Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N+:15]=3[O-])[C:7]=2[CH:21]=1)#[N:2].CC1(C)CC(C2C=CC=CN=2)C2C=C(C(O)=O)C=CC=2O1.IC1N=CC=CN=1>C(N(CC)CC)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:10]([CH3:13])([O:11][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:21][CH:7]=1)[C:9]#[C:8][C:14]1[N:15]=[CH:16][CH:17]=[CH:18][N:19]=1
Reactant: CC1(C)CC(c2nccc[n+]2[O-])c2cc(C#N)ccc2O1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC1(C)CC(c2ccccn2)c2cc(C(=O)O)ccc2O1
Solvent: CCN(CC)CC
Product: CC(C)(C#Cc1ncccn1)Oc1ccc(C#N)cc1

Procedure:
The 3,4-dihydro-2,2-dimethyl-4-(2-pyrimidinyl)-2H-1-benzopyran-6-carbonitrile used as the starting material was prepared as follows: (A) 0.63 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile, 0.75 g of 2-iodopyrimidine, 18 mg of triphenylphosphine, 12 mg of palladium(II) chloride and 3.5 mg of copper(I) iodide were stirred overnight in 20 ml of triethylamine under nitrogen. The mixture was evaporated to dryness and then ethyl acetate and water were added. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:3) and subsequently ethyl acetate/petroleum ether (1:1) for the elution. There were obtained 580 mg of 4-[1,1-dimethyl-3-(2-pyrimidinyl)-2-propynyloxy]benzonitrile as an oil. (B) 580 mg of 4-[1,1-dimethyl-3-(2-pyrimidinyl)-2-propynyloxy]benzonitrile were heated at reflux for 3 hours in 20 ml of dichlorobenzene. The solution was allowed to cool and was then evaporated to dryness. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) and subsequently ethyl acetate/petroleum ether (1:1) for the elution. There was obtained 361 mg of 2,2-dimethyl-4-(2-pyrimidinyl)-2H-1-benzopyran-6-carbonitrile which melted at 108°-109.5° C. after recrystallization from tert-butyl methyl ether. (C) 1.0 g of 2,2-dimethyl-4-(2-pyrimidinyl)-2H-1-benzopyran-6-carbonitrile was dissolved in 100 ml of ethanol, added to 10% palladium-on-charcoal and shaken under an atmosphere of hydrogen at room temperature. After 2 hours the catalyst was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:1) for the elution. The product was recrystallized from cyclohexane to give 0.5 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyrimidinyl)-2H-1-benzopyran-6-carbonitrile of melting point 109°-111° C.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N+:19]([C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=[CH:18][C:9]=1[NH:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCCC2
Reactant: N#Cc1cccc(N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(Nc2ccc3c(c2[N+](=O)[O-])CCCC3)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
An anhydrous toluene (30 mL) suspension of 1-nitro-5,6,7,8-tetrahydronaphthalen-2-yl triflate (1.95 g, 6.00 mmol), 3-aminobenzonitrile (1.06 g, 9.00 mmol), potassium carbonate (830 mg, 6.00 mmol), tetrakis(triphenylphosphine)palladium (346 mg, 0.30 mmol), and triphenylphosphine (158 mg, 0.60 mmol) was stirred at 110° C. for 18 hours. The reaction mixture was cooled on standing, and filtered. The filtrate was diluted with ethyl acetate. The obtained organic solution was washed with purified water, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give the titled compound as orange powder (1.515 g, yield 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:19])[C:12]([CH3:18])=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)(C(Cl)=O)=O.CN(C=O)C.[NH2:31][C:32]1[C:33]([F:40])=[C:34]([OH:39])[CH:35]=[CH:36][C:37]=1[F:38].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.O>[F:40][C:33]1[C:34]([OH:39])=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[NH:31][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH:10]=[C:11]([CH3:19])[C:12]=1[CH3:18]
Reactant: Cc1cc(-c2ccc(F)c(F)c2)cc(C(=O)O)c1C
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2ccc(F)c(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2F)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
To a solution of 5-(3,4-difluorophenyl)-2,3-dimethyl-benzoic acid (395 mg, 1.51 mmol, 1.1 eq) in CH2Cl2 (5 mL) was added (COCl)2 (521.6 mg, 4.11 mmol, 3.0 eq) dropwise at 0° C. DMF (10 mg, 0.14 mmol, 0.1 eq) was added and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to remove the solvent and excess reagent. The residue obtained was dissolved in THF (4 mL) and added dropwise to a mixture of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (198 mg, 1.37 mmol, 1.0 eq) and NaHCO3 (575 mg, 6.85 mmol, 5.0 eq) in THF (4 mL) at 0° C. After addition was completed the reaction mixture was stirred at room temperature for 30 min. Water was added and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with saturated NaHCO3, water and brinc, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 10:1 to 4:1) to give the title compound as a white solid (100 mg, 19%).
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.[N:23]1([CH2:29][CH2:30][N:31]2[CH:39]=[C:38]3[C:33]([CH:34]=[C:35]([NH2:40])[CH:36]=[CH:37]3)=[N:32]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.N1(CCN2C=C3C(C=CC(N)=C3)=N2)CCOCC1>>[CH3:22][N:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[N:4]2[C:5]([CH:6]=[N:7][C:2]([NH:40][C:35]3[CH:36]=[CH:37][C:38]4[C:33]([CH:34]=3)=[N:32][N:31]([CH2:30][CH2:29][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:39]=4)=[N:3]2)=[CH:8][CH:9]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: Nc1ccc2cn(CCN3CCOCC3)nc2c1
Reactant: CN(c1ccccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Agent: Nc1ccc2nn(CCN3CCOCC3)cc2c1
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc4cn(CCN5CCOCC5)nc4c3)nn12)S(C)(=O)=O

