Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9](#[N:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:9](=[NH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCCCC(=N)NO
Reaction time: 0.21 h

Procedure:
To a solution of 0.107 g (15.4 mmol) of hydroxylamine hydrochloride in 11 mL of isopropyl alcohol, 1.90 g (22.64 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 1.0 g (10.2 mmol) of hexanenitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After the reaction period, the reaction mixtures was cooled to 25° C. to 30° C., filtered and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to obtain a crude residue. The residue with chased with 5 mL of toluene, to yield the title compound.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=O>CO.Cl.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[CH2:9][CH2:8][CH2:7][Cl:6])=[CH:13][CH:14]=1
Reactant: NNC(N)=S
Reactant: COc1ccc(C(=O)CCCCl)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(C(CCCCl)=NNC(N)=S)cc1
Reaction time: 72 h
Yield: 63 %

Procedure:
Thiosemicarbazide (6.4 g, 70 mmol) was added under nitrogen to a solution of 4-chloro-4'-methoxybutyrophenone (10.0 g, 47 mmol) in 150 mL of methanol plus 12.7 mL of 1 N HCl plus 11.8 mL of water and the reaction stirred for approximately three days (over the weekend). The solid formed was collected by filtration and dissolved in methylene chloride. The organic solution was washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give a white solid. Recrystallization of the solid from isopropyl alcohol gave 8.46 g (63%) of the title compound as a light yellow solid, mp 137-140° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C-:25]#[N:26].[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.CC#N>[CH3:18][C:15]1[CH:14]=[C:13]([C:6]2[C:7](=[O:12])[NH:8][C:9]3[C:4]([C:5]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3][C:2]([C:25]#[N:26])=[CH:11][CH:10]=3)[O:17][N:16]=1
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(Br)ccc3[nH]c2=O)on1
Reactant: [C-]#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(C#N)ccc3[nH]c2=O)on1
Temperature: 100 °C

Procedure:
A flask was charged with 6-bromo-3-(3-methyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (30 mg, 0.077 mmol)(example 39), Pd(PPh3)4 (5 mg, 5 mol %), NaCN (8 mg, 0.16 mmol), Cul (1.5 mg, 10 mol %), and 0.7 mL CH3CN and heated in a sealed tube in a microwave reactor at 100° C. for 1 hr. The title compound was obtained by elution from a 10 g SPE with 50% EtAc/hex to give 13 mg (50%) of a white solid. 1H NMR (400 MHz, CD3OD) δ 7.78 (dd, 1H), 7.50 (m, 5H), 7.28 (m, 2H), 6.42 (s, 1H), 2.20 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C20H13N3O2 327.1, found 328.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([O:13][C:14](=[O:16])[CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Se](=O)=[O:18].O>O1CCOCC1>[CH:1]([C:2]1[C:11]([CH3:12])=[C:10]([O:13][C:14](=[O:16])[CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:18]
Reactant: O=[Se]=O
Reactant: CC(=O)Oc1c(C)c(C)nc2ccccc12
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Oc1c(C)c(C=O)nc2ccccc12
Yield: 52.3 %

Procedure:
A solution of 4.30 g (20.0 mmols) of 2,3-dimethyl-4-acetoxyquinoline, 2.44 g (22.0 mmols) of selenium dioxide, 8 ml of water and 80 ml 1,4-dioxane was refluxed for 3 hours. The solvent was distilled off under reduced pressure, after which 100 ml of chloroform was added, followed by washing with a saturated sodium hydrogencarbonate aqueous solution and then with water, and drying with sodium sulfate. The solvent was distilled off under reduced pressure and the resultant crude product was purified by silica gel column chromatography (Wako Gel C-200) (solvent: n-hexane : ethyl acetate=10:1) to obtain 2.40 g (yield 52%) of 2-formyl-3-methyl-4-acetoxyquinoline.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH2:8][C:9]([NH:11][CH2:12][C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14]2)=[O:10])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].C[O:35][C:36]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)=[O:37]>COCCOC.O.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:36]([C:38]1[CH:43]=[CH:42][C:41]([C:2]2[S:3][C:4]([S:7][CH2:8][C:9]([NH:11][CH2:12][C@@H:13]3[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:10])=[CH:5][CH:6]=2)=[CH:40][CH:39]=1)([OH:37])=[O:35]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C(CSc1ccc(Br)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(CSc1ccc(-c2ccc(C(=O)O)cc2)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 130 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
The resultant product (200 mg) of Example 31, tetrakistriphenylphosphinepalladium (25 mg), sodium carbonate (200 mg) and 4-methoxycarbonylphenylboronic acid (105 mg) were dissolved in a mixed solution of ethylene glycol dimethylether (4 mL) and water (250 μL), and the mixture was heated under reflux at 130° C. for 6 hrs. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was evaporated under reduced pressure, and the residue was purified by column chromatography using chloroform as an eluent. The eluent was evaporated and the obtained yellow oil was dissolved in ethanol (2 mL). A 1N aqueous sodium hydroxide solution (50 μL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was adjusted to pH=5 with 1N hydrochloric acid, and the mixture was extracted with chloroform. The extract was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (90 mg) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:23]1(=O)[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24]1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=1)=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c(Cl)c1OCC1CCCC1

