Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]([Cl:27])[C:14]=1[OH:28].O>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:16]=[C:15]([Cl:27])[C:14]=1[O:28][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: BrCCCBr
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(OCc2ccccc2)cc(Cl)c1OCCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A reaction vessel was charged with 5.10 g of 1,3-dibromopropane, 2.40 g of potassium carbonate and 50 ml of N,N-dimethylformamide, to which a solution of 4.24 g of 2,6-dichloro-4-(benzyloxy)phenol dissolved in 10 ml of N,N-dimethylformamide was slowly added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with 150 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 4.24 g of 3,5-dichloro-4-(3-bromopropyloxy)-1(benzyloxy)benzene (68% yield).
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C([Li])CCC.C[O:25]B(OC)OC>O1CCCC1>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:3]3[C:2]([OH:25])=[CH:7][N:6]=[CH:5][C:4]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1c(-c2nonc2N)nc2cncc(O)c21
Reaction time: 0.75 h
Yield: 57.9 %

Procedure:
A solution of the product from Example 100 (2.6 g, 8.41 mmol) in tetrahydrofuran (180 ml) at −78° C. was treated with a 2.5M solution of n-butyllithium (8.41 ml, 21.03 mmol) in hexanes. After the addition was complete the mixture was treated with trimethylborate (2.62 g, 25.23 mmol) and allowed to reach room temperature. After 1.5 hours at room temperature the reaction was carefully quenched with 3M aq. NaOH (12.5 ml) followed by a 30% aqueous hydrogen peroxide solution (4.3 ml). After 45 minutes the reaction was acidified with 2M hydrochloric acid and then applied to a SCX ion exchange column and eluted with methanol and then a mixture of methanol/0.880 ammonia (9:1). The basic fractions were then reduced and the solid residue was triturated with dichloromethane and filtered to afford the title compound, (1.2 g, 58%); MS (ES+) m/e 247 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]#[N:16])[CH2:10][CH2:9]2)[C:3]=1[CH2:23][CH3:24].[Li]>C1COCC1>[NH2:16][CH2:15][CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=2[CH2:23][CH3:24])[CH2:9][CH2:10]1)[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCc1c(N)ncnc1N1CCN(C(C#N)C2CCCCC2)CC1
Agent: [Li]
Solvent: C1CCOC1
Product: CCc1c(N)ncnc1N1CCN(C(CN)C2CCCCC2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 44.4 %

Procedure:
To a solution of [4-(6-Amino-5-ethyl-pyrimidin-4-yl)-piperazin-1-yl]-cyclohexyl-acetonitrile (28.00 mg; 0.09 mmol; 1.00 eq.) in THF (4.00 ml; 49.37 mmol; 579.16 eq.), lithium 9-bbn hydride (0.38 ml; 0.38 mmol; 4.50 eq.) in THF was added, and the mixture stirred at 50° C. for four hours. LC-MS analysis indicated the reaction is incomplete, starting material still present. Add 0.1 ml more of lithium 9-bbn hydride solution and stir the reaction mixture overnight at 60° C. LC-MS analysis indicated the reaction was complete. The reaction mixture was filtered through a glass membrane syringe filter unit and evaporated to dryness. The residue was dissolved in DMSO (3 ml) and purified by reverse phase HPLC (Waters, basic buffer) to afford the title compound (13.9 mg; 0.04 mmol) as a white glass in 47.2% yield. LC-MS: (M+1=333.4, obsd.=333.3).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]([CH2:19][C@H:20]([NH:36]C(OC(C)(C)C)=O)[C:21]([O:23][C@H:24]([CH3:35])[CH2:25][O:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])=[O:22])[CH:10]=[CH:11][C:12]=1[O:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].[ClH:44]>O1CCOCC1>[ClH:44].[NH2:36][C@@H:20]([CH2:19][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]([O:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=1)[C:21]([O:23][C@H:24]([CH3:35])[CH2:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])=[O:22]
Reactant: CCOC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H](C)COC(=O)c2ccccc2)cc1OC(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Oc1ccc(C[C@H](N)C(=O)O[C@H](C)COC(=O)c2ccccc2)cc1OC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-3-[3,4-bis(ethoxycarbonyloxy)phenyl]-2-[(tert-butoxy)carbonylamino]propanoate (7) (1.6 g, 2.65 mmol) was dissolved in 10 mL of 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 60 min. Dioxane was completely evaporated under reduced pressure. The resulting white solid was dissolved in water (15 mL) and washed with methyl tert-butyl ether. The aqueous phase was collected and mixed with acetonitrile (10 mL). Lyophilization gave the title compound (6) (1.4 g, 100% yield) as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.31 (3H, d, J=6.8 Hz), 1.35 (6H, t, J=6.8 Hz), 3.23 (1H, d, J=3.2 Hz), 3.25 (1H, d, J=4 Hz), 4.28 (4H, q, 6.8 Hz), 4.31 (1H, dd, J=14, 5.6 Hz), 4.38 (1H, t, J=7.2 Hz), 4.49 (1H, dd, J=12, 3.2 Hz), 5.35 (1H, m), 7.24 (1H, d, J=2 Hz), 7.27 (1H, d, J=8 Hz), 7.28 (1H, d, J=2 Hz), 7.48 (2H, t, J=7.2 Hz), 7.61 (1H, t, J=7.2 Hz), 8.02 (2H, d, J=7.6 Hz). MS (ESI) m/z 504.16 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCc1cccc(NC(=O)c2cccc(Br)n2)c1
Product: CCOC(=O)CCc1cccc(NC(=O)c2cccc(-c3ccccc3)n2)c1

