Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=2[F:31])[C:13]2[C:14]([CH3:22])=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[N:17][CH:18]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C=O.[OH-].[Na+].[C:36](OCC)(=[O:38])C>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=2[F:31])[C:13]2[C:14]([CH3:22])=[CH:15][C:16]([C:19]([NH:21][CH2:36][OH:38])=[O:20])=[N:17][CH:18]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(F)c(F)c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(F)c(F)c1
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of 5-[[(3,4-difluorophenyl)sulfonyl](2,3,6-trifluorophenyl)methyl]-4-methylpyridine-2-carboxamide (160 mg, 0.350 mmol) in ethylene glycol dimethyl ether (3 ml), an aqueous solution of formaldehyde (37%, 78.9 μl) and 1 N aqueous sodium hydroxide (17.5 μl) were added at room temperature, and the mixture was stirred for 18 hours. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed with saturated aqueous ammonium chloride. Subsequently, 1 N hydrochloric acid was added to the organic layer, and the mixture was stirred for 1 hour. After the organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of ethyl acetate and diethyl ether, and then was collected by filtration, to obtain the title compound (100 mg, 0.206 mmol, 59%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[CH2:20][O:21]C(=O)C)[CH2:7][N:6]1[CH2:26][CH2:27][CH3:28].[OH-].[K+].ClCCl>CO>[CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[CH2:20][OH:21])[CH2:7][N:6]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCN1C[C@@H](NC(=O)COC(C)=O)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCN1C[C@@H](NC(=O)CO)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21