Procedure:
Following the procedure of Example 1315, N-[2-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (105 mg, 0.330 mmol) was coupled in parallel fashion to 2-(2-morpholin-4-yl-ethyl)-2H-indazol-6-ylamine (57 mg, 0.23 mmol) and 2-(2-morpholin-4-yl-ethyl)-2H-indazol-5-ylamine (57 mg, 0.23 mmol). Products were purified by RP pHPLC as described in Example 1291c. Yield of TFA salt: 51 mg (46%); LC/MS: 547 (M+H); HPLC: 97% pure, RT=2.20 min; 1H NMR: (DMSO, δ) 9.53 (s, 1H), 9.01 (s, 1H), 8.31 (d, J=7.6, 1H), 8.13 (d, J=7.9, 1H), 8.11 (s, 1H), 7.68 (d, J=7.8, 1H), 7.60 (m, 3H), 7.23 (d, J=8.9, 1H), 7.04 (d, J=4.8, 1H), 6.98 (d, J=4.8, 1H), 4.81 (t, J=5.9, 2H), 3.85 (m, 4H), 3.76 (m, 2H), 3.35 (m, 4H), 3.13 (s, 3H), 2.91 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1)C(=O)C.[OH-].[K+]>C(O)C>[CH3:1][NH:2][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1
Reactant: CC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNc1cccc(-c2ccc3nnc(C)n3n2)c1

Procedure:
A mixture of 13.5 g of -N-methyl-N-[3-(3-methyl-1,2,4-triazolo[4,3-b]-pyridazin-6-yl)phenyl]acetamide and 10 g of potassium hydroxide in 500 ml of ethanol was heated to reflux for 12 hours. The solution was concentrated in vacuo and the residue partitioned between 200 ml of brine and 300 ml dichloromethane. The aqueous layer was extracted with 150 ml portions of dichloromethane. The combined organic layer and extracts were dried, concentrated in vacuo and the residue recrystalized from dichloromethanehexane, to give 11.66 g of yellow crystals, mp 223°-226° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH:7]([F:9])[F:8])[C:5]([CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=1[F:19].C(=O)([O-])[O-].[K+].[K+].Cl[N:27]1[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[NH:28]1>CN(C)C=O>[Cl:1][C:2]1[N:6]([CH:7]([F:8])[F:9])[C:5]([CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[C:15]([O:17][N:27]2[N:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[NH:32]2)[C:14]([Cl:18])=[CH:13][C:12]=1[F:19]
Reactant: Cc1nc(-c2cc(O)c(Cl)cc2F)c(Cl)n1C(F)F
Reactant: COC1=CC(OC)=NN(Cl)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1=CC(OC)=NN(Oc2cc(-c3nc(C)n(C(F)F)c3Cl)c(F)cc2Cl)N1
Temperature: 110 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
5-Chloro-4-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-difluoromethyl-2-methylimidazole (prepared according to the procedure as described in EP 590,834) (0.31 g, 1 mMol) was dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (0.17 g, 1.2 mMol) and 2-chloro-4,6-dimethoxytriazine (0.21 g, 1.2 mMol) were added and the suspension stirred at 110° C. for 2 hours under an atmosphere of nitrogen. The mixture was processed. and the residue chromatographed on silica gel eluting with methylene chloride:methanol, 98:2, to give the title compound (0.25 g, 55%). 1H NMR (CDCl3, TMS): 2.61 (3H, br s), 4.00 (6H, s), 7.17 (1H, t, J=58.1 Hz), 7.29 (1H, d, J=9.3 Hz), 7.53 (1H, d, J=6.6 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3C(OC(C)(C)C)=O)=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:25]#[C:26][CH3:27].Cl.[CH3:29][O:30][C:31]([NH:33][C@@H:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])=[O:32].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.CCOC(C)=O.CN(C=O)C.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:35](=[O:36])[C@@H:34]([NH:33][C:31](=[O:32])[O:30][CH3:29])[CH:38]([CH3:40])[CH3:39])=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:25]#[C:26][CH3:27]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC#Cc1cc(-c2cnc([C@@H]3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC#Cc1cc(-c2cnc([C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]2)ccc1Br
Reaction time: 22 h
Yield: 81.4 %

