Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].[P:21]([O:32]CCCC)([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:22][CH2:23][CH2:24][CH2:25][CH3:26].C(#N)C>CCOC(C)=O>[C:7]1([P:21](=[O:32])([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: CCCCOP(OCCCC)OCCCC
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCOP(=O)(OCCCC)c1ccccc1

Procedure:
2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.083 mmol), Cesium Fluoride (70 mg, 0.461 mmol), Tributyl phosphite (83 mg, 0.335 mmol), Acetonitrile (1 ml): Reaction Time: 24 h; Rf: 0.4 (1:3 EtOAc:Pet. Ether); Thick oil; 16.3 mg, 72%; 1H NMR (400 MHz, CDCl3, TMS) δ 7.80 (dd, J=6.8, 13.3 Hz, 2H), 7.55 (t, J=7.5 Hz, 1H), 7.50-7.42 (m, 2H), 4.12-3.95 (m, 4H), 1.65 (quint, J=7.3 Hz, 4H), 1.39 (sext, J=7.3 Hz, 4H), 0.9 (t, J=7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3, TMS) δ 132.3 (d, J=3.1 Hz), 131.7 (d, J=9.3 Hz), 128.4 (d, J=15.4 Hz), 128.3 (d, J=187.3 Hz), 65.8 (d, J=5.4 Hz), 32.4 (d, J=6.9 Hz), 18.7, 13.6; 31P NMR (162 MHz, CDCl3) δ 18.8; Mass (M+Na)+ 293; Known compound, Lit. X. Lu, J. Zhu, Synthesis 1987, 8, 726.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[CH3:30][NH2:31]>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([CH3:28])[C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([NH:31][CH3:30])[C:3]4=[O:29])=[CH:8][CH:9]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Reactant: CN
Product: CNC1CCN(c2ccc(N(C)C(=O)c3ccc(C4CCCCC4)cc3)cc2)C1=O

Procedure:
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with methylamine by method L. This resulted in the product with the molecular weight of 405.54 (C25H31N3O2); MS (ESI): 406 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[NH:26][C:27]4[CH:37]=[CH:36][C:35]5[C:30](=[C:31]([OH:42])[CH:32]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[CH:34]=5)[C:28]=4[N:29]=3)[CH:20]=2)[CH:15]=[CH:16][C:17]=1[CH3:18].Cl>C1COCC1.O>[CH3:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[NH:26][C:27]4[CH:37]=[CH:36][C:35]5[C:30](=[C:31]([OH:42])[CH:32]=[C:33]([S:38]([NH:1][C:2]6[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=6)[C:5]([OH:7])=[O:6])(=[O:40])=[O:39])[CH:34]=5)[C:28]=4[N:29]=3)[CH:20]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)Cl)cc(O)c54)[nH]3)c2)cc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)Nc6cccc(C(=O)O)c6)cc(O)c54)[nH]3)c2)cc1C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
To an agitated suspension of 3-aminobenzoic acid (0.028 g, 0.2 mmol) in THF (1 mL) was added 2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxyl-3H-naphtho[1,2-d]imidazole-7-sulfonyl chloride (0.083 g, 0.18 mmol) and sodium hydroxy (0.018 g, 0.4 mmol) in water (0.5 mL). After agitated for 30 minutes, the reaction mixture was added 6N hydrochloride (2 ml) and concentrated under reduced pressure. The residue was subjected to HPLC (ODS-A, gradient 10-90% CH3CN/water 0.1% TFA) to provide the title compound (0.005 g, 4%) MS(ES) m/z 564 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](\[C:17]#[N:18])/[C:13]([O:15][CH3:16])=[O:14])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C-:19]#[N:20].[K+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]([C:17]#[N:18])[C:13]([O:15][CH3:16])=[O:14])([C:19]#[N:20])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: COC(=O)/C(C#N)=C1\C(=O)Nc2cc(Cl)ccc21
Agent: [K+]
Product: COC(=O)C(C#N)C1(C#N)C(=O)Nc2cc(Cl)ccc21
Yield: 61 %