Procedure:
0.550 g (1.60 mmol) of 2-chloro-3-cyclopentylmethoxy-4-ethylsulfonylbenzoic acid, 0.196 g (1.70 mmol) of cyclohexane-1,3-dione, 0.279 g (1.40 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 0.002 g of dimethylaminopyridine were stirred for 10 hours at room temperature in 15 ml of methylene chloride. The mixture was subsequently diluted with methylene chloride and washed with 0.5 N HCl, with water, with saturated NaHCO3 solution and again with water. After the combined organic phases had been dried over Na2SO4 and evaporated completely on a rotary evaporator, 3-oxo-1-cyclohexenyl 2-chloro-3-cyclopentylmethoxy-4-ethylsulfonylbenzoate was obtained in the form of a brown resin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:23][C:24]([F:37])([F:36])[C:25]([NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)=[O:26]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH:10]3[N:15]([CH2:30][CH2:29][CH2:28][NH:27][C:25](=[O:26])[C:24]([F:37])([F:36])[F:23])[CH:13]([CH2:12][CH2:11]3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCCNC(=O)C(F)(F)F
Reactant: Clc1ccc(C2=CC3CCC(C2)N3)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCCN1C2C=C(c3ccc(Cl)cc3)CC1CC2)C(F)(F)F
Yield: 46.6 %

Procedure:
Racemic 3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene (1.0 g, 4.55 mmol), triethylamine (0.70 mL, 5.01 mmol), and methanesulfonic acid 3-(2,2,2-trifluoro-acetylamino)-propyl ester (1.13 g, 4.55 mmol) in ethanol (20 mL) were refluxed for 15 hours. The mix was concentrated, diluted with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×150 mL). Combined organic layers were washed with brine (200 mL), dried with magnesium sulfate and concentrated to a light brown oil. Silica gel flash chromatography using 5% methanol/chloroform as the eluent yielded racemic N-{3-[3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-en-8-yl]-propyl}-2,2,2-trifluoro-acetamide (0.79 g, 46.5%) as a light brown oil which had the following properties: 1H NMR CDCl3 δ: 10.00 (brd s, 1H), 7.27 (s, 4H), 6.23 (d, J=5.4 Hz, 1H), 3.69-3.43 (m, 4H), 2.82-2.71 (m, 3H), 2.19-1.88 (m, 4H), 1.77-1.57 (m, 3H). IR (CHCl3): 3157, 2949, 2880, 1714, 1544, 1494, 1466, 1446, 1403, 1377, 1346, 1315, 1245, 1162, 1094, 1012, 973, 937, 817, (cm−1). Analysis calculated for C18H20ClF3N2O.3/4 H2O: C, 55.96; H, 5.61; N, 7.25; Found: C, 55.80; H, 5.09; N, 7.33.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.Cl[CH:20]([CH3:28])[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][O:24]1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH:20]([CH3:28])[C:21]([N:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[O:22])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CC(Cl)C(=O)N1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)N1CCCO1
Reaction time: 5 h
Yield: 92.6 %

Procedure:
A mixture of 4-(5-trifluoromethyl-2-pyridyloxy)phenol (25.6 g), N-[(±)-2-chloropropionyl]isoxazolidine (16.4 g) which was prepared as in Example 1, anhydrous potassium carbonate (15.2 g) and acetonitrile (300 ml) was heated under reflux with stirring for 5 hours. After cooling, the reaction mixture was filtered through a suction filter to remove solid matters and the filtrate was concentrated in vacuo. The residue was washed with the addition of water and benzene and the organic layer formed was separated and dried over anhydrous sodium sulfate. The removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionyl]isoxazolidine (35.5 g) as a pale yellow crystalline solid. Recrystallization from a mixture of n-hexane/ethyl acetate yielded a white crystalline solid. m.p. 83°-85° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]([F:43])([F:42])[F:41])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:34])(=[O:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17][C:16]=3[F:35])[C:10]([CH2:36][CH2:37][CH2:38][CH3:39])=[N:9]2)[CH:7]=1.[C:44](Br)(=[O:47])[CH2:45][CH3:46].C(Cl)Cl>CN(C1C=CN=CC=1)C.CO>[CH2:36]([C:10]1[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:33])(=[O:34])[NH:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:17][C:16]=2[F:35])[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:44](=[O:47])[CH2:45][CH3:46])[CH:3]=[CH:4][C:5]=2[C:40]([F:42])([F:41])[F:43])[N:9]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reactant: CCC(=O)Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F

