Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4OC[CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)[O:33][CH2:32]2)C1=O.Cl.Cl[CH2:47][C:48]1[C:53]([C:54]([F:57])([F:56])[F:55])=[CH:52][CH:51]=[CH:50][N:49]=1.BrCCCCC>>[F:55][C:54]([F:57])([F:56])[C:53]1[C:48]([CH2:47][N:1]2[C:9]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[CH2:32][O:33][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[N:49][CH:50]=[CH:51][CH:52]=1
Reactant: FC(F)(F)c1cccnc1CCl
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cl
Solvent: CCCCCBr
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2C12COc1cc3c(cc12)OCOC3

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride to replace 1-bromopentane, 1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (40%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.62 (d, J=4.7 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.32-6.96 (m, 4H), 6.71-6.54 (m, 2H), 6.48 (s, 1H), 5.22-5.28 (m, 2H), 4.80-4.90 (m, 2H), 4.21-4.06 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.1, 155.1, 152.3, 144.5, 142.3, 138.2, 134.3, 134.2, 134.1, 134.1, 132.7, 129.2, 128.6, 125.6, 124.9, 124.5, 124.1, 123.8, 123.6, 123.2, 122.1, 122.0, 121.6, 112.4, 108.5, 99.1, 80.0, 64.5, 63.9, 58.2, 42.2, 42.2; MS (ES+) m/z 454.8 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:13]=1[C:14]([OH:16])=O>C1COCC1>[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:13]=1[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: Nc1cccc(C(F)(F)F)c1C(=O)O
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(C(F)(F)F)c1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-amino-N-phenyl-6-trifluoromethyl-benzamide was prepared by addition of aniline (1.0 eq.) to a suspension of 2-amino-6-(trifluoromethyl)-benzoic acid trihydrate (1.0 g, 4.0 mmol, 1.3 eq.) and polystyrene-carbodiimide (3.6 g, 1.1-1.7 eq.) in THF (40 mL). The reaction was stirred at ambient temperature for 18 hours, then filtered. The filtrate was concentrated in vacuo and purified by flash chromatography to provide 2-amino-N-phenyl-6-trifluoromethyl-benzamide as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=2)[C:17]([CH3:42])=[C:16]3[CH3:43])=[O:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:50](B1OC(C)(C)C(C)(C)O1)([CH3:52])=[CH2:51]>O1CCOCC1.O.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>[CH3:42][C:17]1[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:19]2[C:15]([C:16]=1[CH3:43])=[CH:14][C:13]([C:11](=[O:12])[NH:10][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:50]([CH3:52])=[CH2:51])[CH:3]=1)[CH3:9])=[CH:21][CH:20]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(Br)c3)cc12
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1cccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1
Temperature: 100 °C

Procedure:
A solution of (S)-tert-butyl 4′-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (83 mg, 0.13 mmol, 1 equiv.), K2CO3 (36 mg, 0.26 mmol, 2 equiv.) and Pd(PPh3)4 (15 mg, 0.013 mmol, 0.1 equiv.) in dioxane/water (1.2 mL/0.3 mL) was degassed with argon. The isopropenylboronic acid pinacol ester (49 μL, 0.26 mmol, 2 equiv.) was added and the solution was heated at 100° C. for 1 h under microwave irradiation. The resulting solution was diluted with ethyl acetate, washed with a 0.5 N HCl solution, saturated aqueous NaHCO3 and brine, and then dried over Na2 SO4. The obtained oil was used without further purification. ESI-MS (m/z): 599 [M+H]+.
Reaction SMILES: [CH2:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:2]=[CH2:3].O1[CH2:21][CH2:20][CH2:19][CH2:18]1.C([Li])CCC.C(Cl)/C=C/C>O.CCCCCC>[CH2:1]([C:4]1([CH2:18]/[CH:19]=[CH:20]/[CH3:21])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH2:3]
Reactant: C=CCC1c2ccccc2-c2ccccc21
Reactant: C1CCOC1
Agent: C/C=C/CCl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: C=CCC1(C/C=C/C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
There were put 2.5 g of 9-allylfluorene and 31.3 mL of dry tetrahydrofuran manufactured by Kanto Chemical Co., Inc. in a 100 mL-three necked flask. There were added dropwise thereto at 0° C. over 30 minutes 9 mL of a hexane solution of n-butyllithium (concentration: 1.6 M) manufactured by Kanto Chemical Co., Inc. The resultant mixture was stirred for 2 hours at room temperature, and then 1.4 mL of trans-crotyl chloride manufactured by Aldrich Chemical Company was added dropwise thereto at 0° C. The temperature of the mixture was raised gradually up to room temperature, and then the mixture was stirred for 6 hours at room temperature. Water was added to the reaction mixture, and the obtained mixture was subjected to extraction with ether. The extract was washed with water and with a saline solution in this order. The washed extract was dried over anhydrous magnesium sulfate manufactured by Nacalai Tesque, Inc. The dried extract was subjected to removal of the solvent by distillation, and the resultant liquid was distilled in vacuo, thereby obtaining 2.43 g of 9-allyl-9-((2E)-2-butenyl)-fluorene at 155° C. under 4 mmHg.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.[Li]CCCC.[CH:13]([C@@H:15]1[N:19]([CH3:20])[C:18](=[O:21])[CH2:17][C@@H:16]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:14].[NH4+].[Cl-]>C1C=CC=CC=1.C1COCC1>[Br:1][C:2]1[S:3][C:4]([C@@H:13]([OH:14])[C@@H:15]2[N:19]([CH3:20])[C:18](=[O:21])[CH2:17][C@@H:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:5][CH:6]=1
Reactant: Brc1ccc(Br)s1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(Br)s1
Reaction time: 2.5 h
Yield: 58.2 %