Procedure:
Following the general method as outlined for Intermediate 5, starting from methyl (2Z)-(6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)(cyano)acetate (intermediate 4) and potassium cyanide, the title compound was isolated, after evaporation, as a light brown solid in 61% yield. This was a mixture of diastereomers.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Li]CCCC.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([CH:31]=[O:32])=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:18][CH:17]=1>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([CH:31]([OH:32])[C:2]4[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=4)=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: N#Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)c2ccc3c(cnn3-c3ccc(F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To solution of 4-bromobenzonitrile (182 mg, 1.0 mmol) in 5 mL of dry THF at −78° C. was added n-BuLi (0.7 mL of 1.6 M hexanes solution, 1.1 mmol). The reaction was stirred 30 min and then 1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (240 mg, 1.0 mmol) was added and the reaction mixture was allowed to warm to RT. After 12 h, quenched with brine and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 by MPLC eluting with a 0-30% EtOAc/hexane gradient to give 180 mg (52% yield) of 4-((1-(4-fluorophenyl)-1H-indazol-5-yl)(hydroxy)methyl)benzonitrile. MS found: (M+H)+=344.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10]C)=[O:9].[H-].[Na+].I[CH2:22][CH3:23].Cl.O1CCOCC1>CN(C=O)C>[CH2:22]([N:12]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:3]1[C:2]([CH3:1])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=[CH:5][N:4]=1)[CH3:23]
Reactant: CCI
Reactant: COC(=O)c1ccnc(NC2CCOCC2)c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCN(c1nccc(C(=O)O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 3-methyl-2-[(oxan-4-yl)amino]pyridine-4-carboxylate (67 mg, 0.27 mmol) in dry DMF (1.0 ml), was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 16 mg, 0.4 mmol) in DMF (0.3 ml) at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction was then treated with iodoethane (16 μl, 0.20 mmol) and stirred for 30 minutes, and then treated again with iodoethane (16 μl, 0.20 mmol) and stirred for a further 30 minutes. The reaction mixture was added to a suspension of sodium hydride (16 mg, 0.4 mmol) in DMF (0.3 ml) at 0° C. Once addition was complete, the reaction mixture was allowed to reach room temperature and stirred for 1 hour before treating with iodoethane (2×16 μl, 0.40 mmol). The reaction mixture was stirred for a further 30 minutes. Sodium hydride (16 mg, 0.4 mmol) was added to the reaction mixture and the mixture stirred for 45 minutes before treating with iodoethane (2×16 μl, 0.40 mmol) and stirred for 15 minutes before adding under nitrogen to a solution of 4M HCl/dioxane (5.0 ml) with cooling.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[Cl-].[NH4+].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C=C[Mg]Br
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c2[nH]ccc12
Temperature: -50 °C
Reaction time: 2 h

Procedure:
A solution of 5.21 g of 1-chloro-4-methyl-2-nitrobenzene in 150 mL of THF was cooled to −50° C. To the solution was added 95 mL of 1 M vinylmagnesium bromide solution in THF while the inner temperature was kept at −30° C. or lower, and the resulting mixture was stirred at −50° C. for 2 hours. To the solution, 100 mL of the saturated aqueous ammonium chloride solution and 100 mL of 1 M hydrochloric acid were added, then the resulting mixture was warmed to room temperature and stirred for 15 minutes, and then extracted twice with 100 mL of ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:9) to obtain 2.69 g of 7-chloro-4-methylindole as a brown oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([CH2:21][NH:22][CH3:23])[S:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].CCN(CC)CC.[N+:31]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)([O-:33])=[O:32].O>C(Cl)Cl>[C:2]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([CH2:21][N:22]([CH3:23])[CH2:38][C:37]3[CH:40]=[CH:41][C:34]([N+:31]([O-:33])=[O:32])=[CH:35][CH:36]=3)[S:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:1]
Reactant: CNCc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cs1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc([N+](=O)[O-])cc1)Cc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cs1
Yield: 63.3 %

