Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][C:14]=3[Cl:23])[CH2:7][CH:6]3[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1.[CH3:28][NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)=[O:31]>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:14]1[CH:15]=[C:16]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:17]=[CH:18][C:13]=1[CH2:12][N:8]1[CH2:7][CH:6]2[CH2:24][O:25][CH2:26][CH2:27][N:5]2[C:4]2[N:3]=[C:2]([C:36]3[CH:35]=[CH:34][C:33]([NH:32][C:30]([NH:29][CH3:28])=[O:31])=[CH:38][CH:37]=3)[N:11]=[CH:10][C:9]1=2
Reactant: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)c(Cl)c1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2CN3Cc2ccc(S(C)(=O)=O)cc2Cl)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 5 using 2-chloro-5-(2-chloro-4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x6, 175 mg, 0.408 mmol), (1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (225 mg, 0.815 mmol) and PdCl2(dppf) (14.91 mg, 0.020 mmol) in dioxane (5 mL) and aqueous saturated NaHCO3 (1 mL). 1H NMR (400 MHz, DMSO-d6) δ 2.61-2.71 (m, 3H), 3.28-3.31 (m, 2H), 3.53-3.66 (m, 1H), 3.87-4.02 (m, 2H), 4.03-4.15 (m, 1H), 4.59-4.79 (m, 2H), 4.79-4.91 (m, 1H), 6.14-6.25 (m, 1H), 7.32-7.38 (m, 1H), 7.53-7.62 (m, 2H), 7.63-7.71 (m, 1H), 7.81-7.90 (m, 1H), 7.99-8.12 (m, 3H), 8.91-9.05 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C25H27ClN6O4S, 543.15. found 543.5.
Reaction SMILES: [Mg].BrC(Br)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])=[CH:9][CH:8]=1.[B:19]([O:24]C)([O:22]C)[O:20]C.Cl>C1COCC1>[CH2:17]([O:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:20][B:19]([OH:24])[OH:22])=[CH:8][CH:9]=1)[CH3:18]
Reactant: COB(OC)OC
Reactant: CCOCCCc1ccc(Br)cc1
Agent: CC(Br)Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOCCCc1ccc(OB(O)O)cc1
Temperature: 50 °C

Procedure:
A suspension of magnesium (0.37 g) in THF (5 ml) was stirred under a nitrogen atmosphere, and thereto was then added dibromoethane (a catalytic amount) and was subsequently added dropwise a solution of 1-bromo-4-(3-ethoxypropyl)benzene (3.4 g) in anhydrous THF (30 ml). The resulting mixture was heated at 50° C. for 1.5 hours and was then cooled to −78° C., and thereto was added dropwise trimethyl borate (3.1 ml). The reaction mixture was brought back to the room temperature and was stirred overnight. The reaction mixture was mixed with 1 N hydrochloric acid, was concentrated and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel chromatography (ethyl acetate/triethylamine) to obtain 4-(3-ethoxypropyl)phenylboric acid (1.25 g) as a light yellow, oily substance.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[Cl:19][C:20]1[C:24](Cl)=[N:23][S:22][N:21]=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>[Cl:19][C:20]1[C:24]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[N:23][S:22][N:21]=1
Reactant: Clc1nsnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1nsnc1-c1ccco1
Yield: 60 %

Procedure:
0.85 g (0.00238 mol) of 2-(tributylstannyl)furan and 0.12 g (0.0001 mol) of tetrakis(triphenylphosphine)palladium(0) were added to a solution of 0.33 g (0.00213 mol) of 3,4-dichloro-1,2,5-thiadiazole in 4 mL of toluene under nitrogen and heated at reflux. After 3 and 6 h respectively, 0.04 g (2 times 3.5×10−5 mol) of tetrakis(triphenylphosphine)palladium(0) were added. After 24 h of reflux (quantitative HPLC: 60% of product formed, all the stannane was consumed), the reaction medium was diluted with 5 mL of ethyl acetate and vigorously stirred with 10 mL of a 1M aqueous solution of KF for 2 h. After filtration through celite, the aqueous phase was re-extracted with ethyl acetate, the combined organic phases were dried over magnesium sulfate and concentrated.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([CH:18]([OH:20])[CH3:19])[O:15][C:14]=12.C(N(CC)CC)C>ClCCl.CS(C)=O.O>[C:18]([C:16]1[O:15][C:14]2=[C:9]([O:8][CH3:7])[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=1)(=[O:20])[CH3:19]
Reactant: COc1nccc2cc(C(C)O)oc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1nccc2cc(C(C)=O)oc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.8 %

