Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:27]=[N:28][CH:29]=2)[C:5]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:6]([C:8](N(OC)C)=[O:9])[CH:7]=1.[CH3:30][Mg]Cl.Cl.O.C([O-])(O)=O.[Na+]>O1CCCC1>[C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]2[N:4]([CH:27]=[N:28][CH:29]=2)[C:5]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=[O:9])[CH3:30]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Into a microwave vial was placed a solution of tert-butyl 4-(8-chloro-6-{[methoxy(methyl)amino]carbonyl}imidazo[1,5-a]pyridin-5-yl)piperazine-1-carboxylate (31 mg, 0.073 mmol) in anhydrous tetrahydrofuran (0.5 mL) under N2 at 0° C. A solution of 3.0 M methylmagnesium chloride in tetrahydrofuran (85 μL, 0.26 mmol) was added dropwise. The solution was stirred at 0° C. for 30 minutes. It was stirred for 2 hours at room temperature. The reaction solution was quenched at 0° C. with 1.0 M hydrogen chloride in water (0.5 mL, 0.5 mmol), poured into 25 mL of saturated NaHCO3 solution and was extracted into ethyl acetate. The ethyl acetate extract was washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to give the crude which was purified on silica gel with ethyl acetate (0-60%) to give desired product (22 mg, 78%). LCMS calculated for C18H24ClN4O3 (M+H)+: m/z=379.2. found: 378.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.[OH-].[Na+].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>CN(C=O)C>[N:24]1([C:2]2[N:7]=[C:6]([N:8]([CH3:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:3]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: CN(c1ccccc1)c1nc(Cl)nc(N2CCOCC2)n1
Reactant: c1c[nH]cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(N2CCOCC2)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.2 %

Procedure:
The obtained 2-chloro-4-(N-methyl-N-phenylamino)-6-morpholino-1,3,5-triazine (135 mg, 0.457 mmol) was dissolved in DMF (5 ml), added with sodium hydroxide (19.2 mg, 0.480 mmol) and imidazole (32.7 mg, 0.480 mmol) and stirred at 110° C.-120° C. for 5 hours. After allowing to cool to room temperature, the solvent was removed under reduced pressure. The residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, using dichloromethane and methanol (20:1) as eluant, to obtain 71.3 mg (yield: 52.8%) of the titled compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:5]([CH2:11]Cl)[C:6]=1[C:7]([F:10])([F:9])[F:8].[O-:22][CH2:23][CH3:24].[Na+]>C(O)C.O.CCOCC>[Br:1][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:5]([CH2:11][O:22][CH2:23][CH3:24])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: N#Cc1c(Br)c(C(F)(F)F)n(CCl)c1-c1ccc(Cl)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOCn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of 4-bromo-1-(chloromethyl)-2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (2.0 g, 0.005 mol) in absolute ethanol is treated with a 21% wt/wt ethanolic solution of sodium ethoxide (0.36 g, 0.0053 mol), heated to 75°-80° C. for 20-30 minutes, cooled to room temperature and diluted with water and ether. The organic phase is dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid which is recrystallized form heptane to give the title product as a white solid (1.75 g, mp 97°-98° C.).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[CH:13]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C=O.[C:34](=O)([O-])O.[Na+]>O.C(OCC)C.C(O)C>[CH:13]([N:26]1[CH2:31][CH2:30][N:29]([CH2:34][CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]2=[O:11])[CH2:28][CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C1CCCc2ccccc21
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: O=C1c2ccccc2CCC1CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 80 °C

