Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:3]=1.[CH:16]1[C:24]2[C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21][C:20]=2[C:19](B(O)O)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O.C(COC)OC>[CH:16]1[C:24]2[C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21][C:20]=2[C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=3)[N:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Reactant: COc1cccc(-c2cccc(Cl)n2)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)n2)c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-6-(3-methoxyphenyl)pyridine (3.5 g, 16 mmol), dibenzothiophene-4-boronic acid (4 g, 17.5 mmol), potassium phosphate (10.2 g, 48 mmol), dimethoxyethane 500 mL and water 50 mL was prepared. Nitrogen was bubbled directly in the mixture for 15 minutes. Next tris dibenzylideneacetone dipalladium (147 mg, 0.16 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (263 mg, 0.64 mmol) were added, and then nitrogen was bubbled in the mixture for another 15 minutes. The reaction mixture was heated to reflux overnight under nitrogen. The next day the reaction mixture was cooled to room temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The mixture was purified by silica column with up to 10% ethyl acetate in hexanes to gain 3.8 g yellow solid (65%).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[S:24]>O.O1CCCC1.[OH-].[Na+]>[CH3:21][N:22]([CH3:26])[C:23](=[S:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:11])[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CN(C)C(=S)Cl
Reactant: O=C(c1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=S)Oc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
1.4 g (0.025 mol) of potassium hydroxide pellets are added to a suspension of 5.4 g (0.0224 mol) of 4-hydroxyphenyl 4-nitrophenyl methanone in 60 ml of water. The reaction mixture is heated at 50° C. for two hours, with vigorous stirring. The mixture is then cooled to 0° C. and a solution of 3.5 g (0.029 mol) of dimethylthiocarbamoyl chloride in 15 ml of tetrahydrofuran (THF) is added dropwise. When the addition is complete, the reaction mixture is stirred for 15 minutes at 0° C. and then for one hour at 20° C. The reaction medium is then hydrolyzed in 25 ml of 1N NaOH at 0° C. The precipitate obtained is filtered off and washed with water until the pH of the washings is neutral. After drying, it is recrystallized from a methylene chloride/hexane mixture to give 5.9 g (yield: 84%) of the expected product melting at 168° C.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O-:11])=O)=[C:7](C)[CH:6]=1)=[CH2:4].[CH3:15][C:16]([CH3:18])=[O:17].Cl.S([O-])([O-])(=O)=O.[Mg+2]>CCOCC.O.O1CCCC1>[CH:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([CH2:15][C:16](=[O:17])[CH3:18])=[O:11])=[CH:12][CH:13]=1)=[CH2:4]
Reactant: C=Cc1ccc(C(=O)[O-])c(C)c1
Reactant: CC(C)=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)CC(C)=O)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
Dry tetrahydrofuran (10 mL), sodium hydride (1.7 g, 70 mmol), and 4-vinyl-methylbenzoate (8.0 g, 49 mmol) were placed in a flame dried, three-necked, round bottomed flask equipped with a reflux condenser, nitrogen inlet, addition funnel and magnetic stir bar. Dry tetrahydrofuran (5 mL) and dry acetone (4.3 mL, 59 mmol) was added dropwise to the refluxing mixture containing 4-vinyl-methylbenzoate. The mixture was allowed to reflux for an additional two hours before allowed to cool to room temperature. Concentrated hydrochloric acid (1 mL) was added, the mixture was diluted with ether (50 mL) and water (50 mL), and the mixture was made acidic by a further addition of concentrated hydrochloric acid. The aqueous phase was rinsed with ether (2×50 mL), and the combined organic phase was washed with 1 M sodium hydroxide (3×50 mL). The combined alkali phases were rinsed with pentane. The alkali solution was acidified with concentrated hydrochloric acid, which formed a precipitate. The precipitate was removed from the aqueous phase by rinsing with ether (2×50 mL), and the combined organic phases were rinsed with saturated sodium bicarbonate solution (3×50 mL). The organic phase was dried with magnesium sulfate for 16 hours before filtration and isolation of the yellow material (4 g, 43% yield). 1H-NMR (200 MHz, 25° C., CDCl3): δ 16.12 (s, 1H), 7.83 (d, 2H), 7.45 (d, 2H), 6.70 (dd, 1H), 6.17 (s, 1H), 5.82 (d, 1H), 5.35 (d, 1H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])=[C:7]([C:11](=[O:22])[C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[N+:19]([O-])=O)[NH:8]2)=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:19][C:13]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=1[C:11]([C:7]1[NH:8][C:9]2[C:5]([C:6]=1[NH:23][C:24](=[O:27])[CH2:25][CH3:26])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)=[O:22]