Procedure:
To a −78° C. solution of 2,5-dibromothiophene (7.2 g, 29.6 mmol, 1.02 equiv) in anhyd. THF (100 mL) was added dropwise a solution of n-BuLi (1.6M in hexane, 18.5 mL, 29.6 mmol, 1.02 equiv) keeping the reaction temperature below −70° C. The resulting brown solution was stirred for 2.5 h. A solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 5.9 g, 29.1 mmol) in benzene (30 mL) was added, keeping the reaction temperature below −70° C. The reaction mixture was diluted with THF (30 mL) and after 30 min was treated with a saturated NH4Cl solution (150 mL). The resulting mixture was extracted with EtOAc (200 mL) and CH2Cl2 (2×200 mL) and dried (Na2SO4). The combined organic layers were concentrated under reduced pressure. The crude product was triturated (MeOH) to give (±)-(4R*,5R*)-5-[(1S*)(5-bromo(2-thienyl))hydroxymethyl]-1-methyl-4-phenyl-pyrrolidin-2-one (6.2 g) as a white solid. The filtrate was treated with silica gel (15 g), concentrated under reduced pressure and purified by flash chromatography to afford an additional 0.92 g of product (total 7.12 g, 67%) as an off-white solid: TLC (60% EtOAc/hex) Rf 0.39; 1H NMR (CDCl3) δ 2.24 (dd, J=6.2, 15.1 Hz, 1H), 2.42 (s, 3H), 2.95 (t, J=13.8 Hz, 1H), 3.76-3.85 (m, 1H), 4.15 (d, J=8.0 Hz, 1H), 4.36 (d, J=4.5 Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 6.70-7.15 (m, 1H), 7.02 (dd, J=1.9, 4.0 Hz, 1H), 7.22-7.44 (m, 5H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1.C(=O)=O.CC(O)C>[CH3:17][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: O=C=O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottom flask was charged THF (8 mL). The flask was flushed with argon, sealed, and fitted to balloon containing argon. The flask was cooled to −78° C. in dry ice/IPA bath. To this solution was added ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-5a, 2.28 g, 10.64 mmol) in 8 mL THF. The resulting solution was allowed to remain at −78° C. while LiHMDS (1.0 M in THF, 12.34 mmol, 12.34 mL) was added dropwise. Upon completion of addition, the solution was allowed to warm to 0° C. in ice bath. The reaction was stirred at 0° C. for one hour, at which point it was cooled back to −78° C. in dry ice/IPA bath. At this point, iodomethane (750 μL, 12.02 mmol) in THF (8 mL) was added dropwise. The reaction was allowed to gradually warm to room temperature as it was stirred overnight. After 18 hours, the reaction was quenched with sat NH4Cl(aq) and extracted with Et2O (x2). The combined organic extracts were washed with H2O (x1), saturated brine (x1), and dried over Na2SO4 and the residue were purified via silica gel chromatography to yield the title compound as a clear oil. Yield=1.44 g.
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:14].[CH3:15][N+:16](=[CH2:18])[CH3:17]>C(#N)C>[ClH:14].[CH:1](=[C:8]1[CH2:12][CH2:11][CH:10]([CH2:15][N:16]([CH3:18])[CH3:17])[C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=[N+](C)C
Reactant: [Cl-]
Reactant: O=C1CCCC1=Cc1ccccc1
Solvent: CC#N
Product: CN(C)CC1CCC(=Cc2ccccc2)C1=O
Product: Cl
Yield: 76.2 %

