Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: S=C=NCCC1=CCCCC1
Reactant: Nc1nccs1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: S=C(NCCC1=CCCCC1)Nc1nccs1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (3.3 g, 20 mmol) and 2-aminothiazole (2.0 g, 20 mmol) in N,N-dimethylformamide (20 mL) was heated at 100° C. for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.66 g (50%) of the title product:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)[CH3:2].[C:29]([C:32]1[N:37]=[CH:36][C:35]([NH:38][C:39](=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][C:44](Br)=[CH:43][C:42]=2[F:48])=[CH:34][C:33]=1[C:50]([F:53])([F:52])[F:51])(=[O:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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:29]([C:32]1[N:37]=[CH:36][C:35]([NH:38][C:39](=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:8]3[CH:7]=[N:6][C:5]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=3)=[CH:43][C:42]=2[F:48])=[CH:34][C:33]=1[C:50]([F:51])([F:53])[F:52])(=[O:31])[CH3:30]
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Reactant: CC(=O)c1ncc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cnc(C(C)=O)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
To a mixture of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100 mg, 0.260 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added N-(6-acetyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-bromo-2-fluorophenyl)acetamide (120 mg, 0.286 mmol), cesium carbonate (169 mg, 0.519 mmol) and PdCl2(dppf) (18.99 mg, 0.026 mmol). The mixture was stirred under a N2 atmosphere at 110° C. for 30 min under microwave. Then the reaction residue was filtered and the filtrate was concentrated to give the crude product, which was purified by preparative TLC (PE/EA=1:1, Rf=0.6) to yield a light yellow solid of N-(6-acetyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (100 mg, 0.100 mmol, 38.7% yield): 1H NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 8.62 (s, 1H), 8.13 (d, J=2.0 Hz, 2H), 7.42 (d, J=9.0 Hz, 4H), 7.33 (d, J=2.5 Hz, 2H), 6.94 (s, 1H), 5.39 (s, 2H), 4.15-4.09 (m, 2H), 3.91 (s, 2H), 2.03 (s, 3H), 1.26 (t, J=7.0 Hz, 3H); ES-LCMS m/z 598.1 (M+H).
Reaction SMILES: C(O)(=O)C.[N+:5]([CH:8]([CH3:17])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10])([O-])=O>C(O)(C)C>[NH2:5][CH:8]([CH3:17])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10]
Reactant: CC(C(O)c1ccccc1)[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(N)C(O)c1ccccc1

Procedure:
In the practice of this invention, the 2-nitro-1-phenyl-1-propanol is dissolved in a lower alkyl alcohol, preferably isopropyl alcohol. The mixture is placed in a vessel suitable for high pressure reactions and equipped with agitation means, e.g. a rocking bomb or a stirred bomb. Acetic acid is added to the solution to produce the acetate salt of 2-amino-1-phenyl-1-propanol during the reduction reaction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]#[CH:19])=[CH:13][CH:14]=2)[C:9]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[N:8][C:7]1=[O:29].C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1>CC(C)=O>[CH:26]([C:23]1[CH:24]=[CH:25][C:20]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]#[CH:19])[CH:11]=3)[N:6]([CH2:5][C:4]3[CH:30]=[CH:31][CH:32]=[C:2]([O:1][CH2:40][CH2:41][O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)[CH:3]=3)[C:7](=[O:29])[N:8]=2)=[CH:21][CH:22]=1)([CH3:27])[CH3:28]
Reactant: BrCCOC1CCCCO1
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(OCCOC2CCCCO2)c1
Temperature: 25 °C

Procedure:
To a solution of 640 mg (1.51 mmol) of 1-(3-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one in acetone (20 ml) is added potassium carbonate (2.08 g, 15.1 mmol) followed by 2-(2-bromo-ethoxy)-tetrahydropyran (475 μl, 3.02 mmol). The reaction mixture is heated at reflux for 2 days. After cooling to room temperature, the reaction mixture is quenched with water and extracted with EtOAc (2×20 ml). The combined organic layers are washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to provide a yellow oil which is purified by flash chromatography on silica gel using dichloromethane/t-butyl methyl ether (1:1) to provide the title compound as a yellow oil. Yield: 830 mg (71%).
Reaction SMILES: [CH2:1]([C:8]1([OH:33])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=2)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[ClH:40].CCOCC>C1COCC1.CO>[ClH:40].[CH2:1]([C:8]1([OH:33])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCN2CCC(O)(Cc3ccccc3)CC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: Oc1ccc(NCCCN2CCC(O)(Cc3ccccc3)CC2)cc1
Temperature: 0 °C
Yield: 26 %