Procedure:
A solution of oxalyl chloride (0.97 ml) in dry dichloromethane (10 ml) was stirred at −55° C. under an atmosphere of dry nitrogen. A solution of dimethyl sulfoxide (1.7 ml) in dry dichloromethane (5 ml) was added dropwise and stirring continued for 5 minutes at −55° C. 1-(7-Methoxyfuro[2,3-c]pyridin-2-yl)ethanol (1.9 g) in dimethyl sulfoxide (15 ml) was added dropwise and stirring continued for a further 15 minutes. Triethylamine (6.9 ml) was added and the mixture stirred for a further 5 minutes at −55° C. before warming to room temperature. The mixture was diluted with water (100 ml) and extracted with dichloromethane (3×100 ml). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate gave the title compound (1.2 g) as a pale yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][C:5]#[N:6])[CH2:3][CH2:2]1.[Li]CCCC.[O:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:21][C:20]=2[F:36])[CH2:15][CH2:14]1>O1CCCC1>[CH:1]1([CH:4]([C:13]2([OH:12])[CH2:14][CH2:15][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]4=[O:35])=[CH:21][C:20]=3[F:36])[CH2:17][CH2:18]2)[C:5]#[N:6])[CH2:3][CH2:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: N#CCC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C(C#N)C4CC4)CC3)c(F)c2)C(=O)O1
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of cyclopropyl acetonitrile (28 mmol) and was treated with n-BuLi (28 mmol) at −78° C. in tetrahydrofuran and was stirred for 1 hour. Addition of (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (14.32 mmol) was done to the reaction mixture and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride solution and was extracted with ethyl acetate. The organic layer was concentrated, dried and evaporated to afford a residue which was purified on silica gel column chromatography to provide title compound in 64% yield. M.P. 170-72° C. and MS (M+1)=431 (H+, 100%) for M.F.=C22H27FN4O4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Nc1cc(F)c(F)cc1C(=O)c1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: O=C(c1cccnc1)c1cc(F)c(F)cc1NS(=O)(=O)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the general procedures for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-4,5-difluoro-phenyl)-pyridin-3-yl-methanone 1 g (4.27 mmol) and 4-bromo-benzenesulfonyl chloride 1.15 g (4.27 mmol) with stirring in 20 ml pyridine. Purification on silica gel with flash column chromatography yielded light orange solid
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](I)=[N:11][CH:10]=1.[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>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(COC)OC>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[N:11][CH:10]=1)=[O:23]
Reactant: OB(O)c1ccncc1
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
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: COCCOC
Product: Cc1ccccc1-c1cc(-c2ccncc2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 60 h
Yield: 65.5 %

Procedure:
A mixture of 100 mg (0.173 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide, 21 mg (0.17 mmol) 4-pyridylboronic acid, 5 ml dimethoxyethane and 5 ml of a 2 M aqueous solution of sodium carbonate was deoxygenated by three freeze-thaw cycles. After addition of 20 mg (0.017 mmol) tetrakis(triphenylphosphine)palladium(0) the reaction mixture was stirred at 90° C. for 60 h. Cooling to room temperature was followed by dilution with water and extraction with 3 portions of ethyl acetate. The organic extract was washed with water, dried with magnesium sulfate and concentrated. Column chromatography afforded 59 mg (64%) of the title compound as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:14]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CNc1cc(F)ccc1[N+](=O)[O-]

