Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:27][CH3:28])[C:6]3[C:11]([N:12]=2)=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:9]=[C:8]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[N:7]=3)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl.[O:48]1[CH2:51][CH:50]([NH2:52])[CH2:49]1>ClCCCl.C(OCC)(=O)C>[CH:1]1([C:4]2[N:5]([CH2:27][CH3:28])[C:6]3[C:11]([N:12]=2)=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:9]=[C:8]([C:20]2[CH:21]=[CH:22][C:23]([NH:24][C:37]([NH:52][CH:50]4[CH2:51][O:48][CH2:49]4)=[O:39])=[CH:25][CH:26]=2)[N:7]=3)[CH2:2][CH2:3]1
Reactant: NC1COC1
Reactant: CCn1c(C2CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3ccc(N)cc3)nc21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCn1c(C2CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3ccc(NC(=O)NC4COC4)cc3)nc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
To a stirred solution of (S)-4-(8-cyclopropyl-9-ethyl-6-(3-methylmorpho-lino)-9H-purin-2-yl)aniline (52.0 mg, 0.14 mmol) in anhydrous 1,2-dichloroethane (3.0 mL) was added triethylamine (0.063 mL, 0.45 mmol, 3.3 eq.). The reaction was cooled to 0° C. and triphosgene (40.8 mg, 0.14 mmol, 1.0 eq) was added in one portion. After stirring at 0° C. under N2 for 5 minutes, the reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was cooled to RT, and 3-oxetanamine (50.2 mg, 0.69 mmol, 5.0 eq.) was then added. The reaction mixture was stirred at RT under N2 for 16 h and then diluted with ethyl acetate (25 mL). The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by reverse phase HPLC to give the title compound as a white solid (30.5 mg, 46.5%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.78 (s, 1H), 8.24 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 6.97 (d, J=6.7 Hz, 1H), 5.37 (broad s, 1H), 5.03 (broad s, 1H), 4.86 to 4.69 (m, 3H), 4.44 (t, J=6.0 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H), 3.97 (d, J=8.7 Hz, 1H), 3.77 (d, J=11.3 Hz, 1H), 3.68 (dd, J=11.4 Hz, 2.6 Hz, 1H), 3.53 (t, J=10.5 Hz, 1H), 3.44 to 3.33 (m, 1H), 2.30 to 2.19 (m, 1H), 1.39 (t, J=7.2 Hz, 3H), 1.28 (d, J=6.7 Hz, 3H), 1.10 to 0.95 (m, 4H); LC-MS m/z (method C)=478.2 [M+H]+, RT=4.44 min.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2.C([Mg]Br)C.[Cl-].[NH4+:23]>C(OCC)C.C(#N)C>[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:7][C:1]1([CH2:2][C:3]#[N:23])[CH2:6][CH2:5]1
Reactant: Cc1ccccc1
Reactant: Brc1cccc2cc[nH]c12
Reactant: [NH4+]
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: CC#N
Solvent: CCOCC
Product: N#CCC1(Cc2c[nH]c3c(Br)cccc23)CC1

Procedure:
To a toluene (12 mL) solution of 7-bromoindole (1.00 g), [1-bromomethyl)cyclopropyl]acetonitrile (444 mg) was added and a diethyl ether solution (1.7 mL) of 3M ethylmagnesium bromide was added dropwise under ice cooling, and then the mixture was refluxed for 2.5 hours. To the reaction mixture, an aqueous saturated ammonium chloride solution was added under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 80:20) to obtain the titled compound having the following physical properties (390 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH:13](Br)([CH3:15])[CH3:14].N1C=CC=C[CH:18]=1>C(O)C>[CH:13]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([O:11][CH3:18])=[O:10])=[CH:6][CH:7]=1)([CH3:15])[CH3:14]
Reactant: CC(C(=O)[O-])c1ccc(N)cc1
Reactant: c1ccncc1
Reactant: CC(C)Br
Solvent: CCO
Product: COC(=O)C(C)c1ccc(NC(C)C)cc1
Reaction time: 16 h

Procedure:
A mixture of 2-(p-aminophenyl)propionate (5.4 g), isopropyl bromide (5g), pyridine (5 ml) and ethanol (80 ml) is boiled during 16 hours. The reaction mixture is concentrated in vacuo, taken up into water, extracted with ether, dried, after which the solvent is removed. Chromatography over silica gives 2.2 g of methyl 2-(p-isopropylaminophenyl)propionate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-])=[CH:4][CH:3]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:11]=[C:12]([C:24]#[N:25])[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: [O-][n+]1ccccc1C=Cc1ccc(Cl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: COS(=O)(=O)OC
Product: N#Cc1cccc(C=Cc2ccc(Cl)cc2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(4-chloro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a beige crystalline material. Mp. 113–115° C. (isopropanol), MS: m/e=240 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