Procedure:
A solution of 3-(4-Benzyl-4-hydroxy-piperidin-1-yl)-N-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionamide (0.71 g, 1.51 mmol) in THF (4 ml) was added dropwise to a 0° C. suspension of LiAlH4 (0.115 g, 3.02 mmol) in THF (4 ml). The reaction mixture was refluxed during 30 min, cooled to 0° C. and quenched carefully with H2O (5 ml). After dilution with H2O (20 ml), the reaction mixture was treated successively with 2N HCl and sat. NaHCO3. The aqueous phase was extracted with CH2Cl2 (3×10 ml), the combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (CH2Cl2 --MeOH 9:1 then 4:1) to give a foam which was dissolved in MeOH and treated with excess HCl/ether. The solution was concentrated and the residue was dissolved with EtOH. Addition of ether provided 4-Benzyl-1-[3-(4-hydroxy-phenylamino)-propyl]-piperidin-4-ol hydrochloride (0.160 g, 26%) as beige solid, m.p. 213°-216° C. and MS: m/e=341.5 (M+H+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:48])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][C:26]=1[O:35][CH2:36][CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1)(=[O:24])=[O:23])[C:15](N(OC)C)=[O:16])([CH3:10])([CH3:9])[CH3:8].OS([O-])(=O)=O.[K+].Cl>CCOCC.O1CCCC1.C(OCC)(=O)C.CCCCCC>[C:7]([O:11][C:12](=[O:48])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][C:26]=1[O:35][CH2:36][CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1)(=[O:23])=[O:24])[CH:15]=[O:16])([CH3:8])([CH3:9])[CH3:10]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCCc1cccc2ccccc12
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C)c(OCCc2cccc3ccccc23)c1
Temperature: -65 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
A solution of lithium aluminum hydride (1.45 mL, 1.0 M in ether) was added in 3 portions over a period of 35 minutes to a solution of 3-(4-acetylamino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (270 mg, 0.45 mmol) in dry ether (12 mL) and tetrahydrofuran (2 mL) at −65° C. under an atmosphere of dry nitrogen. The reaction mixture was stirred at −65° C. for an additional 10 minutes followed by the careful, dropwise addition of 0.3 N KHSO4 (10 mL) at −65° C. The reaction mixture was allowed to warm to room temperature and 0.1 N HCl (20 mL) was added. The organic layer was collected, dried (MgSO4) and evaporated to give the crude aldehyde (230 mg). Flash chromatography (silica, 2:1 ethyl acetate/hexane) provided pure 3-[4-acetylamino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (140 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.Cl[C:22]1[N:23]=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:38]=[CH:37][CH:36]=[N:35]3)=[CH:30][C:29]=2[O:39][CH3:40])=[CH:26][CH:27]=1>C1COCC1>[CH3:40][O:39][C:29]1[CH:30]=[C:31]([N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[CH:32]=[CH:33][C:28]=1[C:25]1[N:24]=[N:23][C:22]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)nn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 0.82 mL, 0.82 mmol) was added to tert-butyl 4-hydroxypiperidine-1-carboxylate (0.17 g, 0.82 mmol) in THF (3 mL) at 0° C. and the mixture was stirred for 10 min at 0° C. 3-Chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine Intermediate 2-1 (0.13 g, 0.45 mmol) was added to the reaction at 0° C. and the mixture was stirred for 1 h at RT. After evaporation under reduced pressure, the crude material was purified by silica chromatography (70 to 100% EtOAc in heptane) to give tert-butyl 4-((6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)oxy)piperidine-1-carboxylate (0.18 g, 89%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:29]1[C:30]([F:38])=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>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>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:26](=[O:28])[CH3:27])[C:30]=2[F:38])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1cccc(B(O)O)c1F
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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+]
Product: CC(=O)c1cccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c1F

