Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:18]=[C:19]3[C:25]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:24][N:23](COCC[Si](C)(C)C)[C:20]3=[N:21][CH:22]=2)=[CH:12][CH:11]=1)[C:4]([NH:6][CH2:7][CH3:8])=[O:5])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3](=[CH:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:18]=[C:19]3[C:25]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:24][NH:23][C:20]3=[N:21][CH:22]=2)=[CH:14][CH:15]=1)[C:4]([NH:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCNC(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)C(C#N)=Cc1ccc(Nc2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 20 ml vial 2-cyano-3-[4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxy-methyl)-pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-N-ethyl-prop-2-enamide (37 mg, 0.07 mmol was dissolved in DCM (3 ml) and TFA (2.63 ml, 18.88 mmol) was added. The reaction mixture was stirred at room temperature for 3 hr. The solvent was evaporated, the residue was neutralized with NaHCO3 to pH 7-8 and the aq. layer was extracted with EtOAc. The solvent was evaporated and the residue was dissolved in methanol (5 ml). HCl (4 drops) and water, were added and the reaction mixture was stirred at RT overnight. The reaction was neutralized with NaHCO3 to pH 7-8. The product was precipitated, filtrated and washed by water to yield 20 mg 2-cyano-3-[4-[[7-(2,2-dimethylpropanoyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-N-ethyl-prop-2-enamide as dark red brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C@H:5]([CH2:7][S:8][CH2:9][CH2:10][CH3:11])[NH2:6])[CH3:2].[C:13]([O:17][C:18](=[O:22])[CH:19](Br)[CH3:20])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(P(N(C)C)(N(C)C)=O)C>[C:13]([O:17][C:18](=[O:22])[C@H:19]([CH3:20])[NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH2:7][S:8][CH2:9][CH2:10][CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCSC[C@H](N)C(=O)OCC
Reactant: CC(Br)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCSC[C@H](N[C@@H](C)C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 40 h

Procedure:
In 40 ml of HMPA were dissolved 7.9 g of S-propyl-L-cysteine ethyl ester and 12.4 g of 2-bromopropionic acid t-butyl ester. To the solution was added 8.3 ml of triethylamine, and the mixture was stirred at room temperature for 40 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was sufficiently washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (a 1:3 mixture of ether and n-hexane as an eluent), producing the α-isomer of the title compound as a colorless oil from the first eluate. Yield 4.4 g
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1.[F:21][C:22]1[C:27](I)=[N:26][CH:25]=[CH:24][N:23]=1>CC(N(C)C)=O.[Zn].[Cu]I>[F:21][C:22]1[C:27]([CH:11]2[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)=[N:26][CH:25]=[CH:24][N:23]=1
Reactant: Fc1nccnc1I
Reactant: IC1CCC2(CC1)OCCO2
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: Fc1nccnc1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of activated zinc dust (51 g, 0.78 mol, 1.94 eq.) in anhydrous DMA (100 mL) was added 1,2-dibromoethane (5.5 mL, 0.064 mol, 0.16 eq.), followed by the slow addition of chlorotrimethylsilane (8.1 mL, 0.064 mol, 0.16 eq.) over 5 min. The resulting mixture was stirred for 15 min under nitrogen. Then a solution of 8-iodo-1,4-dioxaspiro[4.5]decane (172 g, 0.639 mol, 1.59 eq.) in anhydrous DMA (300 mL) was added to the above suspension over 30 min keeping the internal temperature below 65° C. The resulting mixture was stirred for 1 hour and cooled to room temperature. The prepared zinc reagent was allowed to stand and the upper clear solution was transferred to a degassed and well stirred solution of 2-fluoro-3-iodopyrazine (see PREPARATION P6.2; 90 g, 0.402 mol, 1.0 eq.), PdCl2(dppf)CH2Cl2 (9.8 g, 0.012 mol, 0.03 eq.), and CuI (4.75 g, 0.025 mol, 0.062 eq.) in anhydrous DMA (300 mL) using a cannula. DMA (100 mL) was used to rinse the remaining zinc dust and the solution was added to the above mixture. The resulting mixture was heated to 80° C. under nitrogen and stirred overnight.