Procedure:
530 mg of N-(2-methyl6n-propyl-8alpha-ergolinyl)-acetoxyacetamide (1.38 mmol) is dissolved in 20 ml of methanol and 0.5 ml of KOH and stirred for 15 minutes at room temperature. Then it is mixed with ice and shaken out with dichloromethane. The organic phases are dried, concentrated by evaporation and crystallized from diisopropyl ether/hexane, yield 321 mg (63% of theory). [α]D +20° (0.5% in chloroform).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH:11]2[CH2:14][NH:13][CH2:12]2)=[CH:8][CH:7]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27]([C:29]2[S:33][C:32]([NH:34][C:35](=[O:37])[CH3:36])=[N:31][C:30]=2[CH3:38])=[O:28])[CH3:25])=[CH:20][CH:19]=1.CC([O-])(C)C.[Na+].O1CCOCC1>CO.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH:11]2[CH2:14][N:13]([C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27]([C:29]4[S:33][C:32]([NH:34][C:35](=[O:37])[CH3:36])=[N:31][C:30]=4[CH3:38])=[O:28])[CH3:25])=[CH:20][CH:19]=3)[CH2:12]2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc(OC2CNC2)cc1
Reactant: CC(=O)Nc1nc(C)c(C(=O)N[C@@H](C)c2ccc(Br)cc2)s1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COCCOc1ccc(OC2CN(c3ccc([C@H](C)NC(=O)c4sc(NC(C)=O)nc4C)cc3)C2)cc1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
100 mg (0.39 mmol) 3-[4-(2-Methoxy-ethoxy)-phenoxy]-azetidine (IX.4), 165 mg (0.43 mmol) (S)-2-acetylamino-4-methyl-thiazole-5-carboxylic acid [1-(4-bromo-phenyl)-ethyl]-amide (I.6), 45 mg (0.06 mmol) chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) and 150 mg (1.56 mmol) NaOtBu are combined under an argon atmosphere and 1,4-dioxane (4.0 mL) is added. The mixture is stirred for 12 h at 45° C. Some water and methanol are added and the mixture is filtered and purified by HPLC (Zorbax, acetronitrile/H2O (+0.1% TFA)) to yield the desired product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([C:12]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=1[C:14](O)=[O:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>>[CH2:1]([O:8][CH2:9][C:10]1[C:12]2[C:13](=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:14](=[O:15])[NH:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COc1ccc(C(=O)COCc2ccccc2)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(COCc3ccccc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(2-benzyloxyacetyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[F:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Cl-].[Na+].O.O1CCCC1.C(OCC)(=O)C>[NH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=1[F:24])[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Nc1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Temperature: 150 °C
Reaction time: 15 h
Yield: 72.9 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (2.62 g, 8.0 mmol), 3-amino-4-fluorophenol (2.03 g, 16.0 mmol), potassium carbonate (1.66 g, 12.0 mmol) and N,N-dimethylformamide (20 mL) was stirred at 150° C. for 15 hr. Tetrahydrofuran/ethyl acetate and saturated brine were added to the reaction mixture, and insoluble material was filtered off. The filtrate was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/80→0/100) and recrystallized from ethyl acetate to give the title compound (1.91 g, 73%) as pale-yellow crystals.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:17])[C:10]([C:18]([NH:20][NH2:21])=[O:19])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][CH2:29][C:30](Cl)=[O:31].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:28][CH2:29][C:30]([N:20]([C:18]([C:10]1[C:11]2[C:16](=[C:15]([Cl:17])[CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)=[O:19])[NH2:21])=[O:31]
Reactant: O=C(Cl)CCl
Reactant: NNC(=O)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: NN(C(=O)CCl)C(=O)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of 1-cyclohexylmethyl-7-chloro-1H-indole-3-carboxylic acid hydrazide (0.71 g, 2.3 mmol) in dichloromethane (20 ml) was added potassium carbonate (1.6 g, 11 mmol) and the reaction stirred for 1 h. The reaction mixture was cooled in a dry ice/ethanol bath and chloroacetyl chloride (0.2 ml, 3.0 mmol) was added and the reaction stirred for 1 h. Saturated sodium bicarbonate solution (30 ml) was added and the reaction allowed to warm to room temperature. The reaction mixture was extracted with 9:1 (v/v) dichloromethane:methanol (3×20 ml), the organic phases combined, washed with brine (1×30 ml), dried over sodium sulfate, and solvent removed in vacuo to give 1-cyclohexylmethyl-7-chloro-1H-indole-3-carboxylic acid N-(2-chloroacetyl)hydrazide (0.6 g, 2.0 mmol).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[O:14]1[CH2:17][CH:16]([NH2:18])[CH2:15]1.CCN(C(C)C)C(C)C>>[N+:11]([C:6]1[CH:7]=[C:8]2[CH2:9][N:18]([CH:16]3[CH2:17][O:14][CH2:15]3)[CH2:2][CH2:3][N:4]2[N:5]=1)([O-:13])=[O:12]
Reactant: NC1COC1
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc2n(n1)CCN(C1COC1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 250 mL round-bottomed flask, 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (1.54 g, 4.92 mmol, Eq: 1.00) was combined with CH3 CN (60 ml) to give a light yellow solution. To this oxetan-3-amine (432 mg, 5.91 mmol, Eq: 1.20) and dropwise DIPEA (1.14 g, 1.55 ml, 8.86 mmol, Eq: 1.80) were added and the reaction mixture was stirred at room temperature for 24 hr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:19][C@H:20]2[CH2:40][CH2:39][C:22]3([O:26][C@H:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:24]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:23]3)[CH2:21]2)[C:13](N(OC)C)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH:41]([Mg]Br)=[CH2:42].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:19][C@H:20]2[CH2:40][CH2:39][C:22]3([O:23][C@H:24]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C@@H:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[O:26]3)[CH2:21]2)[C:13](=[O:14])[CH:41]=[CH2:42])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CON(C)C(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 2-[3-chloro-4-(methylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]-N-methoxy-N-methylpropaneamide (3.05 g) in tetrahydrofuran (30 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 22.1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 hr, and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (2.58 g, yield 90%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C(O[C:6]([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)C)=O)(C)(C)C.[ClH:29].CO>>[Br:28][C:20]1[C:19]2[C:18]([S:15]([N:12]3[CH2:13][CH2:14][CH:10]([NH:8][CH3:6])[CH2:11]3)(=[O:16])=[O:17])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:23]=[N:22][CH:21]=1.[ClH:29]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: Cl
Solvent: CO
Product: CNC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Intermediate 20 (0.157 g) prepared in Step A mentioned above is added with 10% hydrogen chloride/methanol (2 ml), and the mixture is stirred at room temperature for 12 hours. The solvent is evaporated under reduced pressure to obtain the title compound as hydrochloride (125 mg (predictive yield)).
Reaction SMILES: N1([CH:10]=[O:11])C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O.[N:19]1([C:25]2[N:33]=[C:32]([C:34]3[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=3)[N:31]=[C:30]3[C:26]=2[N:27]=[C:28]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[N:29]3[CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCCC1.C(OCC)(=O)C>[NH2:40][C:37]1[N:36]=[CH:35][C:34]([C:32]2[N:31]=[C:30]3[C:26]([N:27]=[C:28]([N:46]4[CH2:47][CH2:48][N:49]([CH:10]=[O:11])[CH2:50][CH2:51]4)[N:29]3[CH2:41][C:42]([F:44])([F:43])[F:45])=[C:25]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:33]=2)=[CH:39][N:38]=1
Reactant: O=Cn1nnc2ccccc21
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC(F)(F)F)c3n2)cn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCN(C=O)CC4)n(CC(F)(F)F)c3n2)cn1
Reaction time: 0.33 h
Yield: 56 %