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (3-acetyl-2-fluorophenyl)boronic acid (273 mg), sodium carbonate (254 mg), and tetrakis(triphenylphosphine)palladium (173 mg), the title compound was obtained as a pale-yellow oil (yield 443 mg, 91%).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25](Cl)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:28](B1OC(C)(C)C(C)(C)O1)=[CH2:29].C(=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.C(P(CCCC)CCCC)CCC>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:28]=[CH2:29])=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: CCCCP(CCCC)CCCC
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoate (2.00 g, 5.06 mmol), vinylboronic acid pinacol ester (1.56 g, 10.1 mmol) and sodium carbonate (1.61 g, 15.2 mmol) in dioxane (20 mL) and water (5 mL) was bubbled with a nitrogen atmosphere for 10 min, tributylphosphine tetrafluoroborate (0.15 g, 0.51 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.023 g, 0.025 mmol) was added to this reaction mixture. The reaction mixture was heated to 100° C. for 24 h and then cooled to ambient temperature. Water (50 mL) was added and the mixture extracted with ethyl acetate (100 mL×3), the combined organics were washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified over column chromatography, eluting with 30% dichloromethane in hexanes to give the crude product, which was used for next step without further purification: MS (ES+) m/z 398.3 (M+1).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)=[O:7])(=[O:3])[CH3:2].[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:1]([NH:4][CH2:5][C:6]([C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[C:14]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])[S:13][C:12]=12)=[O:7])(=[O:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(=O)NCC(=O)c1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)CNC(C)=O)c2s1
Reaction time: 1 h

Procedure:
7-Acetylaminoacetylimidazo[5,1-b]thiazole (397 mg) was dissolved in 40 ml of THF and 8 ml of HMPA. Tri-n-butylstannyl chloride (0.76 ml) and 7.1 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added dropwise in that order in an argon atmosphere at −73° C. The mixture was stirred at the same temperature for one hr. An ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed twice with brine, dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (eluting with ethyl acetate and then with dichloromethane:methanol=20:1) to give 152 mg of the title compound.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[O:6]=[C:7]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[C:11]([CH2:28][CH2:29][CH3:30])[N:10]2[N:31]=[CH:32][N:33]=[C:9]2[N:8]1[CH:34]1CCC(=O)[CH2:36][CH2:35]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:4]=[C:3]1[CH2:36][CH2:35][CH:34]([N:8]2[C:7](=[O:6])[C:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)=[C:11]([CH2:28][CH2:29][CH3:30])[N:10]3[N:31]=[CH:32][N:33]=[C:9]23)[CH2:1][CH2:2]1
Reactant: [Li]CCCC
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution (15 mL) of methyltriphenylphosphonium bromide (1.2 g) in tetrahydrofuran was added n-butyllithium (1.6M hexane solution, 2 mL) at 0° C., and the mixture was stirred at the same temperature for 30 min. The reaction mixture was warmed to room temperature, and further stirred for 30 min. A solution (5 mL) of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1 g) in tetrahydrofuran was added, and the mixture was stirred at 70° C. for 3 hr. The insoluble material was filtered off, and the obtained filtrate was extracted with ethyl acetate and 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.8 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12]N)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(=[O:18])C.N([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cc2ccc(Cl)o2)cc1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: OCc1ccc(Cc2ccc(Cl)o2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44 %

Procedure:
To a mixture of 4-(5-chloro-furan-2-ylmethyl)-benzylamine (2.6 g) described in Manufacturing Example 62-1-2, acetic acid (25 mL) and water (25 mL) was added sodium nitrite (9.8 g, 140 mmol) at 0° C., which was stirred for 40 minutes at room temperature. Water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed successively with water, saturated sodium hydrogencarbonate and saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. Methanol (25 mL) was added to the residue at 0° C., followed by addition of potassium carbonate (3.3 g, 24 mmol) at the same temperature. This was stirred for 1 hour at the same temperature. Water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed successively with water, saturated sodium hydrogencarbonate and saturated aqueous sodium chloride, and the organic layer was concentrated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:2) to obtain the title compound (1.2 mg, 44%).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH2:9]([O:16][NH:17][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CCCCCCCBr
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCCBr)NOCc1ccccc1
Reaction time: 18 h
Yield: 77.7 %