Procedure:
The pyridyl bromide (161) (100 mg, 0.27 mmol) was coupled to phenylboronic acid (30 mg, 0.25 mmol) using Method E. The residue was purified by column chromatography eluting with 15% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[K+].[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15])([O-:10])=[O:9].Cl>O.C(#N)C>[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](=[O:15])[NH:1][CH2:2][C:3]([OH:5])=[O:4])([O-:10])=[O:9]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(O)CNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
A solution of glycine (200 g) and KOH (200 g) in water (1000 ml) at 0° C. was treated dropwise with a solution of m-nitrobenzoyl chloride (100 g) in acetonitrile (100 ml). The reaction was allowed to warm to room temperature and was stirred for 4 hours. 12N aqueous HCl was added until pH<2. The reaction was allowed to stand overnight at room temperature. The resulting solid was filtered and washed with water (2×250 ml) and dried in vacuo at 60° C. 100 g of m-nitrohippuric acid was isolated. MS, 1H-NMR and CHN analysis were consistent with the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([C:25]3[N:29]([CH3:30])[N:28]=[N:27][N:26]=3)[CH:22]=[C:21]([CH2:31][CH3:32])[CH:20]=2)=[O:17])[CH2:9]1)=O)(C)(C)C.[ClH:33].O1CCOCC1>C(OCC)(=O)C>[ClH:33].[CH2:31]([C:21]1[CH:20]=[C:19]([NH:18][C:16]([NH:15][CH2:14][C@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:17])[CH:24]=[C:23]([C:25]2[N:29]([CH3:30])[N:28]=[N:27][N:26]=2)[CH:22]=1)[CH3:32]
Reactant: CCc1cc(NC(=O)NC[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2nnnn2C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1cc(NC(=O)NC[C@H]2CCCNC2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A solution of (S)-3-{3-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureidomethyl}-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 450 μmol) in ethyl acetate (5 mL) was treated with a solution of hydrogen chloride in dioxane (4.0 N, 2 mL, 8 mmol) and stirred at room temperature for 6 hours. The mixture was concentrated, and the residue was triturated twice in diethyl ether and dried under vacuum to provide a white powder (165 mg, 97%). 1H NMR (300 MHz, DMSO-d6) δ9.24 (s, 1H), 8.89 (bm, 1H), 8.68 (bm, 1H), 7.81 (s, 1H), 7.43 (s, 1H), 7.22 (s, 1H), 6.79 (t, J=6 Hz, 1H), 4.16 (s, 3H), 3.40 (m, 2H), 3.20 (m, 2H), 3.05 (m, 2H), 2.9-2.5 (m, 4H), 2.0-1.6 (m, 4H), 1.21 (t, J=8 Hz, 3H).
Reaction SMILES: F[C:2](F)=[C:3](F)F.[K].[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([CH3:15])[CH:9]=1.O>CN(C)C=O>[C:13]1([O:14][C:8]2[CH:13]=[CH:12][C:2]([CH3:3])=[CH:10][CH:9]=2)[CH:12]=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=1
Reactant: Cc1ccc(O)cc1
Reactant: FC(F)=C(F)F
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(C)cc2)cc1
Reaction time: 2 h