Reactant: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccc2[N+](=O)[O-])[nH]c2cc(Cl)ccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccc2N)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A suspension of 6-chloro-2-(5-chloro-2-nitrobenzoyl)-3-(propionylamino)indole (step 3, 540 mg, 1.33 mmol), ammonium chloride (35.6 mg, 0.665 mmol), iron powder (391 mg, 6.65 mmol), ethanol (20 ml) and water (10 ml) was heated at reflux temperature for 1 h. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate was concentrated to give a crystalline residue. Purification by flash column chromatography eluting with ethyl acetate/hexane (1:3) afforded 394 mg (79%) of 2-(2-amino-5-chlorobenzoyl)-6-chloro-3-(propionylamino)indole. 1H-NMR (CDCl3) δ: 11.67 (1H, br s), 9.76 (1H, br s), 7.58 (1H, d, J=8.6 Hz), 7.43 (1H, d, J=1.5 Hz), 7.35 (1H, d, J=2.5 Hz), 7.26 (1H, dd, J=2.5, 8.9 Hz), 7.09 (1H, dd, J=1.8, 8.6 Hz), 6.99 (2H, br s), 6.83 (1H, d, J=8.9 Hz), 2.12 (2H, q, J=7.6 Hz), 0.90 (3H, t, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]([NH:20][OH:21])=[NH:19])[N:9]=2)=[CH:4][CH:3]=1.[S:22]([C:26]1[S:27][C:28]([C:31](O)=O)=[CH:29][CH:30]=1)(=[O:25])(=[O:24])[NH2:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([C:18]3[N:19]=[C:31]([C:28]4[S:27][C:26]([S:22]([NH2:23])(=[O:25])=[O:24])=[CH:30][CH:29]=4)[O:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: N=C(NO)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Product: NS(=O)(=O)c1ccc(-c2nc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)no2)s1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-N-hydroxy-6-trifluoromethyl-pyrimidine-2-carboxamidine (example C.1) (0.16 g, 0.5 mmol) and commercially available 2-sulfamoyl-thiophene-5-carboxylic acid [CAS-No. 7353-87-9] (104 mg, 0.5 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.085 g, 35%). MS (ISN) 486.1 [(M−H)−]; mp 236.5° C.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][C:10]2[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][CH:11]=2)C(=O)C2=CC=CC=C12.[ClH:24]>CO.O1CCCC1>[ClH:24].[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(CN)n1

Procedure:
A solution of hydrazine hydrate (0.77 g) in methanol (5 ml) was added dropwise to a suspension of 6-phthalimidomethyl-2-pyridinecarbonitrile (3.74 g) in a mixture of methanol (10 ml) and tetrahydrofuran (15 ml) at ambient temperature with stirring. After the mixture was stirred for two hours, diluted hydrochloric acid (prepared by concentrated hydrochloric acid (1.38 ml) and water (6.91 ml)) was dropped to the mixture. After stirring for three hours, the solvent was evaporated in vacuo. The residue was mixed with water (20 ml) and an insoluble material was filtered off. The filtrate was evaporated in vacuo to give 6-aminomethyl-2-pyridinecarbonitrile hydrochloride (2.40 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[NH2:7])([O-:3])=[O:2].[Br:15]Br>CC(O)=O>[Br:15][C:8]1[CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[NH2:7]
Reactant: Nc1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1cc([N+](=O)[O-])c(C(F)(F)F)cc1Br
Temperature: 20 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a solution of 3-nitro-4-(trifluoromethyl)aniline (31.0 g, 150.4 mmol) in HOAc (200 mL) was added bromine (9.3 mL, 180.5 mmol) at 0° C. under an atmosphere of N2. The cooling bath was removed and the mixture was stirred at 20° C. for 1 h. The solvent was removed in vacuo to afford the crude product 2-bromo-5-nitro-4-(trifluoromethyl)aniline (40.0 g, 93%), which was used directly in the next step.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9](O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: Oc1nc(-c2ccccc2)cs1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(-c2ccccc2)cs1