Procedure:
To a mixture of 2,4-difluoronitrobenzene (VII, 19.20 g), glycine ethyl ester hydrochloride (XII, 16.52 g), and acetonitrile (50 ml) is added diisopropylethylamine (42 ml). A mild exotherm ensues. The reaction is stirred (without cooling) for two hours. The acetonitrile is removed under reduced pressure and the residue is partitioned between dichloromethane and water. The organic layers are dried over sodium sulfate and concentrated to give the produce as a solid (single spot by TLC), mp 194°-195°; NMR (CDCl3) 1.33, 4.05, 4.30, 6.35, 6.45, 8.26 and 8.56 β.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:30]2[CH:31]=[CH:32][O:28][CH:29]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccoc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccoc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 3-furylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.13 g, 11%).
Reaction SMILES: [OH-].[NH2:2][NH+:3]=[C:4]([NH2:8])[N:5]([NH2:7])[NH2:6].P(=O)(O)(O)O.[N+:14]([O-:17])([OH:16])=[O:15].NN=C(N)N(N)N>O>[N+:14]([O-:17])([O-:16])=[O:15].[NH2:2][NH+:3]=[C:4]([NH2:8])[N:5]([NH2:7])[NH2:6]
Reactant: O=[N+]([O-])O
Agent: NN=C(N)N(N)N
Agent: N[NH+]=C(N)N(N)N
Agent: O=P(O)(O)O
Solvent: O
Product: O=[N+]([O-])[O-]

Procedure:
One hundred eighty-eight (188) grams of Dowex 2-X8 (total exchange capacity 563 mequiv., an ion exchange resin available commercially from Dow Chemical Company) were slurried in water and transferred to a 250 ml buret. The ion exchange resin was washed with a 5% NaOH solution in the conventional fashion to ensure the resin being in the basic form. The resin was subsequently washed with deionized water until the eluate was neutral to pH paper. A solution of 16.7 grams triaminoguanidinium nitrate in 600 ml of deionized water was prepared. This solution was passed through the column containing the ion-exchange resin. When the pH of the eluate became basic, the solution of triaminoguanidinium hydroxide was added to a flask containing 7.0 ml of 85% phosphoric acid diluted with 10 ml of deionized water. After all of the aqueous solution of triaminoguanidine nitrate had been added to the ion-exchange column, the column was washed with deionized water until the effluent was neutral to pH paper, and these washings were also added to the phosphoric acid solution.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:22]4[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:24]1([C:27]([N:5]2[CH2:4][CH2:3][C:2]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[C@@H:22]5[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]5)[CH2:16][C:15]4=[O:23])[CH2:10][CH2:9]3)([CH3:1])[CH2:7][CH2:6]2)=[O:28])[CH2:26][CH2:25]1
Reactant: O=C(O)C1CC1
Reactant: CC1(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of (3aR,7aS)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-indol-2-one (70 mg, 0.22 mmol) in DMF (3 mL) was added with cyclopropane carboxylic acid (18.86 mg, 0.22 mmol) and diisopropylethyl amine (0.046 mL, 0.26 mmol) at room temperature. After 5-10 minutes HATU (83 mg, 0.22 mmol) was added and the mixture stirred at room temperature over night. The solvent was removed in vacuo, the residue dissolved in dichloromethane (60 mL) and washed with 1N NaOH (7 mL) and brine and concentrated in vacuo. The residue was purified by preparative LC/MS (high pH) to provide the title compound (58 mg, 69%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.54-0.74 (m, 2H), 0.77-0.95 (m, 2H), 0.84 (s, 3H), 1.01-1.44 (m, 6H), 1.45-1.84 (m, 11H), 2.01-2.15 (m, 2H), 2.19-2.40 (m, 2H), 2.73-3.06 (m, 3H), 3.17-3.32 (m, 1H), 3.37 (s, 1H), 3.44-3.68 (m, 2H), 3.69-3.80 (m, 1H), 3.81-3.97 (m, 1H). MS (M+1): 388.3.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@H:7]([CH3:35])[NH:8][C@@H:9]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH2:15]1)(C)(C)C.C(OCC)C.C(OCC)(=O)C.[ClH:48]>>[ClH:48].[CH2:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]([NH:8][C@H:7]([C:6]([OH:36])=[O:5])[CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:15][CH2:16]1)=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)O
Reaction time: 4 h