Procedure:
In 100 ml. of ethanol is dissolved a mixture of 10 g. of 3,4-dihydro-1(2H)-naphthalenone, 22 g. of 1-benzhydrylpiperazine hydrochloride and 10 g. of 37% aqueous formalin and the mixed solution is stirred at room temperature for 3 hours and, then, heated at 80° C. for another 3 hours. To this reaction mixture is added 500 ml. of water and, after shaking with 100 ml. of diethyl ether, the water layer is neutralized with sodium hydrogen carbonate and extracted with chloroform. The extract is dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. By the above procedure is obtained an oil of 2-(4-benzhydryl-1-piperazinylmethyl)-3,4-dihydro-1(2H)-naphthalenone. This product is dissolved in a mixture of 50 ml. of chloroform and 100 ml. of methanol. After addition of 5 g. of sodium borohydride, the mixture is stirred at room temperature for 30 minutes. Following addition of 500 ml. of water, the reaction mixture is extracted with chloroform and the extract is dried. The solvent is distilled off under reduced pressure and the residue is purified by chromatography on a column of silica gel (acetone-benzene=1:9). By the above procedure is obtained 4.3 g. of 2-(4-benzhydryl-1-piperazinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenol as colorless prisms melting at 179°-181° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([NH2:28])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([NH2:28])=[S:43])=[CH:15][CH:14]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(N)=O)ccc2c1=O
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(N)=S)ccc2c1=O
Yield: 144.8 %

Procedure:
To a suspension of 3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (4.05 g, 9 mmol) in toluene (50 ml) was added Lawesson's reagent (2.19 g, 5.4 mmol), and the mixture was refluxed under heating for 1 h. The reaction mixture was purified by silica gel column chromatography to give tert-butyl[6-(aminothiocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (3.64 g, 86.9%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=[O:8])[CH2:6]Br.C(N(CC)C(C)C)(C)C.[CH2:21]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH:22]=[CH2:23].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>ClCCl.C(Cl)(Cl)Cl>[CH2:21]([N:24]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH2:6][C:5]([C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=1)=[O:8])[CH:22]=[CH2:23]
Reactant: C=CCNCc1ccc(OC)cc1OC
Reactant: O=C(CBr)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C=CCN(CC(=O)c1cccc(Br)c1)Cc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
3-Bromophenacyl bromide (20.9 g) was dissolved in dichloromethane (400 mL). After ice-cooling the solution, N,N-diisopropylethylamine (14.3 mL) and allyl(2,4-dimethoxybenzyl)amine (18.7 g) were dissolved in dichloromethane (50 mL) and added dropwise. The reaction solution was gradually warmed to room temperature while dipping in an ice water bath, and stirred for about 20 hours. Chloroform, a saturated sodium bicarbonate solution and a saturated sodium chloride solution were sequentially added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate (2 g). The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain a crude product. The product was subjected to silica gel column chromatography to obtain the title compound (29.88 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([O:18][CH3:19])[CH:12]=2)=O)=[CH:4][N:3]=1.COC(OC)[N:23]([CH3:25])C.O.[NH2:29]N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([O:18][CH3:19])[CH:12]=3)=[N:29][NH:23][CH:25]=2)=[CH:4][N:3]=1
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: COc1cc(C)cc(C(=O)Cc2ccc(Cl)nc2)c1
Solvent: O
Product: COc1cc(C)cc(-c2n[nH]cc2-c2ccc(Cl)nc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
The keto-enol compound (7.28 g, 26.5 mmol) prepared in Example 63 was refluxed for 12 hours with N,N-dimethylformamide dimethylacetal (24 mL, 204 mmol). Excess N,N-dimethylformamide dimethylacetal was removed by vacuum distillation, and the reaction mixture was dissolved in anhydrous ethanol (150 mL). To this solution was dropwise added hydrazine hydrate (2.65 g, 53 mmol), and stirred at room temperature for 4 hours. The solvent was removed by vacuum distillation. The concentrate was purified through column chromatography (silica gel, ethyl acetate-hexane, 1:2, v/v) to afford the title compound as a red liquid (4.92 g, 62%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.N1C=CC=CC=1>O1CCOCC1>[N:22]1[CH:23]=[CH:24][C:19]([C:18]([N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)=[O:25])=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C1Nc2cccnc2N(C(=O)c2ccncc2)c2ccccc21