Procedure:
Tetrafluoroethylene tetramer (40 g) was added dropwise to the potassium salt of p-cresol (15 g) stirred in dry dimethyl formamide (100 ml) at 25° C. to 30° C. After addition of the tetramer, the reaction mixture was stirred at 35° C. to 40° C. for two hours. The cooled reaction mixture was poured into water, and worked up as above to give 33 g of the -cresyl ether, C8F15OC6H4CH3, boiling point 104° C. to 106° C. at 12 mm Hg. Elementary analysis, infra-red spectra, mass spectrometry and nuclear magnetic resonance measurements confirmed the identity of the compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][N:8]=2)[CH2:2]1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[F:27][C:26]([F:29])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([C:7]3[C:11]4=[C:12]5[CH:18]=[CH:17][NH:16][C:13]5=[N:14][CH:15]=[C:10]4[NH:9][N:8]=3)[CH2:2]2)=[N:21][CH:22]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: c1cc2c(ncc3[nH]nc(C4CCCNC4)c32)[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(N2CCCC(c3n[nH]c4cnc5[nH]ccc5c34)C2)nc1
Temperature: 130 °C
Yield: 24.4 %

Procedure:
A mixture of 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.16 g, 0.65 mmol, Example #26, Step E) and 2-chloro-5-(trifluoromethyl)pyridine (0.031 g, 0.17 mmol) with DIEA (0.09 mL, 0.51 mmol) in EtOH (2 mL) was heated at about 130° C. for about 1 h in a microwave reactor (250 psi maximum pressure, 1 min ramp, 300 max watts). The crude material was purified by silica gel chromatography eluting with a 5-100% EtOAc in heptane gradient to give 1-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.016 g, 24%): LC/MS (Table 2, Method a) Rt=2.32 min; m/z: 387 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.O1CCOCCOCCOCCOCCOCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Fc1ccccn1
Reactant: O=Cc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccccn2)cc1
Temperature: 120 °C
Yield: 45.2 %

Procedure:
A stirred mixture of 36.7 grams (0.30 mole) of 4-hydroxybenzaldehyde, 12.9 mL (0.15 mole) of 2-fluoropyridine, and 41.0 grams (0.30 mole) of potassium carbonate, and 1.05 grams of 1,4,7,10,13,16-hexaoxacyclooctadecane in 200 mL of dimethyl sulfoxide was heated at 120° C. for four days. The reaction mixture was cooled to ambient temperature, and 500 mL of water was added. The organic and aqueous layers were separated. The aqueous layer was basified with aqueous 10% sodium hydroxide and extracted with two 400 mL portions of diethyl ether. The ether extracts were combined and washed with one 100 mL portion of aqueous 5% sodium hydroxide, followed by one 100 mL portion of aqueous 10% lithium chloride. The organic layer and extracts were combined, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield a residue, which was subjected to column chromatography on silica gel. Elution was accomplished with 15-20% acetone in petroleum ether mixtures. The product-containing fractions were combined and concentrated under reduced pressure, yielding 13.5 grams of 4-(pyrid-2-yloxy)benzaldehyde. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([N:17]3[CH2:21][CH2:20][C@H:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([N:17]3[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)c3)CC2)C1

Procedure:
tert-Butyl [(3S)-1-({1-[3-(trifluoromethyl)phenyl]piperidin-4-yl}carbonyl)pyrrolidin-3-yl]carbamate (0.975 g, 2.21 mmol) was treated with trifluoroacetic acid (5 mL) and methylene chloride (5 mL) for 1 h at room temperature. The solution was concentrated to give 1.75 g of product which was used for the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[S:11][C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:17]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[S:11][C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)=[N:17][C:6]=1[CH3:7]
Reactant: N
Reactant: Cc1cc(C(=O)c2nc(C)c(C)s2)oc1C
Solvent: CO
Product: Cc1cc(O)c(-c2nc(C)c(C)s2)nc1C
Temperature: 160 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(4,5-dimethylthiazol-2-yl)methanone (910 mg), methanol (7 ml), and 8 ml of a 28% aqueous ammonia solution were placed in a sealed tube, and the mixture was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 5,6-dimethyl-2-(4,5-dimethylthiazol-2-yl)pyridin-3-ol (782 mg, yield 86%).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])(=[O:3])[CH3:2].[C:19](OC(C)=C)(=[O:21])[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:19]([O:13][C:9]1[CH2:10][CH2:11][CH2:12][C:8]=1[CH2:7][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:21])[CH3:20]
Reactant: C=C(C)OC(C)=O
Reactant: CCCCCC(CCC1CCCC1=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCCCCC(CCC1=C(OC(C)=O)CCC1)OC(C)=O