Procedure:
To a cold solution of 1.1 g (3.31 mmol) of 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanamine (Intermediate 58.3) and 0.7 ml (4.96 mmol) of Et3N in 50 ml CH2Cl2 was added portionwise 1.07 g (4.96 mmol) of 4-nitrobenzylbromide. After ovemight stining, another portion (0.35 g; 1.65 mmol) of 4-nitrobenzylbrornide was added. Twenty four hours later, the reaction mixture was poured into 100 ml of cold water and diluted with 50 ml CH2Cl2. The organic layer was decanted, washed with brine, dried over MgSO, and filtered. The solvent was eliminated under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (1/1) as eluent. The pure fractions were collected and concentrated to yield 0.98 g (63%) of a yellow solid. Melting point: 111.4-11.7° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].F[C:10]1[CH:15]=[CH:14][C:13]([S+:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[OH-].[Na+].[CH3:31][SH:32]>ClCCl>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:31][S:32][C:26]1[CH:25]=[CH:24][C:23]([S+:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=2)=[CH:28][CH:27]=1
Reactant: Fc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reactant: CS
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CSc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
26.7 g of 4-fluorophenyl diphenylsulfonium trifluoromethanesulfonate was dissolved in 200 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 200 g of 10 wt % sodium hydroxide aqueous solution and 6.71 g of methane thiol were added. The mixture was stirred for 30 minutes at room temperature and transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the mixture was shaken again and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried using anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 19.8 g of 4-methylthiophenyl diphenylsulfonium trifluoromethane sulfonate.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH2:29]([O:31][C:32]1[N:37]=[N:36][C:35]([NH2:38])=[C:34]([CH3:39])[C:33]=1[CH3:40])[CH3:30].C(N(CC)C(C)C)(C)C>C(#N)CCC>[CH2:29]([O:31][C:32]1[C:33]([CH3:40])=[C:34]([CH3:39])[C:35]2[N:36]([C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:12][CH2:13][CH2:14]4)=[CH:7][CH:6]=3)[N:38]=2)[N:37]=1)[CH3:30]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: CCOc1nnc(N)c(C)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Product: CCOc1nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)c1C
Temperature: 125 °C
Yield: 70 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example Int-1-A] (300 mg, ˜80% purity, 0.540 mmol, 1.0 eq), 6-ethoxy-4,5-dimethylpyridazin-3-amine (that was prepared in a manner analgous to that described for Intermediate Example Int-36, Step 1, 124 mg, ˜80% purity, 0.590 mmol, 1.1 eq) and N,N-diisopropylethylamine (100 μL, 0.590 mmol, 1.1 eq) in butyronitrile (3.3 mL) was heated for 3.5 hours at 125° C. On cooling the reaction mixture was concentrated in vacuo. The crude mixture was purified via preparative MPLC (Biotage Isolera; 50 g SNAP-cartridge: hexane/EtOAc 9/1→hexane/EtOAc 1/1) to give 220 mg (70% yield) of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:29]=[CH:28][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C@@H:19]3[CH2:23][O:22]C(C)(C)[O:20]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C@@H:19]([OH:20])[CH2:23][OH:22])=[CH:15][CH:14]=2)=[CH:28][CH:29]=1
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCOc3ccc(CCCBr)cc3)cc2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: OC[C@H](O)COc1ccc(CCCOc2ccc(CCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-4-(4-{3-[4-(3-bromo-propyl)-phenoxy]-propyl}-phenoxymethyl)-2,2-dimethyl-[1,3]dioxolane (5.0 g, 10.8 mmol) in DCM (50 mL) is added TFA (2.0 mL, 26.9 mmol) dropwise followed by water (2.0 mL) and the reaction mixture is stirred at RT overnight. The solvent is removed in vacuo and the residue is treated with aqueous sodium hydrogen carbonate solution. The mixture is extracted with EtOAc (3×200 mL) and the combined organic portions are washed with water, brine, dried over Na2SO4 and concentrated in vacuo. Recrystallizisation of the residue from diethyl ether-hexane affords the title compound as white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N:12]2[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=3)[C:13]2=[O:28])[CH:9]=[CH:8][C:7]=1[O:29][C:30]([F:33])([F:32])[F:31])=[O:4].[CH3:40][N:41]([CH3:45])[C:42]([NH2:44])=[O:43].CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N:12]2[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:44][C:42](=[O:43])[N:41]([CH3:45])[CH3:40])[CH:22]=3)[C:13]2=[O:28])[CH:9]=[CH:8][C:7]=1[O:29][C:30]([F:33])([F:32])[F:31])=[O:4]
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(NC(=O)[C@H](N)c3ccccc3)c2)C(=O)N1Cc1ccnc(Cl)c1
Reactant: CN(C)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: C1COCCO1
Product: CN(C)C(=O)Nc1cc(CN2C(=O)N(c3ccc(OC(F)(F)F)c(NC(=O)[C@H](N)c4ccccc4)c3)C(=O)C2(C)C)ccn1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 150 mg of (2R)-2-amino-N-[5-{3-[(2-chloropyridin-4-yl)methyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-(trifluoromethoxy)phenyl]-2-phenylacetamide obtained in stage d) of Example 5a in 10 mL of dioxane are successively added, under argon, 30 mg of N,N-dimethylurea, 13 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (Xantphos), 5 mg of palladium acetate and 280 mg of caesium carbonate. The reaction mixture is refluxed for 1 hour and then filtered, and the filtrate is concentrated under reduced pressure. The residue is taken up in 10 mL of dioxane, 5 mL of a 4N solution of hydrogen chloride in dioxane are then added and the reaction mixture is stirred at 40° C. for 1 hour. After concentrating under reduced pressure, the residue is purified by HPLC (gradient: water/acetonitrile containing 0.1% formic acid) to give 45 mg of ((2R)-2-amino-N-{5-[3-({2-[(dimethylcarbamoyl)amino]pyridin-4-yl}methyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethoxy)phenyl}-2-phenylacetamide, the characteristics of which are as follows:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[Cl:14])=[O:4].[I-].[K+].[N-:17]=[N+:18]=[N-:19].[Na+].CN(C)C=O>O>[N:17]([CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[Cl:14])=[O:4])=[N+:18]=[N-:19]
Reactant: Cc1cc(C)c(NC(=O)CCl)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(NC(=O)CN=[N+]=[N-])c(Cl)c1
Temperature: 50 °C