Procedure:
Benzotriazole-1-carboaldehyde (55 mg, 0.38 mmol) was dissolved in tetrahydrofuran (10 ml) followed by the addition of 5-[6-morpholin-4-yl-8-piperazin-1-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine trifluoroacetate (200 mg, 0.29 mmol). The resulting mixture was stirred for 20 minutes and the reaction mixture was diluted with ethyl acetate, washed with 1 M sodium hydroxide and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (chloroform:methanol=19:1) to give a white solid (80 mg, 56%).
Reaction SMILES: [NH2:1][C:2](=[O:43])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[N:28][CH:29]=2)[N:14]=1)[CH3:4]>CN(C=O)C.CCN(CC)CC.[Pd]>[NH2:1][C:2](=[O:43])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[N:28][CH:29]=2)[N:14]=1)[CH3:4]
Reactant: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C(F)(F)F
Reaction time: 112 h

Procedure:
A mixture of tert-Butyl 4-(5-((4-((2-(1-amino-1-oxopropan-2-yl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A71 (0.139 g, 0.234 mmol) and 10% Pd/C (0.156 g) in DMF (3.0 mL) and Et3N (0.30 mL) was stirred under a hydrogen atmosphere for 112 hours. The mixture was filtered through Celite and concentrated under reduced pressure before being purified using silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., 0-20% MeOH in EtOAc) to give the title compound A72 (0.060 g, 42%). LCMS-D: rt 3.568 min; m/z 599.4 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([CH:7]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:19])[CH2:8]1)(=O)[CH3:5]>N1C=CC=CC=1>[CH2:12]([N:10]1[CH2:11][CH:7]([C:4](=[N:2][OH:3])[CH3:5])[CH2:8][C:9]1=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NO
Reactant: CC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)C1CC(=O)N(Cc2ccccc2)C1
Reaction time: 18 h
Yield: 104.2 %

Procedure:
Hydroxylamine hydrochloride (5.58 g, 0.076 mole) was added to a solution of 4-acetyl-1-benzyl-2-pyrrolidinone (15.0 g, 0.069 mole) in pyridine (250 mL) and the reaction mixture was heated at 40° with stirring under nitrogen for 18 hours. The solvent was removed under reduced pressure at 65° and the residue was dissolved in chloroform (900 mL), washed with water (500 mL), 0.5M HCl (3×500 mL), and dried (MgSO4). The solvent was removed under reduced pressure to give 1-benzyl-4-(1-hydroxyiminoethyl)-2-oxo-pyrrolidine (16.7 g, quant) as a brown solid.
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:14]([O:19][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCCCCO
Agent: [Na]
Product: CCCCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of sodium (230 mg, 10 mmol) in 1-pentanol(20 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). The mixturewas stirred at 50° C. for 3 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[C:12](Cl)[N:11]=[CH:10][N:9]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:7][C:8]1[CH:13]=[C:12]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[Cl:1])[N:11]=[CH:10][N:9]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Clc1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1cc(-n2ccnc2Cl)ncn1
Temperature: 120 °C
Yield: 60.5 %