2-(4-Bromophenyl)acetic acid (20 g, 93 mmol), tert-butyl carbazate (14.7 g, 111 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.4 g, 112 mmol) and 1-hydroxybenzotriazole monohydrate (17.1 g, 112 mmol) were dissolved in dichloromethane (400 ml), and N,N-diisopropylethylamine (80 ml) was added. After stirring at room temperature for 16 hrs, the reaction mixture was washed with 1M hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (dichloromethane:methanol=99:1→90:10) to give tert-butyl 2-[(4-bromophenyl)acetyl]hydrazinecarboxylate (27 g, yield 88%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([Cl:19])[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](OB(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[ClH:19].[ClH:19].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(Cl)nc3ccccc23)CC1
Reactant: COc1ccc(OB(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1CCN(c2nc(-c3ccc(OC)cc3)nc3ccccc23)CC1
Product: Cl
Reaction time: 2 h
Yield: 136.1 %

Procedure:
A mixture of 4-(1-ethylpiperazin-4-yl)-2-chloroquinazoline(0.56 g), 4-methoxyphenylboric acid (0.46 g) tetrakistriphenylphosphinepalladium(0) (0.12 g), toluene (50 ml) and a 10% aqueous solution of sodium carbonate (30 ml) was vigorously stirred in nitrogen atmosphere at 100° C. for 1 hr. To the resulting mixture was additionally added 4-methoxyphenylboric acid (0.31 g), and the mixture was further stirred for 2 hr. To the resulting mixture was again added 4-methoxyphenylboric acid (0.31 g), and the mixture was further stirred for 1 hr. To the resulting mixture was further added 4-methoxyphenylboric acid (0.31 g), and the mixture was further stirred overnight. The resulting insoluble matters were filtered off, and then the organic layer was separated and extracted with 2N hydrochloric acid twice, followed by the addition of a 8N aqueous solution of sodium hydroxide to adjust the resulting mixture to pH 10. The resulting mixture was extracted with ethyl acetate twice. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give 0.58 g of the free compound of the title compound as a pale yellow viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.O.NN>C(O)C.CO.[Ni]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CO
Product: N#Cc1ccc(O)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
4-Hydroxy-3-nitrobenzonitrile (0.5 g, 3.05 mmol) was dissolved in ethanol (20 mL) and methanol (10 mL), and Raney-Nickel (1 mL, 10% aqueous solution) was added at rt followed by hydrazine mono hydrate (0.296 mL, 6.09 mmol). The mixture was stirred at rt overnight. The mixture was then filtered through celite and concentrated by rotary evaporation. The residue was purified via chromatography (silica, n-hexane to ethyl acetate) to give 3-amino-4-hydroxybenzonitrile (D19, 200 mg, 49%) as an orange solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[C:11]1(=[O:15])[CH2:14][CH2:13][CH2:12]1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>O1CCCC1>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:5]1[S:1][C:2]([C:11]2([OH:15])[CH2:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: O=C1CCC1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C2(O)CCC2)s1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of thiazole (1.0 mL, 14.1 mmol) in tetrahydrofuran (70 mL) was added n-butyllithium (11.83 mL, 14.1 mmol, 2.38 M in hexane) dropwise. After 15 minutes, cyclobutanone (1.06 mL, 14.1 mmol) was added in a single portion. The reaction was stirred at −78° C. for 30 minutes, and n-butyllithium (11.83 mL, 14.1 mmol, 2.38 M in hexane) was added dropwise. The reaction was stirred for an additional 20 minutes, after which tributyltin chloride (3.82 mL, 14.1 mmol) was added dropwise. After 10 minutes, the cold reaction was quenched by the addition of saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (100 mL). The reaction was warmed to ambient temperature. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×100 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated. Trituration of the residue with hexane gave the title compound, which was used without further purification. MS ESI(+) m/z 445.3 [M+H]+.
