mL, 2.44 mmol) in trifluoroethanol (15 mL) was heated at 170° C. for 40 min in the microwave. The reaction mixture was concentrated onto silica gel and purified by flash column chromatography. Recrystallization from DCM and EtOH afforded the title compound N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide (0.61 g, 56%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][S@:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[O:28])=[CH:8][CH:7]=1)([OH:5])[CH3:4].FC(F)(F)[C@@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2C[S@@](C2C=CC=C(F)C=2)=O)=CC=1)(O)C.FC(F)(F)[C@@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2C[S@](C2C=CC=C(F)C=2)=O)=CC=1)(O)C>>[F:37][C:2]([F:1])([F:36])[C@:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][S@@:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[O:28])=[CH:10][CH:11]=1)([OH:5])[CH3:4]
Reactant: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2C[S@@](=O)c2cccc(F)c2)cc1)C(F)(F)F
Agent: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2C[S@@](=O)c2cccc(F)c2)cc1)C(F)(F)F
Agent: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2C[S@](=O)c2cccc(F)c2)cc1)C(F)(F)F
Product: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2C[S@](=O)c2cccc(F)c2)cc1)C(F)(F)F

Procedure:
(2S)-1,1,1-trifluoro-2-(4-((2R)-2-(((3-fluorophenyl)-(R)-sulfinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((3-fluorophenyl)-(S)-sulfinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2R)-1,1,1-trifluoro-2-(4-((2R)-2-(((3-fluorophenyl)-(R)-sulfinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. Second Eluting Peak (Peak#2) (Mixture of Two Sulfoxide Isomers)
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=4)[NH:12][CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[C:22]1([NH:28][C:29](=[O:32])[NH:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:31][NH:30][C:29]([NH:28][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)=[O:32])=[O:21])[CH:17]=4)[NH:12][CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc2[nH]cc(-c3cncc(C4CC4)n3)c2c1
Reactant: NNC(=O)Nc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNC(=O)c1ccc2[nH]cc(-c3cncc(C4CC4)n3)c2c1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A mixture of 3-(6-cyclopropylpyrazin-2-yl)-1H-indole-5-carboxylic acid (204.5 mg, 0.732 mmol), 4-phenylsemicarbazide (111 mg, 0.732 mmol), EDC (140 mg, 0.732 mmol), and HOBT (112 mg, 0.732 mmol) in DMF (3.5 mL) was stirred at 25° C. for 3 h. DIPEA (0.255 mL, 1.464 mmol) was added and the resulting mixture was stirred at 25° C. for 2 h. Additional 4-phenylsemicarbazide (111 mg, 0.732 mmol), HOBT (112 mg, 0.732 mmol), and EDC (140 mg, 0.732 mmol) were sequentially added, and the resulting mixture was stirred at 25° C. for 17 h. The mixture was diluted with H2O (40 mL), and the precipitated solid was collected by vacuum filtration, sequentially washed with H2O (2×30 mL) and Et2O (2×15 mL), and dried in vacuo to provide 2-(3-(6-cyclopropylpyrazin-2-yl)-1H-indole-5-carbonyl)-N-phenylhydrazinecarboxamide (262 mg, 0.635 mmol, 87%) as a tan solid: MS (ESI, pos. ion) m/z: 413.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90-11.97 (1H, m), 10.19-10.25 (1H, m), 8.97-9.00 (1H, m), 8.94-8.97 (1H, m), 8.84 (1H, s), 8.36 (1H, s), 8.32 (1H, d, J=2.7 Hz), 8.15 (1H, s), 7.79 (1H, d, J=8.4 Hz), 7.51-7.55 (1H, m), 7.50 (2H, d, J=8.0 Hz), 7.27 (2H, t, J=7.7 Hz), 6.96 (1H, t, J=7.3 Hz), 2.18-2.27 (1H, m), 1.16-1.22 (2H, m), 1.04-1.13 (2H, m).
Reaction SMILES: BrC1C=C(CCCC[OH:12])C=CC=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:24]=[CH:25][CH:26]=2)=[O:20])[CH:14]=1>>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][C:30]([OH:12])=[O:31])[CH:24]=[CH:25][CH:26]=2)=[O:20])[CH:14]=1
Reactant: OCCCCc1cccc(Br)c1
Reactant: O=C(c1cccnc1)c1cccc(CCCCO)c1
Product: O=C(O)CCCc1cccc(C(=O)c2cccnc2)c1

Procedure:
4-(3-bromophenyl)butanol and 3-pyridylaldehyde were reacted to synthesize 4-[3-(3-pyridylcarbonyl)phenyl]butanol, then the resultant product was oxidized by a similar method as in Example 2(3) to synthesize the desired compound.