Procedure:
The title compound was prepared by reaction of 2-[5-amino-2-(trifluoromethyl)phenyl]-5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) with propionyl bromide (3 equivalents) in the presence of DMAP (1.1 equiv) following the method of Example 69. Chromatographic purification of the crude product on silica gel (elution with 0.8% MeOH in CH2Cl2) afforded a nearly quantitative yield of off-white, stiff foam; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 682 (M+Li)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:16](=[O:19])[CH2:17][CH3:18])[C:9](=[N:12][N+:13]([O-:15])=[O:14])SC)=[CH:5][N:6]=1.[CH3:20][NH2:21].CO.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:16](=[O:19])[CH2:17][CH3:18])[C:9]([NH:21][CH3:20])=[N:12][N+:13]([O-:15])=[O:14])=[CH:5][N:6]=1
Reactant: CN
Reactant: CCC(=O)N(Cc1cnc(Cl)s1)C(=N[N+](=O)[O-])SC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC(=O)N(Cc1cnc(Cl)s1)C(=N[N+](=O)[O-])NC
Reaction time: 3 h
Yield: 40.9 %

Procedure:
To a solution of N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitro-N-propionylisothiourea (310 mg) in toluene (5 ml) was added 40% methylamine-methanol solution (75 mg) below -10° C. and the mixture was stirred at the same temperature for 3 hours. After addition of 2N hydrochloric acid (5 ml) under ice-cooling, the mixture was extracted with AcOEt (10 ml). The organic layer was washed with an aqueous saturated sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with AcOEt. The fractions containing the desired compound were concentrated and the residue was dissolved in toluene. Crystallization by addition of n-hexane gave 120 mg of 1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitro-1-propionylguanidine (Compound No. 32) as a white crystal, m.p. 89°-90° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[Cl:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21](SC)=[N:22][CH:23]=2)=[CH:15][CH:14]=1>C(O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[N:22][CH:23]=2)=[CH:27][CH:28]=1
Reactant: NCCCNc1ccccn1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Solvent: CCO
Product: O=c1[nH]c(NCCCNc2ccccn2)ncc1Cc1ccc(Cl)cc1

Procedure:
2-(3-Aminopropylamino)pyridine (0.91 g) and 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (1.33 g) were fused together on a oil bath at 160° C. for 2.5 hr. The mixture was dissolved in hot ethanol. Cooling afforded a white solid which on recrystallisation from ethanol gave 5-(4-chlorobenzyl)-2-[3-(pyrid-2-ylamino)propylamino]-4-pyrimidone, (1.24 g; 67%) m.p. 168°-71° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH:23]5[CH2:25][CH2:24]5)=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2)CC1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)cc2)C1=O
Yield: 70.4 %

Procedure:
Using (4-bromophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (240 mg) described in Preparation Example 185 and 1-acetylimidazolidin-2-one (115 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (189 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[NH:14][CH:13]=[CH:12][N:10]3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[CH2:22]([O:21][C:19]([CH2:18][N:14]1[C:9]2[N:10]([N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[CH:12]=[CH:13]1)=[O:20])[CH3:23]
Reactant: c1ccc(-c2cc3[nH]ccn3n2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccn2nc(-c3ccccc3)cc12
Reaction time: 1 h

