Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[C:6]([CH:35]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:29][C:17]=3[N:16]=2)=[C:11]([F:34])[CH:10]=1.C(N(CC)CC)C.Cl[CH2:51][CH2:52][CH2:53][C:54](Cl)=[O:55].O>C(Cl)(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:5]2[CH:4]=[CH:3][C:2]([N:1]3[CH2:51][CH2:52][CH2:53][C:54]3=[O:55])=[CH:35][C:6]=2[CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:19]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[C:18]4[CH:26]=[CH:27][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:29][C:17]=4[N:16]=3)=[C:11]([F:34])[CH:10]=2)=[CH:37][CH:38]=1
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(N)ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(N4CCCC4=O)ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
Methyl 2-[4-{5-amino-2-(4-chlorophenyl)benzyloxy}-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylate (500 mg) obtained in Example 338 and triethylamine (0.14 ml) were dissolved in chloroform (5 ml), and commercially available chlorobutyryl chloride (0.1 ml) was added under ice-cooling, which was followed by stirring at room temperature for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylformamide (6 ml) and potassium carbonate (244 mg) was added, which was followed by stirring at 80° C. for 1 hr. The reaction mixture was allowed to cool, water was added and the precipitated crystals were collected by filtration to give the title compound (502 mg, yield 89%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][C@@H:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:48]([CH3:47])[C@@H:49]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH3:50])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN[C@H](C)c1ccccc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)[C@H](C)c2ccccc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with methyl-((R)-1-phenyl-ethyl)-amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C45H54Cl2N5O3 [(M+H)+] 782.3598, observed 782.3594.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([OH:9])[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH2:10]([N:12](CC)[CH2:13]C)C.[CH3:17][N:18]([S:22][N:23]([CH3:27])[C:24](F)=[O:25])[C:19](F)=[O:20].CNC>C1(C)C=CC=CC=1>[CH:1]([N:4]1[CH:8]=[C:7]([O:9][C:24](=[O:25])[N:23]([CH3:27])[S:22][N:18]([C:19]([N:12]([CH3:13])[CH3:10])=[O:20])[CH3:17])[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc(O)cn1
Reactant: CN(SN(C)C(=O)F)C(=O)F
Reactant: CCN(CC)CC
Agent: CNC
Solvent: Cc1ccccc1
Product: CC(C)n1cc(OC(=O)N(C)SN(C)C(=O)N(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A mixture of 6.3 g (0.05 mol) of 1-isopropyl-4-hydroxy-pyrazole, 5.1 g (0.05 mol) of triethylamine and 200 ml of toluene was added to a solution of 9.2 g (0.05 mol) of bis-(N-methyl-N-fluorocarbonylamino) sulphide in 50 ml of toluene at 0°-5° C. The reaction mixture was subsequently stirred at room temperature for 2 hours, and 11 g of an approximately 45% strength aqueous dimethylamine solution were then added at 15°-20° C. The mixture was subsequently stirred at room temperature for 3 hours, the aqueous phase was separated off and the toluene solution was extracted twice more by shaking with 25 ml of water each time. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was subjected to incipient distillation under a high vacuum. 13.5 g (86% of theory) of N-methyl-N-(N-dimethylaminocarbonyl-N-methyl-amino-sulphenyl)-carbamic acid O-(1-isopropyl-pyrazol-4-yl) ester were thus obtained in the form of a light-brown oil with a refractive index nD22 of 1.5192.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[C:20](O)[CH:19]=[CH:18][CH:17]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:27](Cl)([CH3:30])([CH3:29])[CH3:28].[OH2:32]>>[C:27]([CH:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:32])([CH3:30])([CH3:29])[CH3:28]
Reactant: O
Reactant: CC(C)(C)Cl
Reactant: C=CC/C=C\C/C=C\CCCCCCCc1cccc(O)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCCCCCCCC(Cc1ccccc1O)C(C)(C)C
Reaction time: 4 h

