Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][O:3][C:4]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].[Na].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH2:21][NH:22][C:23]([C:25]1[C:26](=[O:43])[C:27]([OH:42])=[C:28]2[C:33](=[O:34])[N:32]3[CH2:35][C@H:36]4[CH2:40][CH2:39][CH2:38][N:37]4[C@@H:31]3[CH2:30][N:29]2[CH:41]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH2:21][NH:22][C:23]([C:25]1[C:26](=[O:43])[C:27]([O:42][CH2:2][O:3][C:4]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5])=[C:28]2[C:33](=[O:34])[N:32]3[CH2:35][C@H:36]4[CH2:40][CH2:39][CH2:38][N:37]4[C@@H:31]3[CH2:30][N:29]2[CH:41]=1)=[O:24]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C[C@H]3CCCN3[C@@H]1C2
Reactant: COC(=O)COC(=O)OCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Product: COC(=O)COC(=O)OCOc1c2n(cc(C(=O)NCc3ccc(F)cc3F)c1=O)C[C@@H]1N(C[C@H]3CCCN31)C2=O

Procedure:
The title compound was prepared from methyl ({[(iodomethyl)oxy]carbonyl}oxy)acetate (excess), (4aS,13aR)-N-[(2,4-difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide sodium salt (80 mg, 0.177 mmol), potassium carbonate (73 mg, 0.531 mmol), and tetrabutylammonium hydrogen sulfate (60 mg, 0.177 mmol), using a similar process to that described in example 1. 1H NMR (CDCl3) δ 10.23 (m, 1 H), 8.38 (s, 1 H), 7.31 (m, 1 H), 6.76 (m, 2 H), 5.98 (d, J=6.4 Hz, 1 H), 5.89 (d, J=6.4 Hz, 1 H), 4.72-4.53 (m, 5 H), 4.28 (m, 2 H), 4.15 (m, 1 H), 3.92 (m, 1 H), 3.73 (s, 3 H), 3.14-3.03 (m, 2 H), 2.82 (m, 1 H), 2.10-1.91 (m, 3 H), 1.68 (m, 1 H). ES+ MS: 577 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=1[C:5]#[N:6].C1C(=O)N([Br:19])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:19][C:8]1[C:7]([CH3:11])=[C:4]([C:3]([O:2][CH3:1])=[CH:10][CH:9]=1)[C:5]#[N:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C)c1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Br)c(C)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxy-6-methylbenzonitrile (3.6 g, 24 mmol) in TFA (25 mL) was added NBS (6.5 g, 36 mmol) and stirred at room temperature for 2 hours. Analysis of the reaction mixture by LC indicated complete bromination of the starting material. The solution was concentrated in vacuo and the resulting crude was dissolved in EtOAc and washed with brine, then dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (Hexanes:EtOAc=1:1) to provide the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH3:15])[C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH2:17][C:18]1[S:22][N:21]=[C:20]([CH3:23])[CH:19]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@H:11]([CH3:15])[C:12]([NH2:14])=[O:13])=[CH:3][C:2]=1[NH:17][C:18]1[S:22][N:21]=[C:20]([CH3:23])[CH:19]=1)#[N:9]
Reactant: Cc1cc(N)sn1
Reactant: C[C@@H](Nc1ccc(C#N)c(Br)c1)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@H](C)C(N)=O)ccc2C#N)sn1
Reaction time: 18 h
Yield: 61.1 %