Procedure:
In 20 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 1.7 g of N-[(R)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine tert-butyl ester, and the solution is allowed to stand at room temperature for 4 hours. 100 ml of ethyl ether is added to the reaction solution, and the colorless powder, which separates out, is collected by filtration to give 1.2 g of N-[(R)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine.hydrochloride.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]=O)[CH3:5].[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=C2[C:10]=1[C:11](=[O:31])[C:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=CN2.CI>C(OCC)(=O)C.O>[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:5]2[C:10]=1[C:11](=[O:31])[C:12]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[CH:6][N:4]2[CH3:3]
Reactant: CN(C)C=O
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)c[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
Sodium hydride (60% in oil, 76 mg, 1.9 mmol) was added to a DMF solution (10 ml) of 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (400 mg, 1.22 mmol). The mixture was stirred at room temperature for 15 minutes. Methyl iodide (225 mg, 1.6 mmol) was added thereto, and then the resulting mixture was stirred at room temperature for 19 hours. Water and ethyl acetate were added to the reaction mixture to separate the mixture into two layers. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 365 mg of powdery pale yellow 5-fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinolin-4-one (yield: 72%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])([O-])=O>[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8]
Reactant: CN(C)S(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Product: CN(C)S(=O)(=O)Cc1ccccc1N
Reaction time: 8 h
Yield: 95.8 %

Procedure:
The 2-nitrobenzyl-N,N-dimethylsulfonamide (0.825 g, 3.377 mmole) of Step 1 was dissolved/suspended in alcohol in a Parr hydrogenation bottle. Palladium on charcoal (90 mg, 10% Pd) was added and the mixture was placed under an atmosphere of hydrogen at 45 psi in a Parr shaker. After shaking overnight, the mixture was filtered through Celite and evaporated to dryness to afford 0.693 g pure 2-aminobenzyl-N,N-dimethylsulfonamide (96% yield).
Reaction SMILES: Cl[CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3].[Na].[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26]>CN(C)C=O>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25]([O:27][CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3])=[O:26]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC(Cl)c1nc2c(c(=O)n(C)c(=O)n2C)n1C
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(OC(=O)c1cncc(Br)c1)c1nc2c(c(=O)n(C)c(=O)n2C)n1C

Procedure:
2.87 g of 8-α-chloroethylcaffeine are dissolved in 30 ml of anhydrous dimethylformamide, and then 2.7 g of the sodium salt of dry 5-bromonicotinic acid are added.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([O:12][CH2:13][CH2:14][NH:15][CH2:16][CH3:17])C>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]([CH2:14][CH2:13][O:12][CH3:10])[CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCNCCOCC
Solvent: CN(C)C=O
Product: CCN(CCOC)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
4-Bromobenzylbromide (4.01 g) was added to a solution of N-(2-ethoxyethyl)ethanamine (3.64 g) in DMF (40 ml). After stirring at ambient temperature for 18 h, the mixture was partitioned between diethyl ether and water. The organic phase was extracted with 2N aqueous hydrochloric acid which was then taken to pH 10 by addition of 2N sodium hydroxide solution. This was then extracted with diethyl ether which was dried and the solvent removed under vacuum to yield the title compound as a yellow oil (4.25 g). 1H NMR (DMSO-D6) 0.95 (t, 2H), 2.45 (q, 3H), 2.55 (t, 2H), 3.2 (s, 3H), 3.36 (t, 2H), 3.52 (s, 2H), 7.24 (d, 2H), 7.46 (d, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:23][C:18]3=[N:19][CH:20]=[CH:21][N:22]=[C:17]3[C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:12]=[CH:11][N:10]=1.N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>O1CCCC1.CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:37]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:23][C:18]3=[N:19][CH:20]=[CH:21][N:22]=[C:17]3[C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:12]=[CH:11][N:10]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Nc1cc(-c2[nH]c3nccnc3c2-c2ccc(F)cc2)ccn1
Solvent: CO
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(-c2[nH]c3nccnc3c2-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
6-(2-Aminopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine trifluoroacetate salt (0.085 g, 0.28 mmol) was dissolved in tetrahydrofuran and pyridine (0.22 g, 2.8 mmol) was added. Acetyl chloride (0.033 g, 0.42 mmol) in tetrahydrofuran (1 ml) was added and the resulting mixture was stirred at room temperature. After 1 h, the reaction mixture was diluted with methanol (2 ml) and the product was isolated by reverse phase HPLC to give 6-(2-acetylaminopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine trifluoroacetate salt (0.1 g) as a yellow solid. The product was converted to the hydrochloride salt by suspending the product in ether and adding 1.0M solution of HCl in ether (2 ml) to s give a solid which was filtered off to give 6-(2-acetylaminopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine hydrochloride salt (0.0.44 g) as a yellow solid.