Procedure:
2-Tert-butyl pentadecylphenol is prepared as disclosed in Fuel, 82 (2003), the disclosure of which is totally incorporated herein by reference. More specifically, hydrogenated cardanol (0.84 mol) is added to a three-neck round bottom flask containing AlCl3 (0.15 mol) and the system is cooled to a temperature between 0 and 5° C. Tert-butyl chloride (0.25 mol) is then slowly added from a dropping funnel with constant stirring over 4 hours. The formation of the product is monitored by thin layer chromatography (TLC). Thereafter, crushed ice and water are added to the mixture to allow thorough decomposition of intermediate compounds. Separation of two distinct phases is observed, one of the phases turning into a very viscous dark oil. After phase separation, the mixture is distilled under reduced pressure and the product collected and dried with anhydrous Na2SO4. The product is then purified through a silica gel chromatographic column using solutions of CHCl3 and n-hexane of several compositions from 0 to 100% as eluents to yield a compound of the formula
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].Br[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH2:43][C:44]2C=CC=CC=2)=[O:41])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)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>[C:26]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34][CH:33]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:30])[CH2:8][C@@H:9]1[CH3:29])(=[O:28])[CH3:27]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: O=C(CCc1ccc(Br)cc1)OCc1ccccc1
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
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Yield: 35 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (100 mg, 0.240 mmol), phenylmethyl 3-(4-bromophenyl)propanoate (92 mg, 0.288 mmol), potassium carbonate (100 mg, 0.721 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.88 mg, 0.012 mmol) in ethanol (2.5 mL) and toluene (2.500 mL) was degassed for 15 min under house vacuum and quenched several times with nitrogen, and then was heated at 100° C. for 1 h before being cooled to room temperature and partitioned between AcOEt (35 mL) and water (20 mL). The layers were separated and the aqueous phase was extracted with AcOEt (15 mL). The combined organic phases were washed with brine (15 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 40 to 70% AcOEt in Hexanes) gave a residue which was further purified by MDAP (modifier: formic acid) to give ethyl 3-{4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}propanoate (39.7 mg, 0.085 mmol, 35%) as a white solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[NH:11]1[CH2:17][CH2:16][CH:12]1[C:13]([OH:15])=[O:14]>>[NH:11]1[CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14].[C:6]([C@H:4]([C@@H:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7]
Reactant: O=C(O)C1CCN1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Product: O=C(O)[C@@H]1CCN1
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Yield: 64 %

Procedure:
Hydrogenation was carried out on the resultant pure title compound of Example 2 above (70.35 g; 250 mmol) in acetic acid (700 mL), using palladium on carbon catalyst. After hydrogenation was complete, the catalyst was filtered off, and the filtrates were concentrated resulting in a mixture containing a theoretical amount of 25.25 g D,L-AzeOH. Acetic acid was added to the residue, resulting in a 13.5% w/w solution of D,L-AzeOH in acetic acid. A D-tartaric acid resolution was carried out on 5.05 g (50 mmol) of D,L-AzeOH, in analogous fashion to procedures described in international patent application WO 97/41084, yielding 8.05 g (64%) of crude L-AzeOH-D-tartrate with a diastereomeric excess of 95.8%. The crude salt was recrystallised from aqueous ethanol, yielding 6.28 g of pure L-AzeOH-D-tartrate as white crystals. HPLC indicated a diastereomeric excess of 100%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][Mg]Br>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Add 1-benzyl-3-pyrrolidinone (10 g, 61.7 mmol) in dry THF (40 mL) to methyl magnesium bromide (3 M in diethyl ether, 44 mL, 132 mmol) at −20° C. Stir for 3 h and allow the reaction to warm up to 0° C. Pour onto crushed ice and extract with diethyl ether. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give 1-benzyl-3-methylpyrrolidin-3-ol which may be used directly in the next step without further purification (8.6 g, 73%). 1H NMR (400 MHz, CDCl3) δ 7.22-7.33 (5H, m), 3.63 (2H, s), 2.92-2.99 (1H, m), 2.71 (1H, d, J=9.29 Hz), 2.28-2.36 (1H, m), 2.22 (1H, d, J=9.78 Hz), 1.84-1.91 (2H, m), 1.33 (3H, s), MS (ES): m/z=192 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:13]3[N:14]=[CH:15][N:16]([C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:17]=3)([OH:12])[CH:9]([CH3:10])[CH3:11])=[CH:6][CH:7]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)C(O)(c1ccc(Br)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COc1cccc(B(O)O)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: [Na+]
Product: COc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 64.1 %