Procedure:
2-(3-Acetoxyoctyl)cyclopentanone (85 g.) [prepared as described in (d) above], isopropenyl acetate (125 ml.) and p-toluenesulphonic acid (2 g.) were refluxed for 24 hours allowing the acetone formed during the reaction to slowly distil from the head of a Dufton column. The excess isopropenyl acetate was then distilled off and the residue cooled, shaken with 2N sodium carbonate solution and extracted with diethyl ether. The combined ether extracts were dried over anhydrous magnesium sulphate and the ether removed in vacuo. Distillation of the residue gave 1-acetoxy-2-(3-acetoxyoctyl)cyclopent-1-ene (85 g.), b.p. 108°-110°C./0.03 mm.Hg; nD26 = 1.459.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[N:9][OH:10])=[C:6]([Cl:11])[CH:5]=[CH:4][N:3]=1.[Cl:12]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([Cl:12])=[N:9][OH:10])=[C:6]([Cl:11])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1c(Cl)ccnc1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1c(Cl)ccnc1Cl
Temperature: 64 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A solution of 2,4-dichloro-3-pyridinecarbaldehyde oxime (1.88 g, 9.9 mmol) in DMF (7.9 mL) was stirred as N-chlorosuccinimide (1.32 g, 9.9 mmol) was added. The solution was stirred in a 64° C. oil bath for 1 hour then allowed to cool to room temperature. The solution was poured onto ice. The solution was extracted with ether and the organic layer was washed with brine, dried with MgSO4, filtered and concentrated to yield 2,4-dichloro-N-hydroxy-3-pyridinecarboximidoyl chloride (1.94 g, 87%). 1H NMR (400 MHz, DMSO-d6): δ 12.89 (s, 1H), 8.52 (d, J=5 Hz, 1H), 7.81 (d, J=5 Hz, 1H).
Reaction SMILES: [ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.[Br:37][C:38]1[CH:39]=[N:40][C:41](F)=[C:42]([CH:54]=1)[C:43]([NH:45][C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=1[F:53])=[O:44].Cl.O1CCOCC1>CN1C(=O)CCC1>[ClH:1].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:41]4[N:40]=[CH:39][C:38]([Br:37])=[CH:54][C:42]=4[C:43]([NH:45][C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=4[F:53])=[O:44])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: O=C(Nc1ccc(F)cc1F)c1cc(Br)cnc1F
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)cc1F)c1cc(Br)cnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 110 °C
Reaction time: 96 h

Procedure:
To a solution of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluoroaniline (17 mg, 0.07 mmol, Compound C of Example 1) and 5-bromo-N-(2,4-difluorophenyl)-2-fluoronicotinamide (26 mg, 0.08 mmol) in 1 mL of NMP was added 4N HCl in 1,4-dioxane (0.05 mL, 0.20 mmol). The mixture was stirred at 110° C. for 4 d. After cooling, the mixture was purified on preparative (RP) HPLC to give fractions containing the desired product. The fractions were pooled and concentrated in vacuo and the residue was treated with 10 mL of 1N HCl and it was concentrated again to give the title compound (8.0 mg, 18% yield). 1H NMR (DMSO-d6) δ 10.66 (s, 1H), 10.62 (s, 1H), 8.55 (d, 2H, J=7.5 Hz), 8.06 (d, 1H, J=13.4 Hz), 7.35-7.62 (m, 5H), 7.16 (m, 1H), 6.62 (d, 1H, J=6.0 Hz), 6.43 (s, 1H); MS(ESI+) m/z 554.15, 556.14 (M+H)+.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=[O:21])[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28]N1C(=O)CCC1=O.O>C(Cl)Cl>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([Br:28])=[C:13]3[C:18](=[O:21])[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCC2c3c1cccc3N(C(=O)c1ccccc1)C2c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C1CCC2c3c(ccc(Br)c31)N(C(=O)c1ccccc1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.6 %