Procedure:
A mixture of 40.4 gm (0.191 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 46.0 gm (0.258 mol) of isonicotinic acid chloride hydrochloride, 42 ml (0.52 mol) of pyridine, and 600 ml of anhydrous dioxane was refluxed for three hours. After cooling, the mixture was filtered, the filter residue was taken up in 300 ml of water, and the solution obtained was extracted twice, each time with 100 ml of dichloromethane. The aqueous phase was made alkaline with sodium hydroxide solution and exhaustively extracted with methylene chloride. The methylene chloride extracts thus obtained were washed with water and dried over sodium sulphate, and the solvent was eliminated in vacuo. The residue was recrystallized from hot methanol. After washing with ether, the resulting beige-colored crystals melted at 265°-266° C.
Reaction SMILES: Br[C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:5]=2[S:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:6]3[C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:5]=3[S:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1NCCc2scc(Br)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NCCc2scc(-c3ccc(F)cc3)c21
Yield: 93.8 %

Procedure:
Using analogous reaction conditions and workup as described in Example 3, step 5, 3-bromo-6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (I-15b: 300 mg, 1.293 mmol) was reacted with (4-fluoro-phenyl)-dihydroxy-borane (217.11 mg, 1.55 mmol), Pd(PPh3)4 (149.4 mg, 0.1293 mmol), toluene (20 mL) and water (3 mL) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 300 mg of the product (47.02% yield).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([OH:19])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[Cl-].C[CH:22]([OH:40])[CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38]O.Cl>>[CH3:1][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:19][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][OH:40]
Reactant: CC(O)COCCOCCOCCOCCOCCO
Reactant: CC(C)(C)[O-]
Reactant: OCCOCCOCCOCCO
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO
Temperature: 120 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Potassium t-butoxide (Aldrich, 95%, 39.0 g) was added to a solution of tetraethylene glycol (Aldrich, 412.7 g) and methyl hexaethylene glycol chloride from above (95.8 g) at 18° C. over a 25 min period (ice/acetone bath). The reaction mixture was then stirred at 120° C. overnight. The pH was adjusted to 7 by the addition of hydrochloric acid (12 N, 11.7 ml), and volatiles were removed (64 Pa (0.48 Torr), up to 185° C.). The residual dark oil was diluted with toluene (250 ml), and treated with calcium chloride (38.1 g). After stirring for 18 h, the mixture was filtered through Celite™ and concentrated to a dark oil (102 g), which was fractionally distilled to provide decaethylene glycol monomethyl ether as an amber oil (64.4 g, 45%). An analytical sample was obtained via chromatography on silica gel, eluting with 4% methanol in chloroform to provide a colorless oil; 1H-NMR (DMSO-d6) δ: 4.58 (t, J=5.5 Hz, 1, OH), 3.58-3.38 (m, 40, 20 OCH2), 3.24 (s, 3, OCH3).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[N:10]=[C:11]1[NH:15][CH2:14][CH2:13][N:12]1[OH:16].[H-].[Na+].[CH3:19]I>CN(C)C=O>[ClH:2].[Cl:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=1[N:10]=[C:11]1[NH:15][CH2:14][CH2:13][N:12]1[O:16][CH3:19]
Reactant: CI
Reactant: ON1CCNC1=Nc1c(Cl)cccc1Cl
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON1CCNC1=Nc1c(Cl)cccc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
327 mg. of 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine hydrobromide are dissolved in 5 ml. of absolute dimethylformamide, and 90 mg. of sodium hydride are added at 5°. The solution is stirred at room temperature until it becomes clear and is cooled again down to 5° and 1.2 ml. of a 1.0 molar methyl iodide solution in dimethylformamide are added. After 30 minutes, the reaction product is poured onto water and the aqueous phase is extracted twice with ether. The organic extracts are dried and evaporated in vacuo. The residue is dissolved in 1 ml. of acetonitrile, and hydrogen chloride in dioxane is added. The 2-[(2,6-dichlorophenyl)imino]-1-methoxyimidazolidine hydrochloride which has precipitated melts at 228°.
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[N:13]=[CH:12][C:11]([O:14][CH:15]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:16]3=[O:26])=[CH:10][CH:9]=2)[CH:7]=[N:6][N:5]=[N:4]1.CCN(C(C)C)C(C)C.Cl[C:37]1[N:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][N:38]=1.O>CN(C=O)C>[N:3]1([C:8]2[N:13]=[CH:12][C:11]([O:14][CH:15]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:21][CH2:22][N:23]([C:37]5[N:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][N:38]=5)[CH2:24][CH2:25]4)[C:16]3=[O:26])=[CH:10][CH:9]=2)[CH:7]=[N:6][N:5]=[N:4]1
Reactant: O=C1C(Oc2ccc(-n3cnnn3)nc2)CCN1C1CCNCC1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cnc(N2CCC(N3CCC(Oc4ccc(-n5cnnn5)nc4)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 47.8 %