Procedure:
By the reaction in the same manner as in Example 29-(i) using 1-(4-bromophenyl)-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.50 g), 3-methoxyphenylboronic acid (635 mg), 2M aqueous sodium carbonate solution (2.79 ml) and tetrakis(triphenylphosphine)palladium(0) (96.7 mg), the title compound (1.01 g) was obtained as colorless powder crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]([C:21]3[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=3)=[O:20])[CH:15]=[CH:16][CH:17]=1)[N:5]=2.C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>O1CCCC1.O>[CH:35]1([C:38]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:15]=[CH:16][CH:17]=2)[N:5]=3)=[O:39])[CH2:37][CH2:36]1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4n3)c2)n(C)n1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)c2)n(C)n1
Yield: 55.5 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (1.03 g, 2.71 mmol) and triethylamine (563 μL, 4.07 mmol) in tetrahydrofuran (15 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (295 μL, 3.25 mmol), and the mixture was stirred at room temperature for 2 hr. Cyclopropanecarbonyl chloride (500 μL, 5.51 mmol) was further added thereto, and the mixture was stirred for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, sodium carbonate (750 mg), methanol (15 mL) and water (100 μL) were added to the residue, and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=60/40→0/100) and recrystallized from ethanol-ethyl acetate-hexane to give the title compound (675 mg, 56%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[CH:4]=[C:3]2[CH2:8][O:9][CH2:10][CH2:11][C:2]=12.[F:12][C:13]([F:31])([F:30])[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][C@@H:22]([C:27](O)=[O:28])[CH2:21][CH2:20][C:19]=2[N:18]=1)([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:1]1[CH:6]=[C:5]([NH:7][C:27]([CH:22]2[CH2:21][CH2:20][C:19]3[N:18]=[C:17]([C:14]([CH3:16])([CH3:15])[C:13]([F:31])([F:30])[F:12])[CH:26]=[CH:25][C:24]=3[CH2:23]2)=[O:28])[CH:4]=[C:3]2[CH2:8][O:9][CH2:10][CH2:11][C:2]=12
Reactant: Nc1cnc2c(c1)COCC2
Reactant: CC(C)(c1ccc2c(n1)CC[C@H](C(=O)O)C2)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(c1ccc2c(n1)CCC(C(=O)Nc1cnc3c(c1)COCC3)C2)C(F)(F)F
Temperature: 60 °C
Yield: 75.2 %

Procedure:
To a mixture of 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-ylamine (36 mg, 0.24 mmol), (S)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (38 mg, 0.13 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (136 mg, 0.36 mmol) in DMF (1 mL), N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) was added and the reaction was heated at 60° C. for 16 hours. The crude was purified by semi-preparative HPLC (55-75 gradient) to give the titled amide (41 mg, 74%). m/z=420.2 (M+1)+. HPLC: 10.31 min. NMR (400 MHz; d6-DMSO) δ 10.21 (s, 1H), 8.51 (d, 1H, J=2.5 Hz), 7.82 (d, 1H, J=2.3 Hz), 7.56 (d, 1H, J=8.1 Hz), 7.37 (d, 1H, J=8.1 Hz), 4.68 (s, 2H), 3.95 (t, 2H, J=5.9 Hz), 2.97-2.80 (m, 7H), 2.19-2.14 (m, 1H), 1.95-1.85 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[OH:13])#[N:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][C:44](=[O:46])[N:43]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=2)[CH2:42][C@@H:41]1[CH2:54][CH2:55]O)=[O:39])([CH3:36])([CH3:35])[CH3:34].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCCCCC.CCOC(C)=O>[C:33]([O:37][C:38]([N:40]1[CH2:45][C:44](=[O:46])[N:43]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=2)[CH2:42][C@@H:41]1[CH2:54][CH2:55][O:13][C:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[CH:12][C:3]=1[C:1]#[N:2])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#N)c(OCC[C@H]2CN(c3cccc(Cl)c3)C(=O)CN2C(=O)OC(C)(C)C)c1
Reaction time: 16 h

