Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: COc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(NC(=O)C=Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A solution of cinnamoyl chloride (4.25 g, 25.6 mmol) in acetone (25 mL) was added to a solution of 3-methoxyaniline (2.74 mL, 24.4 mmol) and anhydrous K2CO3 (3.7 g, 26.8 mmol) in acetone-ice (28 mL-28 g) and the resulting reaction mixture was stirred at rt for 3 h. The reaction mixture was then poured into ice water, filtered, and washed with water. Recrystallization from EtOH gave N-(3-methoxyphenyl)cinnamamide (intermediate 13) (4.56 g, 74%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:24](=[O:25])[NH:23][N:22]=[CH:21][C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[NH:12][C:13]([CH:14]=1)=[C:9]23)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([NH:39][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:24](=[O:25])[NH:23][N:22]=[CH:21][C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[NH:12][C:13]([CH:14]=1)=[C:9]23)=[O:4])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cn1cc(-c2[nH]c3cc(NC(=O)CCl)cc4c3c2C=NNC4=O)cn1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2[nH]c3cc(NC(=O)CNCc4ccccc4)cc4c3c2C=NNC4=O)cn1
Temperature: 50 °C
Yield: 12.5 %

Procedure:
To a solution of 2-Chloro-N-[2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-acetamide 270(a) (100 mg, 0.28 mmol) in DMF (1.5 mL) was added Cs2CO3 (˜5 eq.) followed by benzyl amine (33 mg, 0.3 mmoL). The resulting mixture was heated at 50° C. overnight. Excess Cs2CO3 was filtered and the clear dark solution was purified by reverse phase HPLC to afford 15 mg of desired product as yellow solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[O:8])=[CH:5][C:4]=1[O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=1.[OH:35]O>C(O)(=O)C.O>[CH3:34][S:33]([C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][O:24][C:4]2[CH:5]=[C:6]([CH:22]=[CH:23][C:3]=2[O:2][CH3:1])[C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18]2)=[O:8])[CH:32]=[CH:31][CH:30]=1)=[O:35]
Reactant: OO
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(SC)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(S(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of example 16 (35 mg, 0.078 mmol) was dissolved in acetic acid (2.5 ml), hydrogen peroxide (43 mg of a 30% solution in water, 0.38 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was partitioned between EA and a 1% aqueous sodium sulfite solution, the aqueous phase extracted with EA, and the combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness to give 36 mg of the title compound.
Reaction SMILES: C([O:8][C:9](=[O:28])[CH2:10][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][C:13]1([O:19][CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)C1C=CC=CC=1.[Li+].[OH-]>C1COCC1.O>[C:24]([O:23][C:21]([N:11]([CH2:12][C:13]1([O:19][CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][C:9]([OH:28])=[O:8])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC1(CN(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC1(CN(CC(=O)O)C(=O)OC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.2 %

Procedure:
The latter ester (1.25 g) was dissolved in THF/H2O (3:2,25 mL). After LiOH (0.30 g, 12.9 mol) was added, the mixture was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure. H2O (13 mL) was added to the residue. The resulting solution was washed with EtOAc, rendered acidic by the addition of aqueous 1M HCl and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4) and concentrated to dryness to give the acetic acid derivative, 2-{tert-butyloxycarbonyl[(1-methoxycyclohexyl)methyl]amino}acetic acid (0.56 g, 72% yield from 1-methoxycyclohexanemethanamine); 1H NMR(CDCl3) δ4.04 (s,0.6H), 3.94 (s,1.4H), 3.41 (s,1.4H), 3.35 (s,0.6H), 3.23 (s,1.9H), 3.18 (s,1.1H), 1.78-1.22 (m,20H); FAB mass spectrum, m/z: 302 (M+H)+.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:25][N:24]=[C:23]([C:26](=O)[C:27]([OH:29])=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][CH2:32][O:33][NH2:34].[OH-].[Na+]>C(O)C.O>[C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:34]/[O:33][CH2:32][F:31])/[C:27]([OH:29])=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C(=O)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NOCF
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)/C(=N\OCF)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
2-(5-Tritylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid (1 g) was added to a mixture of a solution of fluoromethoxyamine (0.58 g) in ethanol (25 ml) and water (0.45 ml). After adjusting the pH of the resulting mixture to 4-5 with a 10% aqueous solution of sodium hydroxide, the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, followed by addition of water (20 ml) and sodium chloride (10 g) to the residue. The pH of the resulting solution was adjusted to 1 with concentrated hydrochloric acid. The solution was extracted four times with ethyl acetate (30 ml). After washing the extract with saturated saline, anhydrous magnesium sulfate was added to the extract to dry the same. The dry was distilled off and the residue was crystallized from a 1:10 mixture of acetone and isopropyl ether, thereby obtaining the target product (0.55 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NC3CC3)cc2c1=O
Yield: 31 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with cyclopropylamine according to the GPA affording 10 mg (31%) of a red powder. Rt=3.15 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][S:17]([CH3:16])(=[O:19])=[O:18])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OC(CO)CN1c1cccc(F)c1
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of alcohol 92 (6.33 g, 30.0 mmol) in CH2Cl2 (60 mL) was treated with TEA (6.07 g, 8.36 mL, 60 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled to 0–5° C. before MsCl (3.78 g, 2.55 mL, 33.0 mmol, 1.1 equiv) was dropwise introduced into the reaction mixture at 0–5° C. under N2. The resulting reaction mixture was subsequently stirred at 0–5° C. for 1 h under N2. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was quenched with H2O (40 mL) and CH2Cl2 (40 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (40 mL). The combined organic extracts were washed with H2O (2×40 mL) and saturated aqueous NaCl (40 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5R)-methanesulfonic acid 3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester (mesylate 97, 7.69 g, 88.7% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C11H12FNO5S, LCMS (EI) m/e 290 (M++H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Cl.[NH2:9][C:10](OCC)=[CH:11][C:12](OCC)=[O:13].CC[O-].[Na+]>C(O)C>[NH2:9][C:10]1[NH:7][C:5](=[O:6])[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:12](=[O:13])[CH:11]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NC(=O)NC1CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(=O)n(C2CC2)c(=O)[nH]1
Yield: 55.9 %