Procedure:
5.2 g (0.03 mol) of 2-benzylidene-cyclopentanone was dissolved in 30 mL anhydrous acetonitrile, treated with 8.4 g (0.09 mol) of N,N-dimethyl-methylene ammonium chloride under refluxing, refluxed for 12 h to yield a solid product, then suction filtered and dried, and recrystallized in acetonitrile/chloroform to give 2-benzylidene-5-dimethylaminomethyl cyclopentanone hydrochloride with a yield of 76.2%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[CH:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>O1CCCC1>[CH:31]1([C:36]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[N:6][N:5]3[CH:30]=2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CCCC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Yield: 56.9 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), cyclopentanecarbonyl chloride (53 μL, 0.435 mmol), triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 388, the title compound (105 mg, 57%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:30]([NH:37][C:38]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C=NCc1ccccc1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (62.8 μL, 0.36 mmol) in DCM (2 mL) was added benzyl isocyanate (44.2 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 to give the title compound as a white solid. MS (ESI, positive ion) m/z: 411 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([C:22]#[N:23])=[C:18]([CH3:24])[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([C:22]#[N:23])=[C:18]([CH3:24])[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1C#N
Reactant: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: Cc1c(C#N)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[5-cyano-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[5-cyano-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 171°-173° C.,
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:12]([C:13]2[N:14]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:15]3[C:20]([C:21]=2[C:22](=O)[C:23]([NH2:25])=[O:24])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([CH3:34])[O:10][N:9]=1.Cl.[NH2:36][OH:37]>CCO>[CH3:7][C:8]1[C:12]([C:13]2[N:14]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[C:15]3[C:20]([C:21]=2[C:22](=[N:36][OH:37])[C:23]([NH2:25])=[O:24])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([CH3:34])[O:10][N:9]=1
Reactant: Cc1noc(C)c1-c1c(C(=O)C(N)=O)c2ccccc2n1-c1ccc(O)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1noc(C)c1-c1c(C(=NO)C(N)=O)c2ccccc2n1-c1ccc(O)cc1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
50 μl Pyridine was added to 8.8 mg 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-oxoacetamide and 32.6 mg hydroxylamine hydrochloride in 1.5 ml EtOH in a microwave vial. The vial was sealed and flushed with nitrogen. The mixture was heated to 150° C. for 7.5 min. and then to 150° C. for 5 min. in a Biotage Initiator microwave oven. The mixture was concentrated in vacuo and purified by preparative HPLC (formic acid buffer/acetonitrile). 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2(hydroxyimino)acetamide (E35) was obtained as a mixture of syn and anti oxime isomers. ES/MS m/z: 391.4 (M+H), 389.5 (M−H); 1H NMR (DMSO-d6, 500 MHz): 7.37 (m, 1H), 7.20-7.03 (m, 5H), 6.84 (m, 2H), 2.15 (s, 3H) and 1.77 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11](/[CH:12]=[C:13]2\[CH2:14][N:15]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH:18]\2O)=[CH:10][N:9]=[CH:8]1)=[O:5])[CH3:2].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:55]([OH:58])(=[S:57])[CH3:56].C(SC1CCN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C/C/1=C\C1N(CC(OCC)=O)C=NC=1)(=O)C>CN(C)C=O>[C:55]([S:57][CH:12]([C:11]1[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=[N:9][CH:10]=1)[C:13]1[CH2:14][N:15]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:16][CH2:17][CH:18]=1)(=[O:58])[CH3:56]
Reactant: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(O)=S
Agent: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cncc1C(SC(C)=O)C1=CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 1.5 h
Yield: 29 %