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]1([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[N+](C1C=CC=CC=1)([O-])=O>[N+:6]([C:13]1[CH:14]=[CH:15][C:10]([C@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]2)=[CH:11][CH:12]=1)([O-:9])=[O:7]
Reactant: O=C(O)[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)[C@H]1CC[C@H](c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of concentrated sulphuric acid (1.5 mL) and concentrated nitric acid (0.9 mL) was added dropwise to a vigorously stirred solution of trans-4-phenylcyclohexanecarboxylic acid (1.7 g. 8.3 mmol) in nitrobenzene (4 mL) at 5° C. The reaction mixture was warmed to room temperature and stirred for 2.5 h and then poured onto ice. The aqueous mixture was extracted with DCM and the organic layer was concentrated in vacuo to leave a yellow oil, which crystallised to a white solid upon standing. The solid was triturated with toluene and filtered to give the title compound (600 mg, 60%) as a solid; 1H NMR δ 1.4-1.6 (4H, m), 1.75-1.9 (2H, m), 1.95-2.1 (2H, m), 2.2-2.38 (1H, m), 2.64-2.77 (1H, m), 7.52 (2H, d), 8.15 (2H, d); MS m/e (M−H)− 248.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH:12]=[C:13]([C:22]2[NH:23][C:24](=[O:46])[C:25]3[C:26](=[C:28]([CH2:44][CH3:45])[N:29]([CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)[N:30]=3)[N:27]=2)[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:15][CH:16]=1)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([C:11]1[CH:12]=[C:13]([C:22]2[NH:23][C:24](=[O:46])[C:25]3[C:26](=[C:28]([CH2:44][CH3:45])[N:29]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:30]=3)[N:27]=2)[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:15][CH:16]=1)(=[O:10])[CH3:9]
Reactant: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CCN(C(=O)OC(C)(C)C)CC3)nc2c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CCNCC3)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (7 ml, 40%vol) was added to a solution of the title compound of example 129 in dry Methylene chloride (10 ml), and the mixture was stirred at room temperature under nitrogen for 45 mins. The mixture was concentrated in vacuo and the residue partitioned between NaHCO3 (sat. aq., 50 ml) and Methylene chloride (100 ml). The organic layer was separated (emulsion) and washed with water (50 ml). Organic layer was removed, and the aqueous extracted with Methylene chloride (2×50 ml). The combined organics were dried (MgSO4), and concentrated in vacuo. The crude product was purified by column chromatography (95:5:0.5 methylene chloride:methanol:0.88 NH3 as eluent) to yield the title compound (containing trace impurity; carried through crude to next step).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=O)=[CH:5][CH:4]=1)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[S:42])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(NS(=O)(=O)c4ccccc4)ccc32)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CCC(=S)N2CCCc3cc(NS(=O)(=O)c4ccccc4)ccc32)cc1

Procedure:
4.9 g of 1-[3-(4-cyano-phenyl)propionyl]-6-phenylsulphonamido-1,2,3,4-tetrahydro-quinoline are dissolved in 110 ml of toluene and boiled with 2.5 g Lawesson reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide] for 1 hour at 110-120° C. Then the mixture is evaporated to dryness and the residue is chromatographed over a silica gel column with methylene chloride/ethyl acetate=19:1.
