Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:26]=[CH:25][C:18]2[C:19](=O)[O:20]C(=O)[NH:22][C:17]=2[CH:16]=1>CCCCCC.O1CCCC1>[NH2:22][C:17]1[CH:16]=[C:15]([C:14]([F:13])([F:27])[F:28])[CH:26]=[CH:25][C:18]=1[C:19](=[O:20])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: Cc1nnnn1C
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2c(=O)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nnnc1CC(=O)c1ccc(C(F)(F)F)cc1N
Reaction time: 0.25 h

Procedure:
A solution of butyl lithium in hexane (2.7M, 11.1 ml) was added during 2 minutes to a stirred solution of 1,5-dimethyltetrazole (2.94 g) in dry tetrahydrofuran (100 ml) at -10° to -5°. After stirring for 15 minutes, 7-trifluoromethyl-1H-3,1-benzoxazine-2,4-dione (2.3 g) was added during 5 minutes at -10° to -5°. The reaction mixture was stirred at ambient temperature for 1 hour. Industrial methylated spirit (2 ml) was added and the mixture kept at ambient temperature for 1.5 hours. The mixture was evaporated to one quarter volume, then poured on to ice. The mixture was acidified to pH 2 with hydrochloric acid (5N). The solid product was collected, dried and recrystallised from ethyl acetate:diethyl ether to give the novel compound 1-(2-amino-4-trifluoromethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 200°-201°.
Reaction SMILES: [N+:1]([C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:32]=[CH:31][C:22]3[C:23]4[CH2:30][CH2:29][CH2:28][C:24]=4[C:25](=[O:27])[O:26][C:21]=3[CH:20]=2)[CH2:11][CH2:10]1)=[O:7])([O-])=O.[H][H]>[Ni].C(O)C>[NH2:1][C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:32]=[CH:31][C:22]3[C:23]4[CH2:30][CH2:29][CH2:28][C:24]=4[C:25](=[O:27])[O:26][C:21]=3[CH:20]=2)[CH2:13][CH2:14]1)=[O:7]
Reactant: [H][H]
Reactant: O=C(NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCC4)CC1)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccccc1C(=O)NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCC4)CC1

Procedure:
A solution of 1.47 g. (3 mMol) 2,3-dihydro-7-{3-[4-(2-nitrobenzamido)-piperidino]-propoxy}-cyclopenta[c][1]benzopyran-4(1H)-one (compound of Example 48) in 100 ml. ethanol is hydrogenated over 1 g. Raney nickel at ambient temperature and 1 bar hydrogen pressure. After filtration, the filtrate is evaporated and the residue is recrystallized from ethanol. There is obtained 0.85 g. (62% of theory) of the desired compound; m.p. 269°-270° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][NH:17][CH2:18][CH2:19][C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26](O)=O.C=O>CN(C)C=O>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c1C(c1ccccc1)CNCC2
Reactant: O=CO
Agent: C=O
Solvent: CN(C)C=O
Product: CN1CCc2ccn(S(=O)(=O)c3ccccc3)c2C(c2ccccc2)C1