Yield: 65.2 %

Procedure:
A mixed solution of 4-phenyl-1,3-thiazol-2-ol (2.00 g, 11.3 mmol) in phosphorus oxychloride (20 ml) was stirred at 100° C. for 2 hours. The solvent was distilled off under reduced pressure. The residue was poured to ice water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.44 g (65.2%) of the desired product as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:28]([CH3:30])[CH3:29]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH:28]([CH3:30])[CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: CC(C)I
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 90 °C
Yield: 65.3 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.12 mmol), potassium carbonate (32 mg, 0.23 mmol) and 2-iodopropane (17 μL, 0.17 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 90° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using a hexanes/ethyl acetate/dichloromethane (3.5:0.5:4) afforded 24 mg (68%) of 3-(2-pyridyl)-5-(3-cyano-5-isopropoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.91 (m, 1H), 7.49 (m, 1H), 7.36 (s, 1H), 4.71 (m, 1H), 1.41 (m, 6H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[C:9]([Br:15])=[C:10]([CH3:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)N1CCc2c(C)cc(C)cc21
Solvent: CC(=O)O
Product: CC(=O)N1CCc2c1cc(C)c(Br)c2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Acetyl-4,6-dimethylindoline (5.5 g) was dissolved in acetic acid (150 ml), and bromine (2.2 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour, and poured into ice water. The precipitated solid was collected by filtration, and recrystallized from methanol to give 6.5 g of the title compound (1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:12][CH2:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: COc1ccc(CNC(=O)c2cn3cc(Br)ccc3n2)cc1OC

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (3,4-dimethoxyphenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][NH:29]1>CN(C=O)C>[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][N:29]1[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Reactant: c1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4Cc5ccccc5C4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 2-[4-(2-bromoethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.50 g, 1.15 mmol) in anhydrous DMF (9 mL) was added isoindoline (0.41 mL, 3.46 mmol) and the reaction mixture was stirred at room temperature for 16 hours under nitrogen. The solvent was removed under reduced pressure and the residue was triturated with water (50 mL). The separated solid was filtered, washed with water and ether, and dried under vacuum to give the title compound as a white solid. Yield: 0.45 g (83%). MP 202-202.5° C. 1H NMR (400 MHz, CDCl3): δ 10.09 (br s, 1H), 7.77 (s, 2H), 7.22 (br s, 4H), 6.83 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 4.11 (s, 4H), 4.03 (t, J=6.0 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.22 (t, J=6.0 Hz, 2H), 2.42 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[N:3]=1.[Na].[CH3:20][OH:21]>>[C:17]([C:14]([NH:13][C:4]1[N:3]=[C:2]([O:21][CH3:20])[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH3:12])[N:5]=1)([CH3:16])[CH3:15])#[N:18]
Reactant: CCNc1nc(NC(C)(C)C#N)nc(Cl)c1C#N
Reactant: CO
Agent: [Na]
Product: CCNc1nc(NC(C)(C)C#N)nc(OC)c1C#N
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2.7 grams of 4-chloro-2-(1-cyano-1-methylethylamino)-6-ethylamino-5-pyrimidinecarbonitrile in 50 ml of methanol was added a solution of 0.3 gram of sodium in 10 ml of methanol. The reaction mixture was heated under reflux for 3 hours. An additional small quantity of sodium in methanol was then added to the reaction mixture, and heating under reflux was continued for 1.5 hours. The excess methanol was removed from the reaction mixture by evaporation under reduced pressure. The residue was extracted with a mixture of diethyl ether and water. The diethyl ether layer was separated, washed with water, then dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure to a residue. The residue was washed with methylcyclohexane, and the insoluble solid was collected by filtration. The solid was recrystallized from benzene to give 1.7 grams of 2-(1-cyano-1-methylethylamino)-6-ethylamino-4-methoxy-5-pyrimidinecarbonitrile; mp, 130°-132°.