Reaction SMILES: [OH:1][C:2]1[C:14]2[O:13][C:9]3([CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH:17]([F:19])[F:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:18][CH:17]([F:19])[O:1][C:2]1[C:14]2[O:13][C:9]3([CH2:10][CH2:11][CH2:12]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2(CCC2)Oc2c(O)cccc21
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CC2(CCC2)Oc2c(OC(F)F)cccc21

Procedure:
This compound was prepared by difluoromethoxylation of 3,4-Dihydro-8-hydroxy-4-oxo-spiro[2H-1-benzopyran-2,1′-cyclobutane] using chlorodifluoromethane gas in the presence: of potassium carbonate in DMF at 30-80° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN(CC)CC>ClCCl>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)C(Br)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(c1cccnc1)N1CCN(C)CC1
Yield: 28.1 %

Procedure:
Bromo-pyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol), was reacted in refluxing dichloromethane, overnight with 1-methylpiperazine (4.54 mL; 41.0 mmol; 4 equiv) and Et3N (5.8 mL; 41.0 mmol; 4 equiv). The reaction solution was evaporated to dryness, dissolved in CH2Cl2, washed five times with saturated NaHCO3 (aq), washed once with saturated NaCl (aq), dried with Na2SO4, filtered, and concentrated in vacuo. The resulting brown oil was purified with silica gel chromatography in a 3×17 cm glass column using a 2% methanol/chloroform (v/v) mobile phase. A second column eluted with 30% EtOAc/hexanes (v/v) followed by a step gradient of 0.5-3% methanol/CH2Cl2 (v/v) produced the desired product as a yellow oil (756 mg; 28% yield). MS(ES) calc'd: [M+H]+=263.1 m/z. Found: 263.1 m/z.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][CH2:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([N:34]2[C:38](=[O:39])[CH2:37][C@@H:36]([CH:40]=[O:41])[CH2:35]2)[CH3:33])=[CH:28][CH:27]=1>C1COCC1>[F:13][CH:14]([S:15]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:16])=[O:17])[CH:40]([C@H:36]1[CH2:35][N:34]([C@@H:32]([C:29]2[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=2)[CH3:33])[C:38](=[O:39])[CH2:37]1)[OH:41]
Reactant: COc1ccc([C@@H](C)N2C[C@H](C=O)CC2=O)cc1
Reactant: O=S(=O)(CF)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc([C@@H](C)N2C[C@H](C(O)C(F)S(=O)(=O)c3ccccc3)CC2=O)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Diisopropyl amine (0.27 ml, 1.88 mmol) was added to THF (5 mL) and this solution was cooled to 0° C. n-butyllithium (1.06 mL, 1.70 mmol, 1.6M in hexanes) was added and the reaction was held at 0° C. for 15 min and cooled to −78° C. To solution this was added (fluoromethylsulfonyl)benzene (327 mg, 1.88 mmol) in THF (5 mL) and the reaction was stirred at −78° C. for 20 min. A solution of (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carbaldehyde 1.07 (400 mg, 1.62 mmol) in THF (5 mL) was added. The reaction was stirred at −78° C. for 1.5 h, at which time LC/MS analysis indicated complete reaction. The reaction was quenched at −78° C. by addition of sat′ d NH4Cl solution (10 mL) and extracted with EtOAc (2×20 mL). The combined organics were washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=3[CH3:16])[CH:7]=[CH:6][C:5]=12.[Cl:20]N1C(=O)CCC1=O>CN(C)C=O>[Cl:20][C:3]1[N:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=3[CH3:16])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2nccn2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2ncc(Cl)n2c1
Yield: 29.3 %

Procedure:
In 10 ml of N,N-dimethylformamide, 0.3 g of 1,2-dihydro-5-(imidazo[1,2-a]pyridin-6-yl)-6-methyl-2-oxo-3-pyridinecarbonitrile was stirred together with 0.19 g of N-chlorosuccinimide at 60° to 80° C. for 2 hours. After cooling, the solvent was removed by distillation under reduced pressure and water was added to the residue to take the solid by filtration. The solid was recrystallized from large quantities of methanol to obtain 0.1 g of 5-(3-chloroimidazo[1,2-a]pyridin-6-yl)-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([P:13]([O:17][CH3:18])([O:15][CH3:16])=[O:14])(O)[CH3:11])=[CH:6][CH:5]=1.CCN(S(F)(F)[F:26])CC>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([P:13]([O:17][CH3:18])([O:15][CH3:16])=[O:14])[CH2:11][F:26])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(C)(O)P(=O)(OC)OC)cc1
Reactant: CCN(CC)S(F)(F)F
Product: COC(=O)c1ccc(C(CF)P(=O)(OC)OC)cc1
Temperature: -78 °C