Procedure:
A mixture of 1-phenylsulphonyl-1,4,5,6,7,8-hexahydro-8-phenylpyrrolo[2,3-d]azepine (1.24 g), formic acid (0.86 gm), 40% formaldehyde (1.3 ml), and dimethylformamide (30 ml) were refluxed for 1 hour. After evaporating to dryness, 5M hydrochloric acid was added to the residue and the solution was washed with ether three times. The aqueous solution was basified with 5M sodium hydroxide and the product was extracted into dichloromethane. The extracts were washed with water, dried and evaporated to give a solid, m.p. 115°-116° C. (ethanol).
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][NH:10][C:11](=[O:12])[CH:5]2[CH2:4][NH:3][CH2:2]1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO.[OH-].[Na+]>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:3]2[CH2:2][CH2:1][N:6]3[C:7]4[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=4[CH2:9][NH:10][C:11](=[O:12])[CH:5]3[CH2:4]2)=[CH:20][CH:19]=1
Reactant: O=C1NCc2ccccc2N2CCNCC12
Reactant: O=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1NCc2ccccc2N2CCN(Cc3ccc(F)cc3)CC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3,4,4a,6,7-Hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one (680.0 mg, 3.13 mmol, Example 2A) was dissolve in methanol (15 mL). 4-Fluorobenzaldehyde (653.5 mg, 5.27 mmol) was added to the reaction and stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (565.3 mg, 9.00 mmol) was then added, and the reaction was stirred at ambient temperature for 17 hours. The reaction was then diluted with 1 M NaOH (50 mL) and extract with dichloromethane (3×50 mL). The organic layers were combined, and purified by silica gel chromatography (ethyl acetate, Rf 0.40) to give the title compound: 1H NMR (400 MHz, benzene-d6) δ ppm 1.93 (td, J=11.0, 2.8 Hz, 1H), 2.42 (t, J=10.6 Hz, 1H), 2.49-2.51 (m, 1H), 2.60 (dt, J=11.0, 2.6 Hz, 1H), 2.85 (td, J=11.2, 2.9 Hz, 1H), 3.02-3.10 (m, 2H), 3.30 (d, J=13.2 Hz, 1H), 3.50 (dt, J=10.7, 2.3 Hz, 1H), 3.75 (dd, J=10.4, 2.8 Hz, 1H), 4.51 (dd, J=13.6, 4.0 Hz, 1H), 6.72-6.73 (d, J=8.1 Hz, 1H), 6.75 (dd, J=7.3, 1.5 Hz, 1H), 6.81-6.84 (m, 3H), 7.02-7.09 (m, 3H); MS (DCI/NH3) m/z 326 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[NH2:22][OH:23].O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:23][NH:22][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]3)[S:11][C:12]=2[CH:18]=1)=[NH:20]
Reactant: CC(C)N1CCN(c2nc3ccc(C#N)cc3s2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)N1CCN(c2nc3ccc(C(=N)NO)cc3s2)CC1
Yield: 71.6 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carbonitrile (5.0 g, 17.5 mmol) in ethanol (50 mL) was added hydroxylamine hydrochloride (3.6 g, 52.4 mmol), water (8 mL) and potassium carbonate (7.2 g, 52.4 mmol). The reaction mixture was heated overnight at reflux. The mixture was allowed to cool and then concentrated in vacuo. The residue was dissolved into THF (30 mL) and then filtered. The filtrate was concentrated in vacuo to give 4 g of crude N-hydroxy-2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxamidine.
Reaction SMILES: [Mg].BrCCCCC(C)C.C([S@@](N=CC1C=CC(C(OC(C)C)=O)=CC=1)=O)(C)(C)C.[NH4+].[Cl-].[CH3:32][C:33]([CH3:58])([S@@:35]([NH:37][CH:38]([C:46]1[CH:57]=[CH:56][C:49]([C:50]([O:52][CH:53]([CH3:55])[CH3:54])=[O:51])=[CH:48][CH:47]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[O:36])[CH3:34]>C(Cl)Cl.CCCCCC.C(O)(C)C.CCOC(C)=O.C(OCC)C>[CH3:34][C:33]([CH3:32])([S@@:35]([NH:37][C@@H:38]([C:46]1[CH:47]=[CH:48][C:49]([C:50]([O:52][CH:53]([CH3:54])[CH3:55])=[O:51])=[CH:56][CH:57]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[O:36])[CH3:58]
Reactant: CC(C)CCCCC(N[S@@](=O)C(C)(C)C)c1ccc(C(=O)OC(C)C)cc1
Agent: CC(C)CCCCBr
Agent: CC(C)OC(=O)c1ccc(C=N[S@@](=O)C(C)(C)C)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)CCCC[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(=O)OC(C)C)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 17.6 %

