Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.C(N(CC)CC)C.[Br:18][C:19]1[N:23]2[N:24]=[C:25]([Cl:29])[CH:26]=[C:27](Br)[C:22]2=[N:21][CH:20]=1>CCO>[Br:18][C:19]1[N:23]2[N:24]=[C:25]([Cl:29])[CH:26]=[C:27]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=3)[C:22]2=[N:21][CH:20]=1
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Reactant: CCOc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOc1ccc(Nc2cc(Cl)nn3c(Br)cnc23)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
p-Phenetidine (0.38 ml, 2.9 mmol) and triethylamine (0.8 ml, 5.8 mmol) were added to a mixture of 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (0.83 g, 2.67 mmol) from 1a in EtOH (10 mL). The mixture was heated to 80° C. and stirred for 16 hrs. The solution was then concentrated in vacuo to give crude 3-bromo-6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:9](=[O:23])[C:10]3[N:11]=[C:12]([CH3:22])[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3[N:15]=2)=[CH:3][CH:2]=1.C1C(=O)N([Br:44])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:2]=[CH:3][C:4]([C:7]2[N:8]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:9](=[O:23])[C:10]3[N:11]=[C:12]([CH2:22][Br:44])[N:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:14]=3[N:15]=2)=[CH:5][CH:6]=1
Reactant: Cc1nc2c(=O)n(-c3ccc(Cl)cc3)c(-c3ccc(-c4ccccc4)cc3)nc2n1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c2nc(CBr)n(-c3ccccc3)c2nc(-c2ccc(-c3ccccc3)cc2)n1-c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 77.9 %

Procedure:
A solution of 2-biphenyl-4-yl-1-(4-chloro-phenyl)-8-methyl-9-phenyl-1,9-dihydro-purin-6-one (51 mg, 0.104 mmol) in CCl4 (2 mL) was treated sequentially with NBS (24 mg, 0.135 mmol) followed by AIBN (22 mg, 0.135 mmol). The reaction was heated at 80° C. for 3 h, allowed to cool to room temperature, and concentrated in vacuo. The crude oil was purified by flash column chromatography (silica, 0 30% Hex/EtOAc) to provide 2-biphenyl-4-yl-8-bromomethyl-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one (46 mg, 78%) as a white solid. HPLC-MS calculated for C30H20BrClN4O (M+H+): 567.1. Found: 567.1.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6](SC)[N:5]=[C:4]([CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=[CH:14]3)[CH:3]=1>[Ni].CCO.O>[OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=[CH:14]3)[CH:3]=1
Reactant: CSc1nc(O)cc(Cc2ccc3c(C(=O)O)cccc3c2)n1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc2cc(Cc3cc(O)ncn3)ccc12
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
29 g Raney Nickel in EtOH are added to a solution of 5.08 mMol 6-(6-hydroxy-2-methylsulfanyl-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid in 220 ml EtOH and 170 ml water. The mixture is stirred for 3.5 h at 80° C., filtered hot and the residue is extensively washed with EtOH/H2O 1:1. Partial concentration in vacuo, acidification of the residue with 1 N HCl (pH=1), filtration of the precipitated product, washing with 50 ml 0.1 N HCl and drying (HV; 90° C.) gives the title compound. Additional product can be isolated from the filtrate by extraction with 3 Portions of EtOAc, washing of the organic layers with brine, drying (Na2SO4), concentration and chromatography (Combi Flash; CH2Cl2→CH2Cl2/MeOH+0.5% HOAc 19:1): TLC (CH2Cl2/MeOH+0.5% HOAc 9:1): Rf=0.17.
Reaction SMILES: [C:1]1([C:7]2[NH:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC(c1ccccc1)=N2
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2nc(-c3ccccc3)ncc2c1
Temperature: 25 °C

Procedure:
2-Phenyl-6-nitro-3,4-dihydroquinazoline (27 g, 0.106 mol) and chloranil (32.4 g, 0.13 mol) in toluene (450 ml) are refluxed for 60 minutes. The mixture is cooled to room temperature, and the precipitate is filtered off and washed with toluene (350 ml). The filtrate is suspended in 0.5N NaOH (400 ml) and the aqueous phase is extracted with dichloromethane (100 ml). The combined organic phases are washed with water and concentrated. The solid is recrystallized from hexane. Yield: 8.8 g (34%); Rf (8/2 petroleum ether/ethyl acetate): 0.71; 1H-NMR (d6-DMSO) 9.91 (s, 1H); 9.18 (d, 1H); 8.61 (m, 3H); 8.24 (d, 1H); 7.55 (m, 3H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:41]([O:43][C:44](=[O:47])[CH2:45]Br)[CH3:42].C(Cl)Cl.CO>CN(C=O)C>[O:34]=[C:23]([N:11]1[CH2:12][CH2:13][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:21][C:22]=2[CH:10]1[C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][C:29]([CH2:32][O:33][CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:47])=[CH:30][CH:31]=1
Reactant: O=C(/C=C/c1ccc(CO)cc1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)COCc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 11 %