Procedure:
A solution of 0.4 g of 6-phenyl-1H-imidazo[1,2-b]pyrazole in 10 ml of dimethylformamide was slowly added dropwise, whilst stirring at room temperature, to 96 mg of a 55% w/w suspension of sodium hydride in mineral oil, which was itself suspended in 10 ml of dimethylformamide, and then the mixture was stirred for a further 1 hour. At the end of this time, 0.24 ml of ethyl bromoacetate and 10 ml of dimethylformamide were added, and then the whole mixture was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between ethyl acetate and water, and then the organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified first by column chromatography through silica gel, eluted with a 1:1 by volume mixture of ethyl acetate and hexane, and then by recrystallization from a mixture of ethyl acetate and hexane, to give 0.38 g of the title compound in the form of plates melting at 85°-87° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:21]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br)([O-:23])=[O:22].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[N+:21]([O-:23])=[O:22])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: O=[N+]([O-])c1ccccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1[N+](=O)[O-]
Yield: 89.5 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.431 g, 1.61 mmol), 2-nitrobenzyl bromide (0.509 g, 2.75 mmol),KI (60 mg, 0.36 mmol), and DIPEA (0.6 mL, 3.44 mmol) in DMF (8 mL) was heated at 60° C. for 24 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.58 g (90%) of COMPOUND 64 as a yellow solid. 1H NMR (CDCl3) δ 1.63-1.70 (m, 3H), 2.04-2.08 (m, 1H), 2.31-2.43 (m, 8H), 3.85 (s, 2H), 4.12 (d, 2H, J=11.1 Hz), 6.83-6.91 (m, 3H), 7.18-7.29 (m, 4H), 7.78 (d, 1H, J=7.5 Hz), 8.24 (d, 2H, J=3.9 Hz); ES-MS m/z 403 (M+H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)=[O:28])[CH3:25].CO.C(O)(=O)C.C([BH3-])#N.[Na+]>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:31]2[CH2:32][CH2:33][CH2:34][C@@H:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH2:30]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1CCCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (500 mg, 2 mmol) was combined with (R)-piperidine-3-carboxylic acid ethyl ester (0.51 g, 3.2 mmol) in methanol (10 mL, 200 mmol) and acetic acid (9.2 μL, 0.16 mmol). Sodium cyanoborohydride (0.25 g, 4.0 mmol) was then added and the reaction was stirred overnight at room temperature. The reaction was then quenched with water and extracted three times with ethyl acetate. Organics were combined and dried over MgSO4. Solids were removed via filtration and 10 g of silica gel was added. All solvent was then removed and the resulting silica gel was loaded onto a 24 g column and the product was eluted using a gradient of 0-60% ethyl acetate/hexanes and then dried under vacuum to give the title compound as a colorless oil. EDI-MS: 438.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:36](=[O:37])[CH2:35][N:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)CN1CCOCC1)c1ccc(F)cc1
Yield: 9.3 %

Procedure:
A solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3, 0.16 g, 0.42 mmol), 2-morpholinoacetic acid (0.06 g, 0.42 mmol), HBTU (0.16 g, 0.42 mmol) and DIEA (0.16 g, 1.2 mmol) in DCM (3 ml) was stirred at room temperature for 1 hour. The reaction was then quenched with a saturated aqueous solution of NaHCO3, and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.02 g, 10%). 1H NMR (400 MHz, CD3OD) δ 7.35 (br s, 2H), 7.17 (br s, 1H), 7.01-6.97 (m, 2H), 6.06 (br s, 1H), 5.16-4.99 (m, 1H), 4.30 (br s, 2H), 3.68 (br s, 4H), 3.06 (br s, 2H), 2.48 (br s, 4H), 1.87-1.82 (m, 1H), 1.51 (d, J=6.4 Hz, 3H), 0.91 (br s, 2H), 0.64 (br s, 2H). MS: Calcd.: 511. Found: [M+H]+ 512.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(O)(C(F)(F)F)=O>>[C:17]1([C:11]2([CH2:10][O:9][CH2:8][C:6]3[CH:7]=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=4)[CH:3]=[N:4][CH:5]=3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1cncc(COCC2(c3ccccc3)CCNCC2)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2cncc(COCC3(c4ccccc4)CCNCC3)c2)cc1
Yield: 62.8 %

Procedure:
This compound was prepared according to the experimental condition of Example 1 method A from 3-bromo-5-(((4-phenylpiperidin-4-yl)methoxy)methyl)pyridine (75 mg, 0.16 mmoL), and 4-cyanobenzene boronic acid (90 mg, 0.64 mmol) to afford 50.0 mg (64%) of the desired compound as its TFA salt. 1H-NMR (CD3OD, 400 MHz) δ 8.99 (s, 1H), 8.52 (s, 1H), 8.25 (s, 1H), 7.92 (d, 2H, J=7.2 Hz), 7.83 (d, 2H, J=7.2 Hz), 7.21-7.46 (m, 5H), 4.64 (s, 2H), 3.58 (s, 2H), 3.32-3.60 (m, 2H), 2.89-2.96 (m, 2H), 2.51-2.56 (m, 2H), 2.21-2.22 (m, 2H). Mass spec.: 384.14 (MH)−.