Procedure:
To a solution of (E)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (560 mg) in N,N-dimethylformamide (5 ml) were added N,N-dimethylformamide dineopentyl acetal (2.5 ml) and thioacetic acid (0.6 ml) at room temperature. After being stirred at the same temperature for 1.5 hour, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Solvents were removed under reduced pressure, and residue was purified by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (1:2:2) as an eluent. In a separate run, further starting material (E)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (1.0 g) was subjected to the similar reaction/purification procedure. Both products were combined to afford an approximately 5:2 mixture of (E)-4-(acetylsulfanyl)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine and 5-{(acetylsulfanyl)[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methyl}-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (500 mg, gross yield: 29%), as a yellow amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][CH3:13])=[N:7][CH:6]=[CH:5]2.I[C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C([Sn](CCCC)(CCCC)[C:30]1[S:31][CH:32]=[CH:33][N:34]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:13][O:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][S:21]([C:18]3[CH:19]=[CH:20][C:15]([C:30]4[S:31][CH:32]=[CH:33][N:34]=4)=[CH:16][CH:17]=3)(=[O:23])=[O:22])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: COc1nccc2cc(N)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1nccc2cc(NS(=O)(=O)c3ccc(-c4nccs4)cc3)ccc12

Procedure:
The compound (40 mg) obtained by the procedure of Example 1, except using 6-amino-1-methoxyisoquinoline (Preparation Example 43) and 4-iodobenzenesulfonyl chloride, 2-tri-n-butylstannylthiazole (136 mg), tetrakis(triphenylphosphine)palladium(0) (11 mg) were heated under reflux in toluene in nitrogen atmosphere for 1 hour. The solvent was evaporated and the residue was purified by silica gel column. The resulting crystals were recrystallized from methanol, to give the title compound (20 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=O)[CH2:9][CH2:10]2)=[CH:5][CH:4]=1.[ClH:16].Cl.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.P(C#N)(=O)(OCC)OCC.Cl.[C:48]([O:51][CH2:52]C)(=O)C>CN(C)C=O.C(N(CC)CC)C>[ClH:16].[CH3:48][O:51][CH2:52][CH2:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([N:27]3[CH2:28][CH2:29][N:24]([CH2:23][C:22]4[CH:21]=[C:20]([O:19][CH3:18])[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=4)[CH2:25][CH2:26]3)=[O:15])[CH2:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(C)=O
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: COc1ccc2c(c1)CCC(C(=O)O)=C2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOc1ccc2c(c1)CCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1)=C2

Procedure:
Using 7-methoxy-1,2-dihydro-3-naphthoic acid (0.5 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.1 g), triethylamine (0.81 g), N,N-dimethylformamide (20 ml) and diethyl phosphorocyanidate (1 ml), an amidation is carried out in a manner as that described in Example 6. The reaction product is purified by silica gel column chromatography (hexane:acetone=1:1-1:2) to afford an oily product, which is converted to the hydrochloride in ethyl acetate to give 1-(7-methoxyethoxy-1,2-dihydro-3-naphthoyl)- 4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.8 g) as colorless crystals, m.p. 187°-190° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]([F:29])([F:28])[F:27])=O)(=O)OC.O.[NH2:31][NH2:32]>>[F:25][C:21]1[C:20]([C:26]([F:29])([F:28])[F:27])=[C:19]([C:17]2[N:32]=[N:31][C:4]3[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][C:5]=3[CH:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COP(=O)(CC(=O)c1cccc(F)c1C(F)(F)F)OC
Reactant: CC1(C)CC(=O)C(=O)C1
Reactant: NN
Solvent: O
Product: CC1(C)Cc2cc(-c3cccc(F)c3C(F)(F)F)nnc2C1

Procedure:
light yellow solid. MS (EI): 310.2 (M+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, [2-(3-Fluoro-2-trifluoromethyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].IC.[N:9]1[CH:10]=[CH:11][N:12]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][C:13]=12>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:19][C:18]([C:16]1[CH:15]=[CH:14][C:13]2[N:12]([CH:11]=[CH:10][N:9]=2)[CH:17]=1)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc2nccn2c1
Agent: [Cl-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
Cesium carbonate (15.7 g, 48.2 mmol) and iodomethane (1.50 ml, 24.2 mmol) were added to a solution of imidazo[1,2-a]pyridine-6-carboxylic acid (2.61 g, 16.1 mmol) in DMF (100 ml). The reaction was stirred at ambient temperature overnight, then poured into brine (100 ml) and extracted with ethyl acetate (3×100 mL). The combined organics were washed with saturated sodium bicarbonate solution (25 mL), and a 1N HCl solution (25 mL) then dried over MgSO4 and evaporated to give imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester as a yellow solid (1.1 g, 39%). 1H NMR (250 MHz, CDCl3): δ 8.96 (s, 1H), 7.8-7.6 (m, 4H), 3.98 (s, 3H). MS [EI+] 177 (M+H)+.