Procedure:
To a solution of Example 39 (0.7 g, 1.5 mmol) in 50 mL of DMF was added K2CO3 (0.25 g, 1.2 equiv.) and ethylbromoacetate (0.2 mL, 1.1 equiv.). The resulting mixture was heated at 60° C. for 16 hours until disappearance of the starting material (tlc monitoring, DCM:MeOH (95:5)). A new compound was formed (Rf=0.8). After evaporation of DMF, the residue was taken up in 150 mL of DCM, washed with 2×50 mL of water, dried over Na2SO4 and purified via radial chromatography with DCM to give the title compound (0.85 g, 11%) as a white powder.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][C:11]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:16]=3)=[C:12]([CH3:14])[N:13]=2)=CC=1>FC(F)(F)C(O)=O.O>[CH3:14][C:12]1[N:13]=[C:9]([NH2:8])[S:10][C:11]=1[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:16]=1
Reactant: COc1ccc(CNc2nc(C)c(-c3ccnc(N4CCOCC4)n3)s2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1nc(N)sc1-c1ccnc(N2CCOCC2)n1
Temperature: 75 °C

Procedure:
A solution comprising (4-methoxy-benzyl)-[4-methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-amine (25c) (0.45 g, 1.13 mmol) in trifluoroacetic acid:water (95:5) (10 ml) is heated at 75° C. for days. The solvent is removed in vacuo and the crude residue is dissolved in ethyl acetate. The pH is adjusted to pH12 using 2N sodium hydroxide and the layers are separated. The aqueous layer is extracted with ethyl acetate (2×30 ml). The organic portions are combined and washed with brine (50 ml), dried over MgSO4 and concentrated in vacuo to yield the titled compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:35]([C:26]4[CH:27]=[CH:28][C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:25]=4)(=[O:37])=[O:36])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc2)c2ccc3ccccc3c2N1
Yield: 64.3 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-naphthalenesulfonyl chloride (32 mg, 0.14 mmol) were treated by heating 11 pyridine (3 mL). A post-treatment was performed in a conventional manner to give the title compound (31 mg, yield 64%) as white amorphous.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([NH:26][C@@:27]1([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:32][C@H:31](OS(C)(=O)=O)[C@@H:30]2[C@H:28]1[C@H:29]2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1.O>[C:19]([O:23][C:24]([NH:26][C@@:27]1([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:32]=[CH:31][C@@H:30]2[C@H:28]1[C@H:29]2[C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](OS(C)(=O)=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C=C[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 25 °C
Yield: 47.5 %

Procedure:
Add 1M tetrabutylammonium fluoride in tetrahydrofuran (3.84 mL, 3.84 mmol) to di-tert-butyl (1S,2S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-4-[(methylsulfonyl)oxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (600.00 mg, 1.22 mmol) in tetrahydrofuran (2.03 mL) and heat at reflux for 3 hours. The reaction is then cooled to room temperature, diluted with water, and extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography eluting with 5-75% ethyl acetate in hexanes to give the title compound (0.23 g, 0.58 mmol, 48%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[N:17]=[C:16]3[N:18]([CH3:21])[CH:19]=[CH:20][C:15]3=[CH:14][CH:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1CCCC1=O>[C:32]([O:31][C:30](=[O:36])[NH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[NH:22][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]2[N:17]=[C:16]3[N:18]([CH3:21])[CH:19]=[CH:20][C:15]3=[CH:14][CH:13]=2)[CH:3]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cn1ccc2ccc(Nc3cc(Cl)nnc3C(N)=O)nc21
Solvent: CN1CCCC1=O
Product: Cn1ccc2ccc(Nc3cc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nnc3C(N)=O)nc21
Temperature: 150 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
6-Chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-pyridazine-3-carboxylic acid amide (42 mg, 0.139 mmol), and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (89 mg, 0.416 mmol) were dissolved in N-methylpyrrolidinone (1.4 mL) and heated at 150° C. for 36 h. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (35 mg, 0.16 mmol) was added and the heating continued for 16 h more. The reaction mixture was cooled and concentrated in vacuo, then diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) gave {(1S,2R)-2-[6-carbamoyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-pyridazin-3-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (12 mg, 18%) as a light brown amorphous residue. LCMS (EI/CI) m/z: 481 [M+H].
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO[C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:12]([O:11][C:9]([NH:8][CH2:7][C:6]([NH:3][CH2:1][CH3:2])=[O:16])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCN
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Product: CCNC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethylamine (37 g, 0.82 mol) was condensed into a pressure vessel at 0° C. N-(tert-butoxycarbonyl)glycine methyl ester (50 mL, 0.34 mol) was added. The vessel was sealed and the mixture was stirred at room temperature overnight. The product mixture was concentrated under vacuum and the residue was passed through a pad of silica gel eluting with ethyl acetate. The solution was concentrated under vacuum to provide the title compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.I[C:29]1[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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]>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][N:19]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=2)=[CH:30][CH:31]=1
Reactant: Nc1ccc(I)cn1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(N)nc2)c1
Temperature: 100 °C