Procedure:
A solution of cyclopropyl urea (10 g, 100 mmol, 1 eq) and ethyl 3-amino-3-ethoxy-acrylate HCl (19.55 g, 100 mmol, 1 eq) in Ethanol (125 ml) was heated at 75° C. for 2 hours. To this solution was added 2 equivalents of NaOEt then heated for an additional one hour. Solvent was evaporated, water (50 ml) was added then acidified via concentrated HCl to pH of 4-5. The resulting precipitate was obtained by filtration and washed with cold water to give the desired product (9.35 g, 56%) after vacuum dried overnight at 40° C.: The desired isomer was determined via 2D-NMR; 1H NMR (400 MHz, DMSO-d6) δ 10.18 (1H), 6.10 (2H), 4.44 (1H), 2.38 (1H), 0.85 (2H), 0.62 (2H); m/z (ES+) 168.17
Reaction SMILES: [C:1]1([S:7]([CH2:10][C@H:11]([NH2:13])[CH3:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:22][C@@H:23]1[C@H:27]([O:28]C(=O)C2C=CC=CC=2)[C@@H:26]([CH2:37][O:38]C(=O)C2C=CC=CC=2)[O:25][C@H:24]1[N:47]1[CH:55]=[N:54][C:53]2[C:48]1=[N:49][C:50]([Cl:57])=[N:51][C:52]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[Cl:57][C:50]1[N:51]=[C:52]([NH:13][C@H:11]([CH3:12])[CH2:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[C:53]2[N:54]=[CH:55][N:47]([C:48]=2[N:49]=1)[C@@H:24]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:28])[C@H:23]1[OH:22]
Reactant: C[C@@H](N)CS(=O)(=O)c1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H](CS(=O)(=O)c1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.3 %

Procedure:
(R)-1-Phenylsulphonyl-2-propylamine (0.4 g, 1.7 mmol) was reacted with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.7 g, 1.0 mmol) in dioxan (20 ml) in the presence of triethylamine (0.4 g, 4.3 mmol). The reaction mixture was stirred at room temperature for 48 h, heated at 60° C. for 4 h, cooled, filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-chloro- N-[(R)-1-phenylsulphonyl-2-propyl]adenosine (after column chromatography) as a foam (0.2 g, 24%), 1H NMR (DMSO-d6)δ 1.24 (3H, d, --CH3), 3.45 (1H, dd, --C--H), 3.53-3.61 (2H, m, H-5'a and --C--H), 3.64-3.71 (1H, m, H-5'b), 3.86 (1H, dd, --C--H), 3.97 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.53 (1H, m, H-2'), 5.09 (1H, t, 5'-OH), 5.23, 5.50 (2H, 2 d, 2' and 3'-OH), 5.83 (1H, d, H-1'), 7.45-7.82 (5H, m, Ar--H), 8.21 (1H, s, --N--H), 8.38 (1H, s, H-8).
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][N:11]=[C:12]([C:17](=[O:21])[CH2:18][O:19][CH3:20])[C:13]([O:15][CH3:16])=[O:14].[CH3:23]OC(OC)N(C)C>>[F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:23]=[C:18]([O:19][CH3:20])[C:17](=[O:21])[C:12]([C:13]([O:15][CH3:16])=[O:14])=[N:11]1
Reactant: COCC(=O)C(=NNc1ccccc1OC(F)F)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2ccccc2OC(F)F)cc(OC)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
A solution of methyl 2-{[2-(difluoromethoxy)phenyl]hydrazono}-4-methoxy-3-oxobutanoate (8.70 g, 27.5 mmol) in N,N-dimethylformamide dimethyl acetal (60 mL) was refluxed for 3 h and stirred at room temperature for 3 days. The precipitate was collected by filtration and washed with hexane/AcOEt (3/1) to give the title compound (7.92 g, 88% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.89 (3H, s), 3.96 (3H, s), 6.55 (1H, d, J=72.7 Hz), 7.35-7.45 (2H, m), 7.49-7.56 (1H, m), 7.61 (1H, dd, J=7.9, 1.5 Hz), 7.73 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>C(O)C.O>[Na+:18].[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:13][CH2:14][C:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C([O-])CNc1cc(Cl)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 58.4 %