Procedure:
To a solution of 3-(6-(1H-tetrazol-1-yl)pyridin-3-yloxy)-1-(piperidin-4-yl)pyrrolidin-2-one bishydrochloride salt (101 mg, 0.25 mmol) and DIEA (0.30 mL, 1.75 mmol) in DMF (3 mL) was added 2-chloro-5-ethylpyrimidine (71 mg, 0.50 mmol). The reaction was heated at 100° C. for 6 hours. The reaction was cooled to ambient temperature and diluted by the addition of water (5 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The material was purified by silica gel chromatography eluting with a gradient of 2:1 hexanes/EtOAc up to 100% EtOAc to yield 3-(6-(1H-tetrazol-1-yl)pyridin-3-yloxy)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (52 mg, 48%) as an off white solid. Mass spectrum (apci) m/z=383.2 (M-N3CH+3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cu][C:16]#[N:17]>>[C:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:17]
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: N#C[Cu]
Product: N#Cc1ccc(-c2ccc(O)cc2)cc1

Procedure:
4'-Bromo-4-hydroxybiphenyl is reacted with copper (I) cyanide to obtain 4'-cyano-4-hydroxybiphenyl (this substance is known), which is then reacted with a β-alkyloxyethylbromide in the presence of an alkaline material.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([C:37]([O:39]C)=[O:38])[CH2:15][O:16][C@@H:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:18][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:21]1[CH2:23][CH2:22]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O1CCCC1>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([C:37]([OH:39])=[O:38])[CH2:15][O:16][C@@H:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:18][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:21]1[CH2:22][CH2:23]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](CO[C@H](CN(CC1CC1)C(=O)OC(C)(C)C)c1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](OC[C@@H](NC(=O)OCc1ccccc1)C(=O)O)c1ccccc1
Reaction time: 18 h