Procedure:
A mixture of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.29 g, 3.41 mmol), 5-iodopyridin-2-amine (500 mg, 2.27 mmol), PdCl2(dppf) (333 mg, 0.455 mmol) and sodium carbonate (2.27 ml, 4.55 mmol) in dioxane (9.10 mL) was heated to 100° C. for 16 hours. The reaction mixture was then filtered through a CELITE plug and washed with 1:1 DCM:methanol. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give N-[3-(6-aminopyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine as a colorless solid. MS APCI calc'd for C17H15F3N5 [M+H]+ 346. found 346.
Reaction SMILES: Br[C:2]1[C:3]([C:17]#[N:18])=[N:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[C:6]=1[CH2:7][C:8]([C:11]#[N:12])([CH3:10])[CH3:9].Cl.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:18][C:17]1[C:3]2=[N:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[C:6]([CH2:7][C:8]([CH3:10])([CH3:9])[C:11]#[N:12])=[C:2]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=1
Reactant: Nc1ccccc1B(O)O
Reactant: COCCn1nc(C#N)c(Br)c1CC(C)(C)C#N
Agent: Cl
Product: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
A modification of the method described in Part B of Example 1283 was used to couple 4-bromo-5-(2-cyano-2-methylpropyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrile (1.56 g, 5.00 mmol) with 2-aminophenylboronic acid hydrochloride (1.73 g, 10.0 mmol). The reaction was completed in one hour. The coupling product was purified by IFC (silica cartridge, eluting with 50% to 90% ethyl acetate in hexane). The reaction with hydrogen chloride was heated at reflux for two hours and allowed to cool to room temperature overnight. 3-[4-Amino-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-2,2-dimethylpropanenitrile (676 mg) was obtained as white crystals, mp 206-208° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N:49]1[CH2:54][CH2:53][CH:52]([NH:55][C:56](N2C=CN=C2)=[O:57])[CH2:51][CH2:50]1>>[C:31]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:29][NH:28][C:9]2[N:8]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][C:56]([NH:55][CH:52]3[CH2:51][CH2:50][N:49]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][N:43]=4)[CH2:54][CH2:53]3)=[O:57])=[O:6])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
Prepared from N-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 10) and N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide (Preparation 30) by a similar method to Example 1.
Reaction SMILES: [CH2:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].C(OC(=O)C)(=O)C>C(OCC)(=O)C>[CH2:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]3[O:17][C:16](=[O:18])[CH2:15][N:14]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc(C(=O)NCC(=O)O)cc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCc1ccc(Oc2ccc(C3=NCC(=O)O3)cc2)cc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
A mixture of N-[4-(4-ethylphenoxy)benzoyl]glycine (200 mg, 0.668 mmol) prepared in Example 89 (89a) and acetic anhydride (0.38 mL, 4.03 mmol) was stirred at 80° C. for 20 minutes. Ethyl acetate was added to the reaction mixture, and then the mixture was cooled to room temperature. The solvent was evaporated, and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 3:1, v/v) to give 2-[4-(4-ethylphenoxy)phenyl]-1,3-oxazol-5(4H)-one (120 mg, 0.427 mmol). All of this 2-[4-(4-ethylphenoxy)phenyl]-1,3-oxazol-5(4H)-one was dissolved in benzene (0.9 mL), and then 4-isopropoxybenzaldehyde (71 mg, 0.432 mmol) and triethylamine (24 μL, 0.172 nmol) were added thereto. The mixture was stirred at 90° C. for 2 hours. After the addition of water to the reaction solution, the mixture was extracted with a solvent mixture of hexane and ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to give 181 mg of the title compound (brown oil, yield: 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:9]1[CH:22]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[C@H:9]1[CH2:22][NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(N)ccc(C#N)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(NC[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CCCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
A mixture of 77F (660 mg, 1.92 mmol), 4-amino-2-chloro-3-methylbenzonitrile (384 mg, 2.3 mmol, 1.2 equiv) and HOAc (165 μL, 2.88 mmol, 1.5 equiv) in 1,2-DCE (10 mL) was stirred at rt for 30 min and Na(OAc)3BH (610 mg, 2.88 mmol, 1.5 equiv) was added. The reaction was stirred at rt overnight. Another 407 mg of Na(OAc)3BH (610 mg, 1.92 mmol, 1.0 equiv) was added and stirred at rt for another 24 h. The mixture was concentrated and the residue was diluted with EtOAc (30 mL), washed with saturated sodium bicarbonate solution (2×15 mL), brine (2×15 mL), dried (MgSO4) and evaporated to give the crude product. Purification of the crude product by flash chromatography (0-50% EtOAc/hexane) yield the desired product 77G (192 mg, 20%) as a white foam: Rf (30% EtOAc/hexane) 0.37; HPLC (Phenomenex Luna 5μ C18 4.6×50 mm, linear gradient over 4 min) retention time 4.6 min (100%); MS (ES) m/z 344.1 [M+1]+; HRMS calcd for C25H41N3O3SiCl 494.2606, Found 494.2613.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]3)[C:6]=2[CH:28]=1.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:7]2[C:6]3[CH:28]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(Br)cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3ccc(Br)cc32)CC1