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[F:22][C:20]1[CH:21]=[C:16]([C:15]2[C:6]([CH:4]([NH2:1])[CH3:5])=[CH:7][CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:17]=[C:18]([F:23])[CH:19]=1
Reactant: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-8-(3,5-difluorophenyl)quinoline (0.040 g, 0.13 mmol) in tetrahydrofuran (0.4 mL) and water (0.093 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.155 mL, 0.155 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl twice. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue showed two peaks by LCMS with same desired mass and was used directly in next step (30 mg, 81%). LCMS calculated for C17H15F2N2(M+H)+: m/z=285.120; found: 285.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[N:10]#[C:11][NH2:12].[N+:13]([O-:16])([OH:15])=[O:14]>C(O)C>[N+:13]([O-:16])([O-:15])=[O:14].[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]([NH2:12])=[NH2+:10])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(N)cc1
Reactant: N#CN
Solvent: CCO
Product: COc1ccc(NC(N)=[NH2+])cc1
Product: O=[N+]([O-])[O-]
Temperature: 25 °C
Yield: 38 %

Procedure:
To a room temperature solution of 4-methoxyaniline (10.0 g, 81.19 mmol) in ethanol (100 mL) was added cyanamide (7.24 mL, 50 wt % in water, 93.37 mmol) followed by the dropwise addition of concentrated nitric acid (5.71 mL). The mixture was heated at reflux for 3 hours and allowed to cool to room temperature. The resulting crystals were isolated on a filter to yield N-(4-Methoxyphenyl)guanidinium nitrate (7.1 g, 38%) as a violet crystals. 1H NMR (DMSO-d6): δ 9.39 (s, 1 H), 7.22 (s, 3 H), 7.17 (d, 2 H), 6.99 (d, 2 H)<3.76 (s, 3 H); 13C NMR (DMSO-d6): δ 158.17, 156.26, 127.48, 127.27, 114.90, 55.40; MS m/z 166 (M+1 of free base).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21].[CH:22](N1CCOCC1)=[O:23]>C1COCC1.Cl>[Cl:13][C:14]1[C:15]([F:21])=[C:16]([C:17]([F:20])=[CH:18][CH:19]=1)[CH:22]=[O:23]
Reactant: Fc1ccc(Cl)c(F)c1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)ccc(Cl)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.43M in hexane, 20.2 mmol, 14.1 ml) was added dropwise at 0° C. to a solution of diisopropylamine (2.91 ml, 22.2 mmol) in THF (80 ml). After 30 min. at 0° C., the solution was cooled to -78° C. and 1-chloro-2,4-difluorobenzene (3 g, 20.2 mmol) in THF (10 ml) added dropwise. After 30 min., 4-formylmorpholine (4.1 ml) was added and the mixture warmed to room temperature over 1 h, diluted with 1N HCl, extracted twice with ethyl acetate, the extracts washed with brine, dried over sodium sulphate and evaporated to give a mobile yellow oil (2.2 g), MS (+EI) 178/177/176/175 (M+), 1H NMR (CDCl3) 10.34 (1H, s), 7.66-7.60 (1H, m), 7.00 (1H, dt, J6.9 Hz, 1.2 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:21])[CH:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:45]>CCCCO>[ClH:45].[NH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]4[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:21])[CH:15]=4)=[O:13])[C:4]=23)[CH2:24]1
Reactant: ClCCl
Reactant: Cn1cc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)ccc1=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: Cl
Product: Cn1cc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](N)C4)c23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (0.22 g, 0.602 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.362 g, 1.81 mmol) in n-BuOH (2 mL) were stirred at 143° C. (bath) for 24 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-80% CH3CN/water gradient; 30 CV) to give a solid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide hydrochloride (0.113 g, 36% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.94 (s, 1H), 9.74 (s, 1H), 8.62 (s, 1H), 8.25 (s, 1H), 8.15 (br s, 3H), 8.06 (d, 1H), 7.51 (s, 1H), 6.49 (d, 1H), 3.44 (m, 1H), 3.32 (m, 1H), 3.20 (m, 2H), 3.07 (m, 1H), 1.93 (m, 1H), 1.66 (m, 1H), 1.49 (m, 1H), 1.35 (m, 1H); LCMS (APCI+) m/z 445 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[N:32]1([CH2:37][CH2:38][NH2:39])[CH:36]=[CH:35][N:34]=[N:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:32]1([CH2:37][CH2:38][NH:39][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:30])[CH:36]=[CH:35][N:34]=[N:33]1