Procedure:
In an ice bath, 14 ml triethylamine was added to a suspension of 3.2 g (20 mmol) O-benzylhydroxylamine hydrochloride in 150 ml dichloromethane. Stirring was continued until the solution became clear. Then, 4.5 g (20 mmol) 8-bromo octanoic acid was added, followed by 5.6 g (22 mmol) bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. Stirring was continued at ambient temperature for 18 h. The solution was extracted twice with 150 ml each of 1M aqueous hydrochloric acid and twice with 150 ml each of 1M aqueous sodium bicarbonate. The organic solvent was removed i. vac. to give 5.1 g (78%) of 8-bromo-octanoic acid benzyloxyamide as a colorless oil. MS: 330 (M+H+)
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:31]1([C:36]2[CH:37]=[CH:38][C:39]3[N:40]([CH:42]=[C:43]([C:45]([OH:47])=O)[N:44]=3)[CH:41]=2)[CH:35]=[CH:34][CH:33]=[N:32]1.Cl.[NH2:49][CH2:50][C:51]([N:53]1[CH2:58][CH2:57][CH:56]([O:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[Cl:66])[CH2:55][CH2:54]1)=[O:52]>CN(C=O)C.O>[Cl:66][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[O:59][CH:56]1[CH2:55][CH2:54][N:53]([C:51](=[O:52])[CH2:50][NH:49][C:45]([C:43]2[N:44]=[C:39]3[CH:38]=[CH:37][C:36]([N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)=[CH:41][N:40]3[CH:42]=2)=[O:47])[CH2:58][CH2:57]1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: O=C(O)c1cn2cc(-n3cccn3)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cn2cc(-n3cccn3)ccc2n1
Reaction time: 0.03 h
Yield: 36.1 %

Procedure:
DIPEA (169 mg, 1.3 mmol) followed by HOBt (39 mg, 0.29 mmol) and EDCI (75 mg, 0.39 mmol) was added to a stirred solution of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid (60 mg, 0.26 mmol) in DMF (1 mL). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (80 mg, 0.26 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and the reaction mixture was partitioned with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC afforded 45 mg (33% Yield) of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 479, 97.25%. 1H NMR (300 MHz, DMSO-d6): δ 9.2 (s, 1H), 8.5 (m, 2H), 8.4 (t, 1H), 8.0 (dd, 1H), 7.8 (m, 2H), 7.4 (dd, 1H), 7.53 (m, 2H), 7.0 (m, 1H), 6.6 (t, 1H), 4.8 (m, 1H), 4.0 (bs, 1H), 4.2 (d, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:10]3([CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=4)[CH2:11]3)[O:9][C:8](=[O:22])[NH:7][C:6]=2[N:23]=1>[Pd].CCO>[NH2:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([O:9][C:8](=[O:22])[NH:7][C:6]3[N:23]=[CH:2][CH:3]=[CH:4][C:5]1=3)[CH2:18]2
Reactant: O=C1Nc2nc(Cl)ccc2C2(Cc3ccc([N+](=O)[O-])cc3C2)O1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)CC1(C2)OC(=O)Nc2ncccc21
Reaction time: 24 h

Procedure:
A mixture of 7′-chloro-5-nitro-1,3-dihydrospiro[indene-2,4′-pyrido[2,3-d][1,3]oxazin]-2′(1H)-one from Step A (1.0 g, 3.0 mmol) and 10% palladium on carbon (200 mg) in EtOH (300 mL) is stirred under hydrogen atmosphere for 24 h. The mixture is then filtered through Celite and the filtrate concentrated to give the title compound.
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:25]([O:35][CH3:36])[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:25]([O:35][CH3:36])[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: COc1cc(C(N)CC(=O)O)ccc1OC1CCCC1
Product: COC(=O)CC(N)c1ccc(OC2CCCC2)c(OC)c1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)-propionic acid was substituted with 3-amino-3-(3-methoxy-4-cyclopentyloxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 6.78-6.88 (m, 3H), 4.69-4.73 (m, 1H), 4.34 (t, 1H, J=5 Hz), 3.82 (s, 3H), 3.66 (s, 3H), 2.62 (d, 2H, J=5 Hz), 1.75-1.92 (m, 8H), 1.58 (s, 2H).