Procedure:
A mixture of 2-Chloro-N-(2-chloro-4,6-dimethyl-phenyl)-acetamide (0.100 g, 0.00043 mol), potassium iodide (0.0072 g, 0.00043 mol), sodium azide (0.056 g, 0.00086 mol), and anhydrous dimethylformamide (7 mL) was heated in a 50° C. oil bath for 4 h. Upon cooling to room temperature, the reaction mixture was cooled to 0° C., water (10 mL) was added, and the solid product was collected by suction filtration, washed several times with water, and placed in a vacuum oven set at low heat for 4 h. The dried product amounted to 0.0934 g (0.391 mmol, 91%). 1H NMR (CDCl3, 300 MHz) δ 7.70 (br s 1H), 7.12 (s, 1H), 6.98 (s, 1H), 4.2 (s, 2H), 2.3 (s, 3H), 2.23 (s, 3H). LC/MS: tR=1.23 min., (MH+)=239.06.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[C-:11]#[N:12].[K+]>C(#N)C.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[N:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: ClCCCc1ccncc1
Reactant: [C-]#N
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: N#CCCCc1ccncc1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
To the product of Example 21 (6.7 g, 42.9 mmol) in 300 mL of acetonitrile (CH3CN), was added potassium cyanide (KCN, 11.2 g, 171.7 mmol) and dibenzo-18-crown-6 (1.0 g, 2.8 mmol). After the reaction had been refluxed for 18 hours, it was cooled to room temperature, and stripped of all solvent under reduced pressure. The residue was partitioned between 100 mL each of water and CH2C2 and the aqueous phase was washed with 3×100 mL of CH2Cl2. The combined organic phase was dried (Na2SO4), filtered, and stripped of solvent to yield 6.7 g of crude product. This material was purified by HPLC on silica gel to yield 5.3 g of the title material as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:33]=1[O:40][CH3:41])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:33]=2[O:40][CH3:41])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(OC)c1OC
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC)c2OC)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.5 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (600 mg, 0.003 mol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (1.80 g, 0.014 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,3-dimethoxy-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-dimethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (430 mg, 33%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:28]=[CH:27][CH:26]=[C:11]([CH:12]=[C:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1Oc1cccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cccnc1Oc1cccc(C=C2CCNCC2)c1

Procedure:
tert-Butyl 4-(3-(3-methylpyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (3.9 g, 10 mmol) from Step 4 was dissolved in CH2Cl2 (50 mL) and treated with HCl in dioxane (20 mL, 4.0 M, 80 mmol). After 16 h the reaction was concentrated in vacuo to provide the title compound as a white solid (3.6 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1.C(N(CC)CC)C.O>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1)=[O:12]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1csc(NC(=O)c2ccc3ccccc3c2)n1
Reaction time: 16 h

Procedure:
4.7 g (24.9 mmol) of 2-naphthoyl chloride, dissolved in 50 ml of anhydrous tetrahydrofuran, were added dropwise at 0° C. to 4 g (23.3 mmol) of ethyl 2-aminothiazole-4-carboxylate and 6.4 ml (46.5 mmol) of triethylamine in 150 ml of anhydrous tetrahydrofuran. The entire mixture was then stirred for 16 h. The reaction solution was then poured into plenty of water and extracted with ethyl acetate. The organic phase was then washed with aqueous sodium hydrogencarbonate solution, dried and concentrated in vacuo. The residue was purified by chromatography (eluent: methylene chloride), 5.6 g (82%) of the product being obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:28]1([S:34][CH2:35][C:36](Cl)=[O:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:28]1([S:34][CH2:35][C:36]([NH:14][NH:13][C:11]([N:10]2[CH2:9][C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]2=3)=[O:12])=[O:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)CSc1ccccc1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CSc1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
To a stirred mixture of 5.89 g of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide (see U.S. Pat. No. 3,534,019) and 2.8 ml of triethylamine in 50 ml of cold (ca. 0° ) dichloromethane was slowly added 3.8 g of the title product of Example 1. The mixture was then stirred for twenty hours at room temperature. The solution was then washed three times with 50-ml portions of water, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound, m.p. 172°-175°.