Procedure:
2-Chloro-1H-imidazole (2.0 g, 20 mmol), 4,6-dichloropyrimidine (6 g, 40 mmol) and DIEA (10.4 ml, 60 mmol) were mixed in 40 mL butanol and refluxed at 120° C. for 24 hours. The solvent was removed by rotary evaporation. The crude product was purified by flash chromatography on silica gel (0% EtOAc/hexanes to 20% EtOAc/hexanes gradient), afforded the title compound (2.6 g, 62% yield) as yellow solid. Rf=0.25 (20% EtOAc/hexanes); 1H NMR 400 MHz (DMSO-d6) δ 9.13 (s, 1H), 8.17 (s, 1H), 7.94 (d, 1H), 7.17 (d, 1 H); MS m/z 215.4 (M+1).
Reaction SMILES: F[C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5].[H-].[Na+]>CN(C)C=O>[CH3:13][N:10]1[CH2:11][CH2:12][CH:7]([N:6]2[C:4](=[O:5])[C:3]3[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=3[O:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]2=3)[CH2:8][CH2:9]1
Reactant: CN1CCC(N(C(=O)c2ccccc2F)c2ccccc2O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(N2C(=O)c3ccccc3Oc3ccccc32)CC1
Reaction time: 18 h

Procedure:
A mixture of 5.3 g 2-fluoro-N-(2-hydroxyphenyl)-N-(1-methyl-piperidin-4-yl)benzamide, 1.1 g of a 55% sodium hydride/oil dispersion and 80 ml dimethylformamide are stirred at 80° for 18 hours. The reaction mixture is worked up as in Example 1(b) to give the heading compound, m.p. 173°-174.5°.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[Cl:24][C:25]1[S:29][C:28]([C:30]([NH:32][CH2:33][C:34]2[N:35]=[CH:36][NH:37][CH:38]=2)=[O:31])=[CH:27][CH:26]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:24][C:25]1[S:29][C:28]([C:30]([NH:32][CH2:33][C:34]2[N:35]=[CH:36][N:37]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]4=[O:14])=[CH:4][C:3]=3[O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:38]=2)=[O:31])=[CH:27][CH:26]=1
Reactant: O=C(NCc1c[nH]cn1)c1ccc(Cl)s1
Reactant: O=c1ccccn1-c1ccc(I)c(OCCN2CCCCC2)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2OCCN2CCCCC2)cn1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 8.4 %

Procedure:
A mixture of 1-(4-iodo-3-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one (116 mg, 0.22 mmol), N-((1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide 3-1 (85 mg, 0.24 mmol), 8-hydroxyquinoline (14 mg, 0.10 mmol) and K2CO3 (200 mg, 1.45 mmol) in DMSO (3 mL) was degassed with Ar before being charged with CuI (19 mg, 0.10 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the titled compound (10 mg). MS 538.2 and 540.2 (M+H, Cl pattern).
Reaction SMILES: B(Br)(Br)Br.ClCCl.C[O:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[C:18](=[O:27])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1>CO>[OH:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[C:18](=[O:27])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(-c2cc(=O)n(C)c3ncccc23)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cn1c(=O)cc(-c2cccc(O)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.5 %

Procedure:
A 1 M-dichloromethane solution of boron tribromide (25 ml, 25 mmol) was added to a dichloromethane solution (30 ml) of 4-(3-methoxyphenyl)-1-methyl-1,8-naphthyridin-2(1H)-one (1.3 g, 4.9 mmol) at -35° C., and the mixture was gradually warmed up to room temperature and then stirred at room temperature for 2 hours. Methanol (10 ml) was added to the reaction solution at -60° C., and the mixture was warmed up to room temperature and then stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, methanol (30 ml) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (benzene-ethyl acetate) to give 4-(3-hydroxyphenyl)-1-methyl-1,8-naphthyridin-2(1H)-one (0.29 g, 23%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=[C:11]2[N:10]([CH2:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[C:9]1=[O:37].Cl>O1CCOCC1>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=2)[C:9]1=[O:37]
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)n(Cc2ccc(C#N)cc2)c2cnc3c(ccn3COCC[Si](C)(C)C)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)n(Cc2ccc(C#N)cc2)c2cnc3[nH]ccc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of rel-4-({1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-6-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}methyl)benzonitrile (50 mg) in dioxane (0.5 mL) was added 4M hydrogen chloride in dioxane (1 mL) and the mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate aqueous solution and brine, dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (1 mL). To the mixture were added 1M NaOH solution (0.29 mL) and 1,2-ethanediamine (0.2 mL). The mixture was stirred at ambient temperature for 2 hours. The mixture was extracted with chloroform. The extract was washed with water, dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give rel-4-({1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}methyl)benzonitrile (36 mg) as a white powder.