Procedure:
(S)-tert-butyl 2-(5-(4-bromo-3-(prop-1-ynyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (400 mg, 0.98 mmol) was dissolved in DCM (8 mL), MeOH (2 mL) and HCl (4 M in dioxane, 2 mL) was added. The reaction mixture was stirred for 22 h and then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (163 mg, 0.93 mmol), HATU (354 mg, 0.98 mmol) and DMF (10 mL), then DIPEA (0.81 mL, 4.65 mmol) was added dropwise. After 2 h, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 30% MeOH/EtOAc) to afford methyl (S)-1-((S)-2-(5-(4-bromo-3-(prop-1-ynyl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (369 mg, 81%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[C:24]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=3)[C:17]=2[CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.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.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:12][CH:13]=1)[C:9](=[O:11])[N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[C:24]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[O:38])=[CH:33][CH:32]=4)[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=3)[C:17]=1[CH3:45])[CH2:14]2)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(NCc2cc(C(C)(C)C)ccc2C(=O)O)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2cn(C)c(=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
To 25 mL round bottom flask charged with acid 101i (97 mg, 0.16 mmol), diisopropyethylamine (0.08 mL, 0.48 mmol) in DMF (5 mL) was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (84 mg, 0.19 mmol). After the reaction was stirred at room temperature for 2 h, H2O (5 mL) and EtOAc (10 mL) were added. The organic phase was extracted with aqueous HCl (1M, 2×5 mL), H2O (5 mL), aqueous Na2CO3 (1M, 5 mL), brine (5 mL), dried with Na2SO4 and concentrated. The residue was chromatographed (gradient, 0%-100% 60:35:5 CH2Cl2:Et2O:MeOH/CH2Cl2) to afford 45 mg (48%) of 101. MH+(m/z): 591.5. 1H NMR (300 MHz, CDCl3) 6 m; 8.44 (s, 1 H), 8.39 (m, 1 H), 7.88 (s, 1 H), 7.82 (s, 1 H), 7.39-7.49 (m, 5 H), 7.31-7.35 (, 2 H), 7.07 (d, J=7.5 Hz, 1 H), 6.81 (s, 1 H), 6.58 (d, J=7.5 Hz, 1 H), 3.69 (broad s, 6 H), 3.62 (s, 3 H), 3.07 (m, 1 H), 2.21 (s, 3 H), 1.35 (s, 3 H), 1.33 (s, 3 H); MS (ESI+) m/z (M+H) 590.58.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([N:26]1CCOCC1)[CH3:25].ClC(OCC(C)C)=O.[Cl-].C([NH3+])C>O1CCCC1.CN(C)C=O>[CH2:24]([NH:26][C:18](=[O:20])[C@@H:17]1[CH2:21][CH2:22][CH2:23][N:16]1[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:25]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CC[NH3+]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 59.6 %

Procedure:
32 g (0.1 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 250 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 12.7 ml (0.1 mol) of N-ethylmorpholine and 13.1 ml (0.1 mol) of isobutyl chloroformate were then added and the solution was stirred at -10° C. for 20 minutes. To this mixture was then added a further 12.7 ml of N-ethylmorpholine followed by a solution of 8.15 g (0.1 mol) of ethylammonium chloride in 50 ml of dimethylformamide. The solution was stirred for 1 hour at 0° C. then left for 16 hours at room temperature. The solvents were removed by evaporation and the residue was triturated with 450 ml of ethyl acetate and washed successively with 200 ml of 1-N hydrochloric acid, 200 ml of water and 200 ml of 5% sodium bicarbonate solution. After drying over sodium sulphate and filtration, the solvent was removed by evaporation. The resulting oil crystallised slowly from ethyl acetate ether to yield 20.7 g of N-benzyloxycarbonyl-L-alanyl-L-proline ethylamide of melting point 110°-113° C. Evaporation of the mother liquors followed by treatment with ethyl acetate/ether gave a further crop of 1.2 g of melting point 107°-110° C.; total yield 68% [α]D20 =-96.0° (c=1.04% in methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[Cl:11][C:12]1[C:13]([OH:21])=[N:14][CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:11][C:12]1[C:13](=[O:21])[N:14]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc([N+](=O)[O-])cc(Cl)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-methoxybenzyl bromide (5.0 mL, 34.4 mmol) was added to a cold (0° C.) mixture 3-chloro-2-hydroxy-5-nitropyridine (5 g, 28.6 mmol) and K2CO3 (7.9 g, 57.3 mmol) in DMF (25 mL). The reaction mixture was allowed to warm to rt, stirred for 2 h, quenched by addition of a saturated aqueous NaHCO3 solution, and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by trituration in EtOAc. tR: 0.98 min (LC-MS 2); ESI-MS: 295.2 [M+H]+ (LC-MS 2).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][CH:8]2[CH2:14][O:15][CH2:16][CH:7]12)=[O:5])[CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>C(O)C>[C:27]([CH:26]([NH:1][C@H:2]([C:4]([N:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][CH:8]2[CH2:14][O:15][CH2:16][CH:7]12)=[O:5])[CH3:3])[CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=1)([O:29][CH2:30][CH3:31])=[O:28]
Reactant: C[C@H](N)C(=O)N1C2COCC2C[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccc(Cl)cc1)N[C@@H](C)C(=O)N1C2COCC2C[C@H]1C(=O)O