Procedure:
To a stirred solution of 1-chloro-2,5-difluoro-4-nitrobenzene (0.825 g, 4.26 mmol) in ethanol (8.0 mL), was added a solution of sodium glycinate (0.415 g, 4.27 mmol) in water (1.5 mL). The resulting suspension was refluxed for 60 h. The solution was cooled to room temperature and the precipitated bright orange solid was filtered, washed with cold ethanol (5 mL), and dried under vacuum to give 0.673 g (64%) title compound as a bright orange powder; 1H NMR (DMSO-d6) δ 3.50 (d, 2H, J=3.6 Hz), 7.04 (d, 1H, J=6.6 Hz), 8.01 (d, 1H J=9.9 Hz), 8.74 (s, 1H). The unreacted 1-chloro-2,5-difluoro-4-nitrobenzene was recovered almost quantitatively from the filtrate.
Reaction SMILES: Br[C:2]1[C:3]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[NH:17][N:16]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:23]([Sn](CCCC)(CCCC)/C=C/C)[CH2:24][CH2:25]C>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH:20]1([C:18]2[NH:17][N:16]=[C:15]([NH:14][C:3]3[C:2](/[CH:23]=[CH:24]/[CH3:25])=[CH:7][N:6]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:4]=3)[CH:19]=2)[CH2:22][CH2:21]1
Reactant: C/C=C/[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1COCCO1
Product: C/C=C/c1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1

Procedure:
The mixture of 5-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylpyrimidin-4-amine (0.3 g, 0.84 mmol, 1.0 equiv.), (E)-tributyl(prop-1-enyl)stannane (0.5 g, 1.5 mmol, 1.5 eq), Bu4NBr (0.32 g, 0.84 mmol, 1.0 eq), Pd(PPh3)2Cl2 (0.1 g, 0.034 mmol, 0.04 eq) and dioxane (10 mL) was heated to reflux for 18 h. Then, silica gel was added to the reaction mixture and evaporated to dry. The residue was purified by silica gel chromatography (hexane/EtOAc/Et3N=100:100:1 as eluent) to generate (E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenyl-5-(prop-1-enyl)pyrimidin-4-amine (Compound 11) (0.1 g, 37.5%). LC-MS (m/z): 357.2 [M+H]+. 1H NMR (300 MHz, DMSO-d6): δ 0.71-0.72 (m, 2H), 0.94-1.02 (m, 2H), 1.74-1.80 (m, 3H), 1.87-1.96 (m, 1H), 5.98 (d, J=11.4 Hz, 1H), 6.48 (d, J=11.4 Hz, 1H), 7.47-7.49 (m, 3H), 8.24-8.32 (m, 2H), 8.71 (s, 1H), 12.12 (s, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[CH:39]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:40]([O:42][CH3:43])=[O:41]>CN(C=O)C>[C:44]1([CH:39]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)[C:40]([O:42][CH3:43])=[O:41])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Yield: 83.2 %

Procedure:
A mixture of intermediate (2) (0.007 mol) and Na2CO3 (0.007 mol) in DMF (50 ml) was stirred. Methyl 2-bromo-2-phenylacetate (0.007 mol) was added dropwise. The mixture was stirred for 4 hours. The solvent was evaporated. The residue was dissolved in DCM. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was triturated in 2-propanol. The precipitate was filtered off and dried, yielding 3.34 g of methyl α-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-1-piperazineacetate (intermediate 3).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH3:21])/[C:16]([O:18]CC)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:39])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]>C(O)C.O1CCCC1>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH3:21])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:39])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)OCC)cc2OCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)O)cc2OCCCC)c1
Temperature: 50 °C
Yield: 73.2 %