Reaction SMILES: CS(OC[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])[CH:16]=2)[CH:10]=1)(=O)=O.N1CCOCC1.[CH:41]([OH:43])=[O:42].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=C[C:53]([C:69]([N:71]3[CH2:75][C:74](=[O:76])N[CH2:72]3)=O)=N2)C=CC=1>O1CCCC1>[CH:41]([OH:43])=[O:42].[Cl:26][C:22]1[CH:21]=[C:20]([N:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:72][N:71]4[CH2:69][CH2:53][O:76][CH2:74][CH2:75]4)[CH:10]=3)=[CH:16][C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])=[N:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: CS(=O)(=O)OCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: C1COCCN1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=C1CN(C(=O)c2cc(-c3cccc(OCCN4CCOCC4)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 121A and morpholine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 47 mg (43% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:59])[C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([C:54]([CH:56]4[CH2:58][CH2:57]4)=[O:55])[CH2:50][CH2:49]3)=[CH:44][CH:43]=2)=[CH:36][CH:35]=1.CN(C)C=O.C(=O)(O)[O-].[Na+].O>CO.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]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:34]3[CH:35]=[CH:36][C:37]([NH:40][C:41](=[O:59])[C:42]4[CH:43]=[CH:44][C:45]([N:48]5[CH2:49][CH2:50][N:51]([C:54]([CH:56]6[CH2:57][CH2:58]6)=[O:55])[CH2:52][CH2:53]5)=[CH:46][CH:47]=4)=[CH:38][CH:39]=3)=[CH:22][CH:23]=2)[N:17]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1
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: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCN(C(=O)C6CC6)CC5)cc4)cc3)cc2)c[nH]1
Temperature: 90 °C
Yield: 10.7 %

Procedure:
To a mixture of (S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.40 g, 3.19 mmol) and N-(4-bromo-phenyl)-4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzamide (0.910 g, 2.12 mmol) in N,N-dimethylformamide (16.53 mL, 213.5 mmol) at RT was added sodium bicarbonate (1.338 g, 15.93 mmol). Water (12.06 mL, 669.2 mmol) was then added. Nitrogen was bubbled through the resulting mixture for 5 min and then tetrakis(triphenylphosphine)palladium(0) (0.258 g, 0.223 mmol) was added. The reaction mixture was heated at 90° C. under nitrogen overnight, cooled to RT, diluted with methanol (30.0 mL), and filtered. The filtrate was concentrated and dissolved in ethyl acetate (˜3 mL) and hexanes (2 mL) was slowly added to give a precipitate of crude product. This material was filtered to provide 150 mg of the product. The filtrate was concentrated and subjected to the same precipitation conditions to provide an additional 50 mg of product. This material was combined with the first precipitation crop and was used without further purification in the next step.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[N:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:14][C:13]=1[C:32]1[N:40]=[C:39]([CH3:41])[N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][N:36]2[CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1.[NH2:48][C:49]1[CH:50]=[N:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=1.O1CCCC1>>[CH3:56][O:55][C:52]1[N:51]=[CH:50][C:49]([NH:48][C:12]2[N:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:14][C:13]=2[C:32]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3[CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)=[CH:54][CH:53]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1nc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reaction time: 1 h
Yield: 75 %

Procedure:
LiHMDS (1.0 M in THF, 3.75 mL, 3.75 mmol) was slowly added to a stirred mixture of tert-butyl 4-((6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.6397 g, 1.250 mmol) and 3-amino-6-methoxypyridine (Aldrich, St. Louis, Mo.; 186 mg, 1.50 mmol) in tetrahydrofuran (10 mL, 1.250 mmol) at 0° C. and the mixture was stirred at the same temperature for 1 h before being quenched with NH4Cl(aq) (10 mL) and water (10 mL). The separated aqueous layer was extracted with EtOAc (3×15 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatograph (hexanes to 50% ethyl acetate/hexanes) to give tert-butyl 4-((6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.577 g, 0.937 mmol, 74.9% yield) as a yellow foam. LCMS (API-ES) m/z 616 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH3:3].[NH:12]1C=CN=[CH:13]1>C1(C)C(C)=CC=CC=1>[N:2]1([CH2:4][C:5]2[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:1]=[CH:13][N:12]=[CH:3]1
Reactant: CN(C)Cc1ncccc1O
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1C
Product: Oc1cccnc1Cn1ccnc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
A solution consisting of 2-dimethylaminomethyl-3-hydroxypyridine (30.4 g.) and imidazole (13.6 g.) dissolved in xylene (100 ml.) was heated under reflux for a period of five hours and then allowed to cool to room temperature (~25° C.). The resulting precipitated oil was then scratched so as to induce crystallization and the solid product so obtained was thereafter crystallized from isopropanol/petroleum ether (b.p. 60°-80° C.) to afford pure 2-(imidazol-1-ylmethyl)-3-hydroxypyridine (yield, 24.9 g.), m.p. 154°-155° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:12][CH2:13][CH3:14])(=[O:11])[CH3:10].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]([CH2:10][C:9]([O:12][CH2:13][CH3:14])=[O:11])([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3.01 ml (6.02 mmol) of a 2M solution of LDA in THF are diluted in 7 ml of THF and cooled to −78° C. 540 μl (5.52 mmol) of ethyl acetate are added and the solution is stirred at −78° C. for 30 min. A solution of 1.00 g (5.01 mmol) of N-tert-butoxycarbonylpiperidin-4-one in 10 ml of THF is added dropwise. The mixture is stirred at −78° C. for a further 1 h and then warmed slowly to RT overnight. A saturated ammonium chloride solution is added and the product is extracted with dichloromethane. The removal of the solvent gives the ethyl (N-tert-butoxycarbonyl-4-hydroxypiperidin-4-yl)acetate. This crude product is chromatographed by HPLC (method 6), whereby the tert-butoxycarbonyl protecting group is cleaved by the hydrochloric acid in the eluent. 478 mg (42% of theory) of the title compound are obtained.