Procedure:
4-[1-(Dimethoxy-phosphoryl)-1-hydroxy-ethyl]-benzoic acid methyl ester (0.60 g, 2.08 mmol) was added over 30 minutes to a stirring solution of DAST (1M in CH2Cl2) cooled to −78° C. under a dry nitrogen environment. The mixture was warmed to ambient temperature and stirred. After stirring for 90 minutes the reaction mixture was carefully quenched with ethanol containing pyridine (pyr: twice volume of DAST). After stirring for 30 mins the mixture was poured into ice cold water and extracted into DCM (3×). The combined organic extracts were washed with dilute HCl, water, brine, dried (MgSO4) then concentrated in vacuo. The material was carried forward without further purification. MS: cal'd 291 (MH+), exp 291 (MH+)
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:17])[CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.Br[CH:21]([CH3:31])[C:22]([O:24][CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:6][C:5]1[CH:18]=[CH:19][C:2]([O:1][CH:21]([CH3:31])[C:22]([O:24][CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:23])=[CH:3][CH:4]=1)[CH:16]=[N:15]2
Reactant: Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Reactant: CC(Br)C(=O)OCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)OCc1cccs1

Procedure:
To a 250 milliliter roundbottom flask equipped with stir bar, reflux condenser, connecting tube, and nitrogen atmosphere were added 4.3781 grams (0.0161 moles) of 2-(4-hydroxyphenoxy)-6-chloroquinoxaline, 4.000 grams (0.0161 moles) of 2-thiophenylmethyl 2-bromopropanoate, 4.4377 grams (0.0321 moles) of anhydrous potassium carbonate, and 100 milliters of acetonitrile.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:34])[N:26]([CH3:33])[C:27](=[O:32])[N:28]([CH3:31])[C:29]=2[CH3:30])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[OH-].[Na+]>C(O)C>[CH3:16][O:15][CH2:14][CH2:13][C:8]1([C:6]([NH:5][C@H:4]([C:3]([OH:35])=[O:2])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25](=[O:34])[N:26]([CH3:33])[C:27](=[O:32])[N:28]([CH3:31])[C:29]=3[CH3:30])=[CH:20][CH:19]=2)=[O:7])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3c(C)n(C)c(=O)n(C)c3=O)cc2)C(=O)OC)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3c(C)n(C)c(=O)n(C)c3=O)cc2)C(=O)O)CCCC1
Temperature: 42.5 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
To a suspension of N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester (0.273 mmol, 133 mg) in ethanol (3 mL) was added aqueous 1.0 N sodium hydroxide (1.5 mL) at room temperature. The mixture was heated to 40-45° C. and the resulting clear solution was stirred for 15 h. The ethanol was removed under reduced pressure and the residue was diluted with water (25 mL) and NaOH (3 mL, 1.0N) to dissolve the sodium salt. The aqueous solution was washed with diethyl ether (50 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×25 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate afforded 121 mg (94% yield) of N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine as an amorphous white solid. FAB-HRMS m/e calcd for C25H33N3O6 (M+H) 472.2448, found 472.2467.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1cncc(Br)c1
Product: CCOC(=O)c1cncc(-c2cc(OC)c(OC)c(OC)c2)c1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (6.36 g) and ethyl 5-bromonicotinate (6.90 g) were reacted in the same manner as described in Preparation Example 1 to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([NH:21][C:22](=[O:31])[C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])[CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[CH3:32]>CN1CCCC1=O>[Cl:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=1[C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[CH:13][C:12]([CH3:32])=[C:11]2[O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:31]
Reactant: Oc1ccccc1
Reactant: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Oc1ccccc1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a mixture of sodium hydride (60% in oil, 28.9 mg) and N-methylpyrrolidone (3 ml) was added phenol (113 mg) under ice-cooling, and the mixture was stirred for 30 minutes. To the mixture was added 4-chloro-8-(2,6-dichlorobenzoylamino)-3-methylquinoline (200 mg), and the mixture was stirred for 30 minutes at ambient temperature and for 4.5 hours at 120° C. The mixture was extracted with ethyl acetate, and the extract was washed with water, 1N sodium hydroxide solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-3-methyl-4-phenoxyquinoline (170 mg) as white crystal.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:10](O)=[N:9][CH:8]=[N:7][C:6]=2[CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:10]1[C:11]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1ncc2ncnc(O)c21