Procedure:
Magnesium turnings (2.21 g, 90.9 mmol) were stirred with a magnetic stir bar overnight in a 500 ml round-bottom flask. Anhydrous ethyl ether 9173 ml) was added. 1-Bromo-5-methylhexane (15.0 g, 90.9 mmol) was added dropwise over 40 minutes. The solution was stirred at RT for 3.5 hours. The grignard solution was added to (S)-isopropyl 4-((tert-butylsulfinylimino)methyl)benzoate (13.4 g, 45.4 mmol) in 100 mL anhydrous DCM at −48° C. The solution was allowed to gradually warm to RT and was stirred at RT for 18 h. Saturated NH4Cl (150 ml) and EtOAc (200 mL) were added. The aqueous layer was separated and extracted with EtOAc (100 mL). The organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by SiO2 chromatography (200 g, Hexane/EtOAc, 25% to 33%) to give a mixture of R isomer and S isomer of isopropyl 4-(1-((S)-1,1-dimethylethylsulfinamido)-6-methylheptyl)benzoate (14.8 g, 82.4%, R:S=2:1). This mixture of two isomers (6 g) was resolved by Chiralpak AD column (4% isopropyl alcohol in hexane) to give isopropyl 4-((R)-1-((S)-1,1-dimethylethylsulfinamido)-6-methylheptyl)benzoate (2.61 g).
Reaction SMILES: C(OC(C[NH:7][C:8](=[O:27])[NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)[CH3:21])=O)C.[H-].[Na+].[C:30](OCC)(=[O:32])[CH3:31].Cl>O1CCCC1.O>[O:27]=[C:8]1[NH:7][C:30](=[O:32])[CH2:31][N:9]1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)[CH3:21]
Reactant: CCOC(=O)CNC(=O)Nc1ccc2c(c1)C(=C(C)c1ccc[nH]1)C(=O)N2
Reactant: CCOC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=C1C(=O)Nc2ccc(N3CC(=O)NC3=O)cc21)c1ccc[nH]1
Reaction time: 8 h

Procedure:
A solution of 5-(N′-(ethoxycarbonylmethyl)ureido)-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one (95 mg, 0.25 mmol) in tetrahydrofuran (2.5 mL) was treated with NaH (16 mg, 0.40 mmol). After stirring overnight, ethyl acetate (15 mL) and water (5 mL) were added and the reaction mixture was neutralized with 6N HCl. The organic layer dried (NaSO4) and concentrated to afford a crude product (90 mg). Purification by reverse phase HPLC (acetonitrile/water) afforded 5-(2,4-dioxoimidazolidin-1-yl)-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; (8 mg); 1H NMR (400 MHz, DMSO-d6) δ 2.72 (s, 3H), 4.02 (s, 2H), 6.36 (m, 1H), 6.96 (d, 1H), 7.04 (m, 2H), 7.36 (d, 1H), 7.60 (m, 1H), 8.22 (s, 1H), 11.14 (s, 1H) ppm.
Reaction SMILES: [C:1]([S:9][S:10]Cl)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH3:12][NH:13][C:14]([F:16])=[O:15]>>[CH3:12][N:13]([S:10][S:9][C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[C:14]([F:16])=[O:15]
Reactant: CNC(=O)F
Reactant: CC(C)(C)CC(C)(C)SSCl
Product: CN(SSC(C)(C)CC(C)(C)C)C(=O)F

Procedure:
Prepared by the procedure of Example II by reacting t-octylthiosulfenylchloride with methylcarbamoyl fluoride. b.p. 112° C/0.5 Torr ND23 1.4960.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]([CH2:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)C(=O)C(F)(F)F)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN(CCCc2ccccc2)C(=O)C(F)(F)F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(CCCNCC2CCNCC2)cc1
Reaction time: 20 h

Procedure:
To a solution of 1.49 g (3.48 mM) of N-(3-phenylpropan-1-yl)-N-[1-tert-butoxycarbonylpiperidin-4-ylmethyl]trifluoroacetamide in ethanol (10 ml) was added 1.0 ml (12 mM) of 12N-hydrochloric acid at room temperature and the mixture was stirred for 20 hours. The solvent was then distilled off under reduced pressure and 3 ml (36 mM) of 12N-hydrochloric acid was added to the residue. This mixture was stirred at room temperature for 20 minutes. To this reaction mixture was added ethanol and the solvent was distilled off under reduced pressure to provide 1.29 g (quantitative) of a crude product as white solid. To a solution of 0.33 g (0.90 mM) of this crude product in ethanol (4 ml) was added 4 ml (4 mM) of 1N-aqueous solution of sodium hydroxide at room temperature and the mixture was stirred for 30 minutes. The ethanol was then distilled off under reduced pressure and the residue was extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:19][CH2:20]Cl)[C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH3:16].[CH3:22][N:23]1[C:27]([NH2:28])=[CH:26][CH:25]=[N:24]1>>[CH3:22][N:23]1[C:27]([N:28]2[CH2:20][CH2:19][N:4]([C:5]3[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]4[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=4[C:15]=3[CH3:16])[CH2:3][CH2:2]2)=[CH:26][CH:25]=[N:24]1
Reactant: Cn1nccc1N
Reactant: Cc1c(C)c(N(CCCl)CCCl)c(C)c2c1OC(C)(C)C2
Product: Cc1c(C)c(N2CCN(c3ccnn3C)CC2)c(C)c2c1OC(C)(C)C2
Yield: 3.7 %