Procedure:
A mixture of (R)-2-(3-bromo-4-cyanophenylamino)propanamide (185 mg, 0.690 mmol), 5-amino-3-methylisothiazole hydrochloride (133 mg, 0.883 mmol), BINAP (40 mg, 0.064 mmol), Pd(OAc)2 (30 mg, 0.13 mmol) and K2CO3 (300 mg, 2.17 mmol) in dioxane (4 mL) was degassed with Ar, then was stirred at 120 C for 18 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give ((R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)propanamide (127 mg).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.Cl.[CH3:14][O:15][C:16](=[O:24])[C@@H:17]([NH2:23])[C@H:18]([N:20]=[N+:21]=[N-:22])[CH3:19].C1C=CC2N(O)N=NC=2C=1.[CH2:35]([C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49](O)=[O:50])=[CH:45][CH:44]=2)=[CH:39][CH:38]=1)[CH3:36].CCN(C(C)C)C(C)C>C(Cl)Cl.CCCCCC.CCOC(C)=O>[CH3:14][O:15][C:16](=[O:24])[C@@H:17]([NH:23][C:49]([C:46]1[CH:45]=[CH:44][C:43]([C:40]2[CH:41]=[CH:42][C:37]([CH2:35][CH3:36])=[CH:38][CH:39]=2)=[CH:48][CH:47]=1)=[O:50])[C@H:18]([N:20]=[N+:21]=[N-:22])[CH3:19]
Reactant: COC(=O)[C@@H](N)[C@@H](C)N=[N+]=[N-]
Reactant: CCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCc1ccc(-c2ccc(C(=O)N[C@H](C(=O)OC)[C@@H](C)N=[N+]=[N-])cc2)cc1
Reaction time: 24 h
Yield: 66.9 %

Procedure:
A EDC.HCl (249 mg, 1.3 mmol) was added to a stirred colorless solution of azido-Thr-OMe.HCl (4) (195 mg, 1.0 mmol), HOBT (158 mg, 1.0 mmol), 4′-Ethyl-biphenyl-4-carboxylic acid (5) (226 mg, 1.0 mmol) and DIEA (0.44 ml, 2.5 mmol) in DCM (10 ml) at rt under N2. After 24 h, the reaction had reached completion by TLC (Hexane/EtOAc (60:40) (Rf=0.3)) and LCMS. The reaction was evaporated under reduced pressure to a brown tar. The crude product was dissolved in EtOAc (100 ml) and washed with 0.2N aq. HCl (2×50 ml), aq. sat. NaHCO3 (50 ml), brine (50 ml), dried (Na2SO4), filtered and concentrated under reduced pressure to yield a crude brown solid. The crude material was further purified by column chromatography eluting with Hexane/EtOAc (70:30) giving 245 mg (67% yield) of pure product after evaporation and drying in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](O)=[O:12])[N:8]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[N:7]=1)=[O:5])[CH3:2].CO>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][OH:12])[N:8]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)O)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CO)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Temperature: 40 °C

Procedure:
To a solution of 4 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrazole-3,5-dicarboxylic acid 3-ethyl ester in 50 ml THF 26 ml BH3*THF (1M in THF) were added slowly at RT. Then the mixture was warmed to 40° C. for 6h. After cooling to 0° C. 20 ml MeOH were added cautiously and the mixture was concentrated to dryness. The residue was again codistilled with 20 ml of MeOH and then purified by chromatography on silica gel eluting with n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.9 g.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH2:27][OH:28])[CH:26]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:29][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)=[CH:26][C:25]=1[CH2:27][OH:28]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1ccc(F)c(CO)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)Nc2ccc(F)c(CO)c2)nc(N2CCOCC2)cc1=O
Yield: 45.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 184 mg of (5-amino-2-fluorophenyl)methanol, and 285 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 157 mg of N-[4-fluoro-3-(hydroxymethyl)phenyl]-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a grey solid, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[C:12]1[N:17]=[C:16]2[C:18]([C:40]([O:42][CH3:43])=[O:41])=[CH:19][N:20]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]2=[N:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:51][CH2:52][CH2:53][C:54]([CH3:59])([N+:56]([O-:58])=[O:57])[CH3:55].O>CN(C=O)C>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:51][CH2:52][CH2:53][C:54]([CH3:59])([N+:56]([O-:58])=[O:57])[CH3:55])=[CH:10][CH:9]=2)[C:5]([C:12]2[N:17]=[C:16]3[C:18]([C:40]([O:42][CH3:43])=[O:41])=[CH:19][N:20]([C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:15]3=[N:14][CH:13]=2)=[N:6]1
Reactant: CC(C)(CCCCl)[N+](=O)[O-]
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(C)c4ccc(O)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(C)c4ccc(OCCCC(C)(C)[N+](=O)[O-])cc34)nc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
To a solution of methyl 2-(5-hydroxy-1-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (2.2 g, 3.9 mmol) in DMF (25 mL) was added K2CO3 (1.8 g, 12.8 mmol) and 1-chloro-4-methyl-4-nitropentane (1.0 g, 5.9 mmol), after the addition, the reaction mixture was heated to 100° C. with stirring for 4 hours. The reaction mixture was cooled to room temperature, H2O (25 mL) was added and product extracted with EtOAc (100 mL). The organic layer was washed with H2O (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give methyl 2-(1-methyl-5-(4-methyl-4-nitropentyloxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (1.8 g, 66.7%) as yellow solid. LCMS: (M+H)+=695.
Reaction SMILES: [CH3:1]N(C)CCN(C)C.BrCBr.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[O:32][C:33]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)=O)=[CH:15][CH:14]=1.[Cl-].[NH4+]>C(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH:20]2[O:32][C:33]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)=[CH2:1])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OC(=O)c2ccc3ccccc3c2)C1
Reactant: CN(C)CCN(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: BrCBr
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C(OC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(F)cc1)c1ccc2ccccc2c1
Reaction time: 0.17 h
Yield: 45.8 %