Procedure:
A portion (2.0 g) of the compound obtained in Example 1 was dissolved in anhydrous methylene chloride (20 ml) and to the solution was added N-bromosuccinimide (NBS; 1.01 g). The mixture was stirred for 3 days at room temperature. After adding water, the reaction mixture was extracted three times with methylene chloride. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride/hexane/ethyl acetate=5:5:1) and further crystallized from an ether/hexane mixed solvent to yield 2.02 g (83%) of the titled compound as pale yellow crystals.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+]>O1CCCC1>[CH2:16]([O:20][C:5]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][S:13][CH2:14][CH2:15]2)[S:7][N:6]=1)[C:17]#[C:18][CH3:19]
Reactant: CS(=O)(=O)c1nsc(N2CCSCC2)n1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CCOc1nsc(N2CCSCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
In 3 ml of tetrahydrofuran were dissolved 398 mg of 3-methylsulfonyl-5-(thiomorpholino)-1,2,4-thiadiazole and 180 mg of 2-butyn-1-ol, and 102 mg of sodium hydride (oil suspension; content: 60 weight %) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was subjected to recrystallization from a mixed solvent of hexane-ethyl acetate to obtain 246 mg of 3-(2-butynyloxy)-5-thiomorpholino-1,2,4-thiadiazole (hereinafter, referred to as the present compound (23)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:5]=[CH:6][C:7]([CH:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11][C:10]1=[O:17])=[O:8]>[Pd].O1CCOCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][CH2:6][C:7]([CH:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11][C:10]1=[O:17])=[O:8]
Reactant: COc1ccc(C=CC(=O)C2C(=O)C=C(C)OC2=O)cc1O
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc(CCC(=O)C2C(=O)C=C(C)OC2=O)cc1O

Procedure:
The hydrogenation of 3-(3-hydroxy-4-methoxycinnamoyl)-6-methyl-2H-pyran-2,4(3H)-dione as prepared in the above step of Claisen-Schmidt condensation was carried out in the following way. The condensation product (1.39 g.) obtained in the above step was dissolved in 150 ml. of dioxane, and the hydrogenation was effected in the presence of 0.1 g. of 5% palladium-charcoal at room temperature and under the atmospheric pressure. One mole equivalent of hydrogen was absorbed in 8 hours. After removal of the catalyst and the solvent, the remaining crystalline product was subjected to silica gel chromatography for purification. Upon recrystallization from a mixed solvent of ethanol and n-hexane, 1.11 g. of 3-(3-hydroxy-4-methoxyhydrocinnamoyl)-6-methyl-2H-pyran-2,4(3H)-dione was obtained, showing mp. 115°-116°C.
Reaction SMILES: [C:1](=O)([S:3][CH2:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)C.C[O-].[Na+].CI.C(=O)(O)[O-].[Na+]>CO>[CH3:1][S:3][CH2:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CC(=O)SCc1ccc(-c2cccnc2)o1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSCc1ccc(-c2cccnc2)o1
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
(See FIG. 7.) To a solution of 13 (27 mg, 0.12 mmol) in anhydrous CH3OH (3 mL) at 0° C. under argon was added a solution of sodium methoxide (15 mg, 0.28 mmol) in anhydrous CH3OH (1 mL) dropwise, over 10 min and the resultant solution was stirred for 30 min. To the solution was added methyl iodide (17 μL, 0.28 mmol) in anhydrous CH3OH (1 mL) dropwise over 1 min and the resultant solution was stirred for 30 min. The reaction was stopped by the addition of aqueous sodium bicarbonate (satd. soln., 10 mL). The CH3OH was removed in vacuo and the aqueous fraction was extracted with EtOAc (3×10 mL). The combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (EtOAc/Hex, 25/75, Rf=0.2) to afford the title compound 15 (13 mg, 54% yield) as an off white solid: mp=67-68° C.; 1H NMR (CDCl3) δ 8.90 (br s, 1H), 8.46 (m, 1H), 7.90 (m, 1H), 7.29 (m, 1H), 6.66 (d, J=3.3 Hz, 1H), 6.29 (d, J=3.3 Hz, 1H), 3.74 (s, 2H), 2.14 (s, 3H); LRMS (ESI) m/z calcd for C11H12NOS [M+H]+ 206. found 206.