Procedure:
Treat 1-[(S)-alanyl]hexahydrofuro[3,4-b]pyrrole-2-(S)-carboxylic acid (prepared as described in Example 47) and ethyl 4-(p-chlorophenyl)-2-oxobutyrate with sodium cyanoborohydride as described in Example 47D (ethanol solvent) to obtain the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[Na].[NH:35]1[CH:39]=[CH:38][N:37]=[CH:36]1>C(C(C)=O)C>[N:35]1([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:12](\[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)/[CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=2)[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: OCC/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCC(C)=O
Product: OCC/C(=C(\c1ccccc1)c1ccc(OCCn2ccnc2)cc1)c1ccccc1

Procedure:
(Z)-4-[4-(2-Bromoethoxy)phenyl]-3,4-diphenylbut-3-en-1-ol (preparation described in U.S. Pat. No. 4,996,225) (4.97 g, 0.0117 mol) is dissolved in methyl ethyl ketone (50 ml) and potassium carbonate (4.8 g, 0.035 mol) and imidazole sodium salt (2.1 1 g, 0.0234 mol) is added to the solution. Mixture is stirred and refluxed for five hours. Then the solution is filtered and the filtrate is evaporated to dryness. The residue is dissolved in ethyl acetate, washed with 2 N aqueous sodium hydroxide solution and with water, dried and evaporated to dryness. The residue is recrystallized from the mixture of toluene and acetonitrile.
Reaction SMILES: [O:1]=[C:2]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH:27]=1)[C@@H:3]([N:11]([CH2:19][C:20]1[N:21]=[CH:22][S:23][CH:24]=1)C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Na+].[CH3:40]I.Cl>CN(C=O)C>[CH3:40][N:25]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)[CH:27]=1)[C:2](=[O:1])[C@@H:3]([NH:11][CH2:19][C:20]1[N:21]=[CH:22][S:23][CH:24]=1)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N(Cc1cscn1)[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2ccncc2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)[C@H](Cc1ccccc1)NCc1cscn1)c1cccc(-c2ccncc2)c1
Yield: 43.8 %

Procedure:
Amide 34.8.F (40 mg, 0.08 mmol) was dissolved in DMF, treated with NaH (3 mg, 0.08 mmol) and then MeI (5 μl, 0.08 mmol). The reaction mixture was partitioned with H2O/EtOAc. The organic layer was dried with sodium sulfate, filtered, and concentrated. The residue was purified on a prepHPLC (C18, ACN:H2O:0.1% TFA, gradient). The desired fractions were combined and partitioned with NaHCO3 (sat)/EtOAc. The organic layer was dried with sodium sulfate, filtered, and concentrated to yield 22 mg. The residue was treated with HCl (4.0 M, dioxane) and concentrated to dryness. The solid was partitioned with NaHCO3 (sat)/EtOAc. The organic layer was dried with sodium sulfate, filtered, and concentrated to yield 34.8 (15 mg). LC-MS (+esi, M+H+=429.1).
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.[C:39](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[OH:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(O)c1)c1cccc2c1C=CCCC2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(3-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and methyl iodide (2 ml), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was is washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (115 mg, 28%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]([OH:18])=O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.CN.[CH2:22]([N:24](CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C.O1CCCC1>[CH3:22][NH:24][C:16]([C:10]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:18]
Reactant: CCN(CC)CC
Reactant: O=C(O)C1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CNC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 50.7 %

Procedure:
To a solution of 4-(4-nitrophenyl)tetrahydro-2H-pyran-4-carboxylic acid (750 mg) obtained in Step B of Example 151, methanamine hydrochloride (1.0 g) and triethylamine (3.0 g) in a mixed solvent of tetrahydrofuran (20 mL) and N,N-dimethylacetamide (5.0 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.86 g), and the mixture was stirred at room temperature for 10 hr. The solvent was evaporated under reduced pressure, and the reaction mixture was poured into water, and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (400 mg).