Procedure:
A solution of 2.7 ml (24.6 mmol) of titanium tetrachloride in 18 ml of methylene chloride was added dropwise at 0° C. under argon and with the exclusion of moisture to 30 ml of tetrahydrofuran, a yellow suspension resulting. After warming to room temperature 15 ml (95 mmol) of tetramethylethylenediamine were added and the reaction mixture was stirred for 10 minutes. After the addition of 3.6 g (55 mmol) of zinc dust the mixture was stirred at room temperature for a further 30 minutes. Thereupon, a solution of 2.1 ml (30 mmol) of dibromomethane and 2.7 g (6.0 mmol) of tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-(naphthalen-2-ylcarbonyloxy)-piperidine-1-carboxylate dissolved in 30 ml of tetrahydrofuran was added dropwise in such a manner that the temperature did not rise above 36° C. Subsequently, the reaction mixture was stirred at room temperature for 60 hours, then poured into saturated ammonium chloride solution and extracted with ether. The combined ether phases were dried over magnesium sulphate, concentrated and the residue was chromatographed on silica gel using a 99:1 mixture of methylene chloride and triethylamine as the eluent. Therefrom there were obtained 1.23 g (46% of theory) of tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-(1-naphthalen-2-yl-vinyloxy)-piperidine-1-carboxylate as an amorphous colourless solid; MS: 448 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C([N:25]([C:33]1[S:42][CH2:41][C@H:40]2[C@:35]([C:43]3[CH:48]=[C:47](Br)[CH:46]=[CH:45][C:44]=3[F:50])([CH2:36][O:37][CH2:38][CH2:39]2)[N:34]=1)C(OC(C)(C)C)=O)(=O)C1C=CC=CC=1>CN(C=O)C.O.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>[F:50][C:44]1[CH:45]=[CH:46][C:47]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:48][C:43]=1[C@@:35]12[N:34]=[C:33]([NH2:25])[S:42][CH2:41][C@@H:40]1[CH2:39][CH2:38][O:37][CH2:36]2
Reactant: CC(C)(C)OC(=O)N(C(=O)c1ccccc1)C1=N[C@@]2(c3cc(Br)ccc3F)COCC[C@H]2CS1
Reactant: OB(O)c1cccnc1F
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: O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)ccc3F)COCC[C@H]2CS1
Temperature: 90 °C
Reaction time: 6 h
Yield: 38.6 %