Procedure:
tert-Butyl {1-[2-(6-bromo-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 66) (261 mg, 0.57 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2.C(N(CC)CC)C>ClCCl>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc2c(O)c(N)cnc2c1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1cnc2cc(OC)ccc2c1O
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Butyryl chloride (0.63 mL, 6.1 mmol) was added dropwise to a solution containing 3-amino-7-methoxyquinolin-4-ol hydrochloride (1.0 g, 5.26 mmol), triethylamine (2.35 mL, 16.8 mmol), dichloromethane (30 mL) and N,N-dimethylfonnamide (10 mL). The reaction mixture was maintained at ambient temperature overnight. The N,N-dimethylformamide was removed under vacuum and the resulting solid was partitioned between dichloromethane (100 mL) and water (100 mL). The organic fraction was washed with water, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 0.86 g of N-(4-hydroxy-7-methoxyquinolin-3-yl)butanamide as a tan solid.
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[S:3].Br[CH:24]1[C:30](=O)[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[O:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CCO>[CH2:15]([O:14][C:13](=[O:22])[NH:12][CH:9]1[CH2:10][CH2:11][CH:6]([CH2:5][NH:4][C:2]2[S:3][C:24]3[CH2:25][CH2:26][O:27][C:28]4[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=4[C:30]=3[N:1]=2)[CH2:7][CH2:8]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC(=S)NCC1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: O=C1c2ccccc2OCCC1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(NC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1)OCc1ccccc1
Yield: 64.3 %

Procedure:
A solution containing benzyl N-(4-{[(aminocarbothioyl)amino]methyl}-cyclohexyl)carbamate (3.45 g, 10.73 mmol), 4-bromo-2,3,4,5-tetrahydro-1-benzoxepin-5-one (2.60 g, 10.78 mmol), and diisopropylethylamine (2.50 ml) in EtOH (50 ml) was heated at reflux for 4 hours. The solvent was removed and the residue was chromatographed on silica gel eluting with 1:3 EtOAc/hexane to yield 65% (3.2 g) of the product as a white solid: m.p. 124-127° C.; 1H-NMR (CDCl3) δ 1.09 (4H, pentet, J=10.4 Hz), 1.55 (1H, broad), 1.83 (2H, m), 2.04 (2H, broad), 3.10 (2H, t, J=6.2 Hz), 3.15 (2H, t, J=5.2 Hz), 3.43 (1H, broad) 4.33 (2H, t, J=5.2 Hz), 4.62 (1H, d, J=8.0 Hz), 5.08 (2H, s), 5.31 (1H, m), 7.00 (1H, dd, J=1.2 Hz, 7.8 Hz), 7.12 (2H, m), 7.35 (5H, s), 8.25 (1H, dd, J=1.7 Hz, 7.8 Hz). ESIMS m/z=464 (MH+).