Procedure:
By using N,N-bis(2-chloroethyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (660 mg, 2.0 mmol) synthesized in Reference Example 146 and 1-methyl-1H-pyrazole-5-amine (233 mg, 2.4 mmol), the reaction was carried out in the same manner as Example 117 to obtain 26 mg of the title compound as a colorless solid (yield 4%). Melting point was 126 to 128° C. (ethanol-water).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:18][C@H:17]([O:19][C:20](=[O:22])[CH3:21])[C@@H:16]([CH3:23])[O:15][C@:6]1([NH:24][C:25](=[O:28])[CH2:26]Cl)[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[P:29]([O:36]CC)([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>>[C:1]([O:4][C@H:5]1[CH2:18][C@H:17]([O:19][C:20](=[O:22])[CH3:21])[C@@H:16]([CH3:23])[O:15][C@:6]1([NH:24][C:25](=[O:28])[CH2:26][P:29]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:36])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CC(=O)O[C@H]1C[C@H](OC(C)=O)[C@@](NC(=O)CCl)(OCc2ccccc2)O[C@@H]1C
Product: CCOP(=O)(CC(=O)N[C@]1(OCc2ccccc2)O[C@H](C)[C@@H](OC(C)=O)C[C@@H]1OC(C)=O)OCC

Procedure:
Benzyl 2,4-di-O-acetyl-3,6-dideoxychloroacetamido-alpha-D-mannopyranoside, 20, 0.65 g (0.00157 mole) and triethyl phosphite (5 mL) were heated at 110°-120° C. for 4.5 h with stirring under argon. The solvent was distilled at high vacuum, 50 mg of the residue was saved, and the rest carried on.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30]>CS(C)=O.O>[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]3[C:3]=2[CH2:4][N:5]([CH3:15])[C:6]3=[O:14])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: CC(C)N1CCNCC1
Reactant: CN1Cc2c(F)ccc([N+](=O)[O-])c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To a suspension of 4-fluoro-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (5.0 g, 24 mmol) and potassium carbonate (3.32 g, 24 mmol), triethylamine (6.7 mL, 28.8 mmol) in dimethylsulfoxide (50 mL), 1-isopropyl piperazine (4.1 mL, 28.8 mmol) is added and the mixture is stirred at 60° C. for 4 hours. The mixture is poured into iced water, and the resulting brown solids are collected by filtration and dried in vacuo at 50° C. to afford 4-(4-Isopropyl-piperazin-1-yl)-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one as brown solids in 91% yield. Rf=0.14 (AcOEt). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.09 (s, 3H), 1.11 (s, 3H), 2.70 (t, 4H), 2.80-2.74 (m, 1H), 3.19 (s, 3H), 3.21 (t, 4H), 4.37 (s, 2H), 7.01 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[N:38][CH:37]=[CH:36][N:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][N:38]=[CH:39][C:34]=1[C:30]1[CH:29]=[C:28]([C:27]2[CH2:26][C:25](=[O:41])[NH:24][C:9]3[CH:10]=[C:11]([C:20]([F:22])([F:23])[F:21])[C:12]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[CH:13][C:8]=3[N:7]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M103) (0.37 g, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (220 mg, 74%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[F:1])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccccc1OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1OCc1ccccc1)c1ccncc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a mixture of 3-fluoroisonicotinic acid (2.20 g, 15.6 mmol), 2-(benzyloxy)aniline (2.84 g, 14.2 mmol) and BOP (6.94 g, 15.6 mmol) in DMF (20.0 mL) was added TEA (4.4 mL, 31.2 mmol). The reaction mixture was stirred at room temperature for 20 min and poured into water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo to a quarter volume. The resulting solid was found to be the desired compound. The filtrate was concentrated in vacuo to dryness. The residue was triturated in 30% ethyl acetate in hexanes and the 2 solids were combined to afford compound 24 (4.45 g, 97%) as a white solid. LRMS (ESI): (calc) 322.11. (found) 323.2 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].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.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:28]([N:35]1[CH2:36][CH2:37][N:38]([C:2]2[CH:3]=[C:4]([CH:8]3[N:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:39][CH2:40]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(Br)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