Reactant: NCCn1ccnn1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCCn2ccnn2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 2-[1,2,3]triazol-1-yl ethylamine (200 mg, 1.78 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (15-95% of ACN/water) rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (83.7 mg, 34.7%) as an off-white powder. HRMS ES+) m/z Calcd for C27H28Cl2F2N6O+H [(M+H)+]: 561.1743. found: 561.1741.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]([CH3:28])([CH3:27])[CH2:9][C:10]([OH:26])([C:22]([F:25])([F:24])[F:23])[CH2:11][NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([NH2:17])=[O:16])[CH:7]=1.F[C:32](F)(F)C(O)=O>COC(OC)OC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]([CH3:27])([CH3:28])[CH2:9][C:10]([OH:26])([C:22]([F:25])([F:23])[F:24])[CH2:11][N:12]2[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:16])[N:17]=[CH:32]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1ccccc1C(N)=O)C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: COC(OC)OC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1cnc(=O)c2ccccc21)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]benzamide (106 mg) in trimethylorthoformate (6 mL) was added trifluoroacetic acid (0.1 mL). After 1.5 hours, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 70% ethyl acetate-hexanes) to give the title compound as a white solid (82 mg), m.p. 118° C.-121° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16](=[N:19][OH:20])[C:17]#[N:18]>N1C=CC=CC=1>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16](=[N:19][O:20][C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:17]#[N:18]
Reactant: CCOC(=O)Cl
Reactant: N#CC(=NO)c1nc2ccccc2o1
Solvent: c1ccncc1
Product: CCOC(=O)ON=C(C#N)c1nc2ccccc2o1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
12 g (0.11 mol) of ethyl chloroformate are added dropwise to a solution of 18.7 g (0.1 mol) of α-[benzoxazol-2-yl]-α-oximino-acetonitrile in 120 ml of pyridine, with ice-cooling. After stirring for 3 hours, the mixture is poured into 1 liter of ice-water and the residue is filtered off and washed with water: 23 g (89% of theory) of end product, which is recrystallised from acetonitrile; melting point 187° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8]O)=[CH:5][CH:4]=1.Cl.[H][H].[OH-].[Na+]>CO.CCOCC>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1
Reactant: ON=Cc1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: NCc1ccc(C(F)(F)F)cc1
Yield: 93.6 %

Procedure:
The first and second steps of the process of the present invention were conducted as follows. At first, 8.79 g (50.5 mmol) of 4-trifluoromethylbenzaldehyde and 3.83 g (55.1 mmol) of hydroxylamine hydrochloride were dissolved in 12.5 ml of ethanol and 34 ml of water followed by the addition of 2,5 g of sodium hydroxide and stirring for 1 hour at room temperature. After adding ether and washing with dilute hydrochloric acid, the reaction liquid was further washed with saturated brine followed by drying with mirabilite and concentrating to obtain 9.25 g (48.2 mmol) of 4-trifluoromethylbenzylaldehyde oxime (yield: 95.5%). 5.00 g (26.4 mmol) of this 4-trifluoromethylbenzaldehyde oxime were dissolved in methanol followed by the addition of 4.0 g (109.7 mmol) of hydrogen chloride gas and 252 mg of the same catalyst as that of Example 1 and stirring for 3 hours in a hydrogen atmosphere at 10 atm and room temperature (approx. 250° C.). After removing the catalyst, ether was added to the reaction liquid, and the reaction liquid was neutralized with aqueous sodium hydroxide solution. As a result of analyzing the separated ether layer by gas chromatography, 4-trifluoromethylbenzylamine was formed at a yield of 93.6%.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:25])[C:5]([N+:22]([O-:24])=[O:23])=[C:6]([C:8]([C:20]#[N:21])([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)C(OCC)=O)[N:7]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:25])[C:5]([N+:22]([O-:24])=[O:23])=[C:6]([CH:8]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[N:7]=1
Reactant: CCOC(=O)C(C#N)(Cc1cccs1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(Cc1cccs1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-Amino-α-cyano-1,6-dihydro-5-nitro-6-oxo-α-(2-thienylmethyl)-4-pyrimidineacetic acid, ethyl ester as prepared above (5.0 g) in 1N NaOH (200 mL) is stirred at room temperature for 90 min. The reaction mixture is acidified to pH 1 with 4N HCl and stirred for 5 min. The reaction mixture is neutralized (pH 7) with IN NaOH and the product 2-Amino-1,6-dihydro-5-nitro-6-oxo-α-(2-thienylmethyl)-4-pyrimidineacetonitrile (4.1 g, 98%) is collected by filtration. ##STR16##
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]([CH3:12])[CH3:11])=[N:4][CH:5]=[N:6][C:7]=1[S:8][CH3:9].[C:13](Cl)(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH3:12][N:10]([CH3:11])[C:3]1[C:2]([NH:1][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:7]([S:8][CH3:9])[N:6]=[CH:5][N:4]=1
Reactant: CSc1ncnc(N(C)C)c1N
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1c(SC)ncnc1N(C)C

Procedure:
5-Amino-4-dimethylamino-6-methylthiopyrimidine (prepared by reacting 5-amino-4-dimethylamino-6-chloropyrimidine with sodium thiomethoxide) was coupled with oleoyl chloride using the procedure described in Example 4 to give the title compound.