Procedure:
2-Fluoropyridine-3-boronic acid (25.6 mg), tetrakis(triphenylphosphine)palladium (10.5 mg) and a 1 N sodium carbonate solution (182 μl ) were added to a solution of (±)-N-benzoyl-N-(tert-butyloxycarbonyl)-[(4aR*,8aS*)-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (50 mg) in DMF (5.0 ml). After replacement with nitrogen, the mixture was stirred at 90° C. for six hours. The reaction solution was cooled to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound (12.7 mg).
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1)O)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:31])=O>ClCCl>[Si:5]([O:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[Cl:31])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:28])[CH3:27]
Reactant: O=S(Cl)Cl
Reactant: CN(C)S(=O)(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(C(Cl)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1

Procedure:
The alcohol (88.8 g, 0.21 mol) was treated with thionyl chloride in dichloromethane as described in Example 1 to give 93.7 g of 4-(3-(tert-butyldimethylsilyloxy)-α-chlorobenzyl)-N,N-dimethylbenzenesulfonamide as a brown oil. The crude benzhydryl chloride (93.7 g, 0.21 mol) was combined with trans-2,5-dimethylpiperazine (71.8 g, 0.63 mol) in 400 mL of dimethylformamide and heated to 140° C. for 1 hour. The mixture was cooled to room temperature, poured into ice water and extracted with diethyl ether. The ether extracts were washed with 1M sodium hydroxide, water, and saturated aqueous sodium chloride, and dried over sodium sulfate. The solvent was removed and the residue was purified by chromatography on silica gel with dichloromethane:methanol to give 28.9 g (27%) of trans-4-(α-(2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-dimethylbenzenesulfonamide as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:25][CH2:24]2)=[CH:4][C:5]([O:20][CH2:21][CH3:22])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].[CH:36]1([C:39]2[O:40][CH:41]=[C:42]([C:44](O)=[O:45])[N:43]=2)[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH2:21]([O:20][C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:44]([C:42]2[N:43]=[C:39]([CH:36]3[CH2:38][CH2:37]3)[O:40][CH:41]=2)=[O:45])=[C:3]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:27][CH2:28]2)[CH:4]=1)[CH3:22]
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: CCOc1cc(N2CCN(c3ccccc3C)CC2)c(N)cc1C(=O)NCCCN1CCCC1=O
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
Solvent: O
Product: CCOc1cc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2coc(C3CC3)n2)cc1C(=O)NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
5-Amino-2-ethoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 8c (58.3 mg, 0.12 mmol, 100 mol %), 2-cyclopropyl-oxazole-4-carboxylic acid 1 h (27.9 mg, 0.18 mmol, 150 mol %) and N,N-diisopropylethylamine (0.06 ml, 0.36 mmol, 300 mol %) were combined in N,N-dimethylformamide (3.0 ml) and HATU (69.3 mg, 0.18 mmol, mol %) was added and the reaction was stirred at room temperature for 16 h. The reaction was then diluted with water and extracted three times with ethyl acetate. The combined organics were dried over sodium sulfate and then concentrated to a residue that was purified by reverse phase HPLC (methanol+0.1% formic acid/water) to afford 2-cyclopropyl-oxazole-4-carboxylic acid [4-ethoxy-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 8e (54.8 mg, 0.09 mmol, 73.3%) as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([C:11]#[N:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1B(O)O.O>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][C:25]=1[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([C:11]#[N:12])[N:3]=1
Reactant: CCCc1cc(I)nc(C#N)n1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1cc(-c2cc(C(F)(F)F)ccc2Cl)nc(C#N)n1
Temperature: 105 °C
Yield: 58 %