Product: CCn1ncc2ncnc(Cl)c21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 1-ethyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol (2.91 g) and POCl3 (30 mL) was stirred at 100° C. overnight. The mixture was concentrated under reduced pressure. The residue was neutralized with saturated NaHCO3 aqueous solution and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (2.14 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C:23]1([CH3:40])[CH2:26][N:25]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24]1)=[N+]=[N-]>C1COCC1.O>[CH:27]([N:25]1[CH2:26][C:23]([NH2:20])([CH3:40])[CH2:24]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC1(N=[N+]=[N-])CN(C(c2ccccc2)c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(N)CN(C(c2ccccc2)c2ccccc2)C1
Yield: 84.1 %

Procedure:
A solution of triphenylphosphine (3.97 g, 15.14 mmol) and 3-azido-1-benzhydryl-3-methyl-azetidine (2.1 g, 7.57 mmol) in THF (20 mL) and water (2 mL) was stirred for 48 h. The solvent was removed in vacuo and a solution of hydrochloric acid (1M, 100 mL) was added to the residue. The aqueous solution was washed with DCM (50 mL) and the aqueous solution was basified to pH 8 with a solution of sodium hydroxide in water (1M). Then, the aqueous solution was extracted with EtOAc (3×50 mL). The combined organic phase was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10-100% EtOAc in petroleum ether) to give crude 1-benzhydryl-3-methyl-azetidin-3-ylamine (1.6 g, 6.37 mmol, 84%). 1H NMR (CDCl3, 400 MHz): δ7.40-7.33 (m, 4H), 7.21-7.25 (m, 4H), 7.12-7.18 (m, 2H), 4.22-4.30 (m, 1H), 3.10-3.20 (m, 2H), 2.80-2.92 (m, 2H), 1.41-1.47 (m, 3H). The two NH2 protons were not observed in CDCl3.
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[Cl:12][C:13]1[N:14]=[CH:15][C:16]2[CH2:17][CH2:18][CH2:19][C:20](=[O:23])[C:21]=2[CH:22]=1.Cl>CCO>[CH2:10]([O:9][C:2](=[O:8])[C:3]([CH:19]1[CH2:18][CH2:17][C:16]2[CH:15]=[N:14][C:13]([Cl:12])=[CH:22][C:21]=2[C:20]1=[O:23])=[O:5])[CH3:11]
Reactant: O=C1CCCc2cnc(Cl)cc21
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)C1CCc2cnc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium (253 mg; 11 mmol) is added portion-wise to EtOH (6 ml). After complete dissolution, diethyl oxalate (800 mg; 5.5 mmol) is introduced at room temperature, followed by 3-chloro-7,8-dihydro-6H-isoquinolin-5-one (1 g; 5.5 mmol) in EtOH (30 ml). The reaction mixture is stirred for 3 h at room temperature, poured on 1 N HCl and extracted with TBME three times. The organic phases are combined, dried over Na2SO4 and evaporated to dryness, yielding the desired product as orange oil. 1H-NMR (400 MHz; DMSO-d6): 8.47 (s, 1H); 7.68 (s, 1H); 4.29 (q, 2H); 3.42 (bs, 1H); 2.86 (bt, 2H); 2.63 (bt, 2H); 1.29 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10](=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:32]([C:34]1[CH:47]=[CH:46][C:37]([CH2:38][N:39]2[C:43]([CH:44]=[O:45])=[CH:42][N:41]=[CH:40]2)=[CH:36][CH:35]=1)#[N:33]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10](=[O:21])[CH:9]1[CH:44]([C:43]1[N:39]([CH2:38][C:37]2[CH:46]=[CH:47][C:34]([C:32]#[N:33])=[CH:35][CH:36]=2)[CH:40]=[N:41][CH:42]=1)[OH:45])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2)C(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2)C(=O)C1C(O)c1cncn1Cc1ccc(C#N)cc1
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To a solution of the piperazinone from Step I (98.0 mg, 0.316 mmol) in 1.5 mL of THF at -78 ° C. was added dropwise 1M lithium hexamethyldisilazide solution (0.332 mL, 0.332 mmol). After 20 minutes. a solution of the aldehyde from Step E (76 mg, 0.360 mmol) in 0.5 mL of THF was added. After 30 min, the reaction was quenched with sat aq. NH4Cl soln., poured into EtOAc, and washed with sat. aq. NaHCO3 soln., and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. The product was purified by flash chromatography on silica gel (3-6% MeOH/CH2Cl2) to provide 60 mg of the titled product as a 9:1 mixture of diastereomers.