5-(3-Bromo-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (1.0 g, 2.20 mmol) prepared in Step 2 of Preparation 5, 1-BOC-piperazine (614.0 mg, 3.30 mmol), Pd2(dba)3 (101.0 mg, cat.), BINAP (137.0 mg, cat.) and sodium t-butoxide (380.0 mg, 4.00 mmol) were added to toluene (33.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 760.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.[CH:12]1([Mg]Br)[CH2:14][CH2:13]1.Cl.C(OCC)(=O)C>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH:6]([CH:12]2[CH2:14][CH2:13]2)[OH:7])=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1c(F)cc(Cl)cc1F
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1c(F)cc(Cl)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (11.33 mmol) of 4-chloro-2,6-difluorobenzaldehyde were dissolved in 15 ml of diethyl ether at 0° C., and 34.0 ml (16.99 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. After stirring at RT for 2 h, the reaction solution was mixed with 1N hydrochloric acid and ethyl acetate, and the phases were separated. The aqueous phase was extracted three times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.20 g (48% of theory) of the title compound were obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH3:13])[N:7]=1)=[O:5].[CH3:15][Mg]Br.[Cl-].[NH4+]>O1CCCC1.CCOCC>[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH3:13])[N:7]=1)(=[O:5])[CH3:15]
Reactant: C[Mg]Br
Reactant: CCc1cc(C(=O)N(C)OC)nn1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cc(C(C)=O)nn1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Methoxy-N-methyl-5ethyl-1-methylpyrazole-3-carboxamide (2.9 g) in dry tetrahydrofuran (100 ml), under argon was cooled to −20° C. and treated with methylmagnesium bromide (9.8 ml of a 3M solution in ether). A precipitate was initially formed that re-dissolved on complete addition. The reaction mixture was stirred at 0° C. for 2 h. and then poured into saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate and the combined organic phases washed with brine, dried over anhydrous magnesium sulphate and concentrated to a brown oil. The crude product was purified by silica gel chromatography eluting with 50% ethyl acetate/hexane to give the title compound as a pale brown oil. (1.97 g, 88%); (Found: M+, 152.0950. C8H12N2O requires M 152.0950); nmax (CH2Cl2) 1693, 1472, 1376 and 1352 cm−1; dH(CDCl3) 1.28 (3H, t, J7.4 Hz), 2.54 (3H, s), 2.61 (2H, q, J7.4 Hz), 3.84 (3H, s) and 6.56 (1H, s).
Reaction SMILES: [C:1]([C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([C:9]([NH:11][C:12]2[CH:23]=[CH:22][C:15]([CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:14][CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:30][C:31]1([Cl:38])[CH2:33][C:32]1([CH3:37])[C:34](O)=[O:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[C:1]([C:3]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:8][CH2:7][N:6]([C:9]([NH:11][C:12]2[CH:23]=[CH:22][C:15]([CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH:18][C:34]([C:32]3([CH3:37])[CH2:33][C:31]3([Cl:38])[Cl:30])=[O:35])=[CH:14][CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC1(C(=O)O)CC1(Cl)Cl
Reactant: N#CC1(c2ccccc2)CCN(C(=O)Nc2ccc(C[C@H](N)C(=O)O)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)N[C@@H](Cc2ccc(NC(=O)N3CCC(C#N)(c4ccccc4)CC3)cc2)C(=O)O)CC1(Cl)Cl
Reaction time: 3 h

Procedure:
A suspension of 4-[[(4-cyano-4-phenyl-1-piperidinyl)carbonyl]amino]-L-phenylalanine on Wang resin (0.30 g, 0.228 mmol), 2,2-dichloro-1-methylcyclopropane carboxylic acid (0.19 g, 1.14 mmol), BOP (0.50 g, 1.14 mmol) and DIPEA (0.26 mL, 1.5 mmol) in N-methylpyrrolidinone (3 mL) was agitated for 3 hr. The mixture was filtered and washed with dichloromethane and methanol. Cleavage from the resin was effected by treatment with 90% TFA in dichloromethane for 3 min. The mixture was filtered and the filtrate evaporated to give 4[[(4-cyano-4-phenyl 1-piperidinyl)carbonyl]amino]-N-[(2,2-dichloro-1-methylcyclopropyl)carbonyl]-L-phenylalanine. FAB MS m/z 543 (M+H).