Procedure:
Under nitrogen atmosphere, a solution (c=0.18 M) of 4-iodo-6-propyl-pyrimidine-2-carbonitrile (1 mL, 0.18 mmol) in degassed toluene, an aqueous solution (c=2 M) of potassium carbonate (0.225 mL, 0.45 mmol) and tetrakis(triphenylphosphine) palladium (10 mg, 0.09 mmol) were successively added to a solution (c=0.216 M) of 2-chloro-5-(trifluoromethyl)phenyl boronic acid (1 ml, 0.216 mmol) in degassed toluene. The mixture was heated at 105° C. for 4 h, then was allowed to cool to room temperature and mixed with water (4 mL). The organic layer was evaporated under reduced pressure. The residue was chromatographed by preparative HPLC (H2O+0.05% TFA/CH3CN+0.05% TFA) to afford 4-(2-chloro-5-trifluoromethyl-phenyl)-6-propyl-pyrimidine-2-carbonitrile (34 mg, 58%) as a solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:24][N:23]=[C:22](CC(C)(C)C([O-])=O)[CH:21]=4)=[CH:16][CH:15]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[OH:33]>CO.[OH-].[K+]>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:24][N:23]=[C:22]([OH:33])[CH:21]=4)=[CH:16][CH:15]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(Cc1cc(-c2ccc(OCc3cc(-c4ccccc4)on3)cc2)on1)C(=O)[O-]
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: Oc1cc(-c2ccc(OCc3cc(-c4ccccc4)on3)cc2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(4-((5-phenylisoxazol-3-yl)methoxy)phenyl)isoxazol-3-ylpivalate (21 mg) in methanol (2 ml), 0.4 ml of 5M potassium hydroxide methanol solution was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was neutralized, then extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified through reversed phase medium pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid). The solvent of the resultant fraction was distilled off under reduced pressure to afford the title compound as a white solid.
Reaction SMILES: C1(C2C[C:9](=[O:11])C2)C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:22][C:21](=O)[CH2:20]2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:22][C@H:21]([CH:9]=[O:11])[CH2:20]2)=[CH:15][CH:14]=1
Reactant: O=C1CC(c2ccc(F)cc2)C1
Reactant: O=C1CC(c2ccccc2)C1
Product: O=C[C@H]1C[C@H](c2ccc(F)cc2)C1

Procedure:
Instead of 3-phenylcyclobutanone, 3-(4-fluorophenyl)cyclobutanone (4.63 g) was used and treated by the same technique as in Reference Example 24-1 to give the titled compound as a colorless oil (720 mg).
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]1[CH2:10][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]1=[O:21])=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:5][C@H:6]1[CH2:10][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:7]1=[O:21]
Reactant: CC(C)CN1C(=O)[C@@H](NC(=O)C(F)(F)F)C[C@@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)CN1C(=O)[C@@H](N)C[C@@H]1c1ccccc1
Reaction time: 27 h
Yield: 100.2 %

Procedure:
To a solution of trans-2,2,2-trifluoro-N-(1-isobutyl-2-oxo-5-phenylpyrrolidin-3-yl)acetamide (63.2 mg, 0.192 mmol) in methanol (3 mL) and water (1 mL) was added potassium carbonate (79.8 mg, 0.578 mmol). After 27 hours, the reaction solution was concentrated and worked up with methylene chloride and water. The organic extracts were dried over sodium sulfate, filtered and concentrated to produce the title compound (44.7 mg). MS 233 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.I[CH2:15][CH2:16][C@@H:17]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:22][C:19]1([CH3:23])[O:18][C@H:17]([CH2:16][CH2:15][N:8]2[C:9](=[O:12])[CH:10]=[N:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:13][C:7]2=3)[CH2:21][O:20]1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Reactant: CC1(C)OC[C@@H](CCI)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ncc(=O)n(CC[C@@H]3COC(C)(C)O3)c2n1
Temperature: 50 °C
Reaction time: 13 h
Yield: 100.1 %

Procedure:
In N,N-dimethylformamide (40 ml) were dissolved 6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (1.48 g, 8.34 mmol) and (4R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (3.20 g, 12.51 mmol). Cesium carbonate (3.81 g, 11.68 mmol) was added to the solution and the mixture was stirred at 50° C. for 13 hours. After cooling in the air, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 2.55 g (100%) of the title compound in the form of a light yellow oily product.