Procedure:
40 mg (1.1 mmol) of sodium hydroxide are added to a solution of 552 mg (1.1 mmol) of ethyl (E)-3-[2-butoxy-3′-(1-methyl-3-heptylureido)biphenyl-4-yl]-2-methylacrylate in 1 mL of ethanol and 10 mL of tetrahydrofuran. The reaction mixture is heated at 50° C. for 24 hours. The reaction medium is evaporated to dryness, taken up in water and acidified with aqueous 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. After filtration, the solvent is evaporated off and the oil obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture and then precipitated from heptane. 387 mg (85%) of (E)-3-[2-butoxy-3′-(1-methyl-3-heptylureido)biphenyl-4-yl]-2-methylacrylic acid are obtained in the form of a white powder with a melting point of 70-72° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[N:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1.O.NN>C(O)C>[F:1][C:2]1[C:7]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccn(Cc2cccnc2F)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccn(Cc2cccnc2F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of Intermediate 46 (180 mg, 0.558 mmol) and hydrazine monohydrate (FLUKA, 0.035 mL, 1.117 mmol) in ethanol (10 mL) was stirred at room temperature for 4 h. Precipitate was filtered and washed with DCM. Filtrate was evaporated to dryness. Residue was purified by silica column chromatography using a linear gradient of DCM/MeOH as eluents to yield the title compound (102 mg, 0.53 mmol, 95% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.15 (m, 1H), 7.57-7.62 (m, 1H), 7.45 (d, 1H), 7.29-7.33 (m, 1H), 5.41 (d, 1H), 5.08 (s, 2H), 4.62 (br s, 2H). [ES+MS] m/z 193 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH:19]1[CH2:28][OH:29].Cl>>[O:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH:19]1[CH2:28][O:29][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc2ccccc2nc1N1CCNCC1
Reactant: OCC1CCc2ccccc2O1
Agent: Cl
Product: c1ccc2c(c1)CCC(COc1nc3ccccc3nc1N1CCNCC1)O2
Yield: 23 %

Procedure:
The title product was prepared according to the procedure described in Example 162, Step 2, starting from 2-chloro-3-(1-piperazinyl)quinoxaline (described in Example 162. Step 1) and 3.4-dihydro-2H-chromen-2-ylmethanol.* The product was obtained as a yellow amorphous substance yield 23%; mp 202-204° C.; HRMS m/z calcd for C13H16N4O2 (M)+ 376.1899, found 376.1899. Anal. (C22H24N4O2 . HCl) H; C: calcd, 61.32; found, 60.7; N: calcd, 13.00; found 13.5.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[N:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[CH:26][CH:25]=[N:24]1>>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:7][N:6]2[CH:8]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(Br)ccc2n1
Reactant: c1cn[nH]c1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(-n3cccn3)ccc2n1
Yield: 16 %

Procedure:
As described for Example 60, 6-bromo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine (70.8 mg, 0.2 mmol) instead of 6-iodo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine was converted, using pyrazole instead of benzamide, to the title compound (11 mg, 16%) which was obtained as a light yellow gum. MS: m/e=342.3 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][Si:7]([CH3:22])([CH3:21])[O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][CH2:2][C:3]([N:12]1[CH2:13][C@H:9]([O:8][Si:7]([CH3:21])([CH3:22])[CH3:6])[CH2:10][C@H:11]1[C:14]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)CCl
Temperature: 0 °C
Yield: 96.1 %

Procedure:
A solution of chloroacetyl chloride (1.0 mL, 12.6 mmol) in 1 mL of dichloromethane was added slowly into a stirred solution of trimethylsilyl (2S,4R)-4-(trimethylsilyoxy)pyrrolidine-2-carboxylate (3.62 g, 13.1 mmol) [which was contaminated with trimethylsilyl (2R,4R)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate in about 20% content] and di(isopropyl)ethylamine (3 ml, 17.2 mmol) in 100 mL of dry dichloromethane cooled on an ice bath. An additional 1.0 ml of di(isopropyl)ethylamine was added and the mixture was stirred an additional 30 minutes on the ice bath. The reaction solution was then evaporated to dryness by a vacuum pump. The residue was slurried in pentane and filtered. The filtrate was then evaporated by a vacuum pump to yield 4.26 g (96% crude yield) of crude trimethylsilyl (2S,4R)—N-chloroacetyl-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate as an oil, which solidified upon cooling.