Procedure:
Aqueous sodium hydroxide (1N, 3.81 mL, 3.81 mmol) was added to a solution of methyl N-[(benzyloxy)carbonyl]-O-{(1S)-2-[(tert-butoxycarbonyl) (cyclopropylmethyl)amino]-1-phenylethyl}-D-serinate (1.30 g, 2.46 mmol) in tetrahydrofuran (20 mL). After 18 h, aqueous hydrochloric acid (1N, 3.81 mL, 3.81 mmol) was added. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the title compound. (1.27 g) MS 535 (M+Na).
Reaction SMILES: Cl.[CH3:2][C:3]([O:6][C:7](=[O:22])[CH2:8][NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([CH3:5])[CH3:4].CN1CCOCC1.[C:30]([S:38][CH2:39][CH2:40][C:41](Cl)=[O:42])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:5][C:3]([O:6][C:7](=[O:22])[CH2:8][N:9]([C:41](=[O:42])[CH2:40][CH2:39][S:38][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH2:15]1)([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: O=C(Cl)CCSC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CN(C(=O)CCSC(=O)c1ccccc1)[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To a mixture of the compound of Example I (0.60 g, 0.0018 mole) and CH2Cl2 (6 ml) was added N-methylmorpholine (0.44 g, 0.0043 mole). The resulting mixture was cooled on an ice bath and 3-benzoylthiopropanoyl chloride (0.45 g, 0.0020 mole) was added dropwise. After stirring 10 min the mixture was filtered removing the insolubles. The CH2Cl2 solution was washed with 20% citric acid, H2O, 10% NaHCO3, H2O and dried over MgSO4. The filtered solution was concentrated under reduced pressure to dryness and then azeotroped with diethyl ether to a semi-solid residue. This residue was dissolved in a small amount of diethyl ether and precipitated with hexane to give a crystalline solid. Drying in vacuo at 60° overnight gave 0.48 g (0.001 mole, 55%) of trans-N-(3-benzoylthio-1-oxopropyl)-N-(4-phenylcyclohexyl)glycine-1,1-dimethylethyl ester.
Reaction SMILES: C(O[C:6]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][C:20](C)=[CH:19][CH:18]=3)[CH2:15][CH2:16][C:11]=2[C:10]([NH2:25])=[N:9]1)=[O:7])(C)(C)C.[C:26](=O)([O-])[O-].[K+].[K+].ClC[CH2:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[C:44]=2[CH3:50])[CH2:39][CH2:38]1)=O>>[NH2:25][C:10]1[C:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([CH3:26])=[CH:21][CH:22]=3)[C:13](=[O:24])[C:12]=2[N:8]([C:6](=[O:7])[CH2:34][CH2:35][N:37]2[CH2:38][CH2:39][N:40]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[C:44]=3[CH3:50])[CH2:41][CH2:42]2)[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(N2CCc3c(N)nn(C(=O)OC(C)(C)C)c3C2=O)cc1
Reactant: Cc1cccc(N2CCN(C(=O)CCCl)CC2)c1C
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(c5cccc(C)c5C)CC4)c3C2=O)cc1

Procedure:
A target compound (80.9 mg, 0.166 mmol, 47.5%) was yielded as white solid in the same manner as Example 1 by reacting 1-N-t-butoxycarbonyl-3-amino-4,5,6,7-tetrahydro-6-N-(p-tolyl)pyrazolo[3,4-c]pyridin-7-one (120 mg, 0.350 mmol) with potassium carbonate (53.2 mg, 0.385 mmol) and 3-chloro-1-(4-(2,3-dimethylphenyl)piperazin-1-yl)propan-1-one (103.0 mg, 0.367 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][NH:6][C:7]1[N:11]([CH3:12])[C:10]2[CH:13]=[CH:14][C:15]([N:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[N:20]=3)[CH3:18])=[CH:16][C:9]=2[N:8]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33](C)=[C:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:35]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][NH:6][C:7]1[N:11]([CH3:12])[C:10]2[CH:13]=[CH:14][C:15]([N:17]([CH3:18])[C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:29][C:30]4[CH:35]=[C:34]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:33]=[CH:32][CH:31]=4)[N:20]=3)=[CH:16][C:9]=2[N:8]=1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: CN(c1ccc2c(c1)nc(NCc1cccc(Cl)c1)n2C)c1ccnc(Cl)n1
Product: CN(c1ccc2c(c1)nc(NCc1cccc(Cl)c1)n2C)c1ccnc(Nc2cccc(S(N)(=O)=O)c2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N2-(3-Chloro-benzyl)-N5-(2-chloro-pyrimidin-4-yl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (50 mg, 0.12 mmol) and 5-amino-2-methyl-benzenesulfonamide (22 mg, 0.12 mmol) as a white solid (42 mg, 58%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.79 (s, 1H), 8.54 (s, 1H), 7.81-7.84 (M, 1H), 7.66-7.69 (m, 1H), 7.11-7.56 (m, 11H), 5.69 (d, J=6.0 Hz, 1H), 4.72 (d, J=5.4 Hz, 2H), 3.70 (s, 3H), 3.48 (s, 3H), 2.51 (s, 3H). MS (ESI) m/z=563 [M+H]+.