Procedure:
To a solution of 250 mg of methyl 4-cyano-3-hydroxybenzoate (1.42 mmol), as described in Example 4, Step C, and PPh3 (465 mg, 1.77 mmol) in THF (10 mL) was added dropwise a solution of the alcohol from Step E above (503 mg, 1.42 mmol) and DEAD (0.28 mL, 1.77 mmol) in THF (5 mL). After stirring for 16 hr, the solution was concentrated in vacuo and the residue taken up in EtOAc. This was then washed with 10% citric acid solution, saturated NaHCO3 solution, brine and dried over MgSO4. Filtration and removal of the solvent afforded an oil. Column chromatography (silica gel; hexane:EtOAc 4:1) afforded the title compound as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1O
Solvent: CO
Product: COc1cc(C=Nc2ccccc2)cc(OC)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-Dimethoxy-4-hydroxybenzaldehyde (1 g, 5.46 mmol) was dissolved in methanol (50 ml) and aniline (560 mg, 6.01 mmol, 0.35 ml, neat liquid) was added to the solution by syringe. The resultant reaction mixture was stirred overnight at room temperature under nitrogen then taken to dryness in-vacuo. The yellow crystals thus obtained were triturated with hot ether, allowed to cool, filtered and the collected solid was washed with ether to yield the title product: 1H NMR (300 MHZ, CDCl3) δ , 8.33 (S, 1H), 7.42-7.39 (m, 2H), 7.21-7.18 (m, 5H), 5.84 (S, 1H), 3.98 (S, 6H)
Reaction SMILES: OCC(N[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])CO.COC(OC)(C)C.O>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:15]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:7]=1)[C:11]#[N:12])([O-:17])=[O:16]
Reactant: N#Cc1ccc(NC(CO)CO)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: N#Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 154.2 %

Procedure:
A mixture of 4-[2-hydroxy-1-(hydroxymethyl)ethylamino]-3-nitrobenzonitrile (1.35 g), 2,2-dimethoxypropane (1.4 g) and p-toluenesulfonic acid (10 mg) in anhydrous dichloromethane (30 mL) was stirred at ambient temperature for 8 hours. The mixture was poured into water and extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was triturated with diethyl ether to give 4-[(2,2-dimethyl-1,3-dioxan-5-yl)amino[-3-nitrobenzonitrile (1.3 g) as yellow powders.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11].[H-].[Na+].Br[CH2:19][O:20][CH3:21].O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11]
Reactant: COCBr
Reactant: CON(C)C(=O)Cc1ccc(O)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(CC(=O)N(C)OC)c(Br)c1
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
A solution of 2-(2-bromo-4-hydroxyphenyl)-N-methoxy-N-methylacetamide (1.37 g) in THF (5 mL) was slowly added to a suspension of sodium hydride (0.22 g) in THF (30 mL) at 0° C. After stirring for 10 min, bromo(methoxy)methane (1.25 g) was added dropwise at 0° C. The mixture was stirred at 0° C. for 2 hr. The mixture was poured into water and extracted with ethyl acetate (30 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the title compound (1.34 g).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:23]=[CH:22][C:10]([CH2:11][N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[CH:9][C:8]=2[O:24][CH3:25])[CH:5]=[CH:4][CH:3]=[N:2]1>C1COCC1.CCO.O>[N:1]1([CH2:6][C:7]2[CH:23]=[CH:22][C:10]([CH2:11][N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[CH:9][C:8]=2[O:24][CH3:25])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1cnn(Cc2ccc(Cn3cccn3)c(OC)c2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(Cn2cc(C(=O)O)cn2)ccc1Cn1cccn1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of crude ethyl 1-(4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzyl)-1H-pyrazole-4-carboxylate (998 mg, 29%, 0.85 mmol) in THF:EtOH:H2O 2:1:1 (15 ml), LiOH Monohydrate (107 mg, 2.55 mmol) was added and stirred for 12 h at 50° C. The reaction mixture was concentrated under reduced pressure. The remaining solid was taken up in ethyl acetate and extracted with water. The aqueous phase was acidified by adding aqueous HCl and extracted with ethy acetate. The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude 1-(4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzyl)-1H-pyrazole-4-carboxylic acid. MS [M+H]+=313.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH:16]1[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C:22]([OH:24])=O.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:33](OC([O-])=O)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)CC)C>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:36]([O:35][C:33]([N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C:22](=[O:24])[NH:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.5 %

Procedure:
N,N′-Dicyclohexyl carbodiimide (DCC; 8.2 g, 40 mmol) was added to a solution of pyroglutamic acid (5.16 g, 40 mmol) in dimethylformamide (DMF; 60 ml). The mixture was stirred at room temperature for 2 h and a precipitate formed. Benzylamine (4.8 ml, 44 mmol) was added and the mixture was stirred for 2 h. t-butyl dicarbonate (Boc2O; 9.6 g, 44 mmol), triethylamine (TEA; 6.3 ml, 44 mmol) and 4-dimethylaminopyridine (DMAP; 488 mg, 4 mmol) were added and the mixture was stirred at room temperature for 16 h. The DMF was removed under vacuum and the residue was taken up with water (20 ml) and extracted with dichloromethane (DCM; 3×20 ml). The organic layers were concentrated and the crude product was purified via silica gel chromatography to afford (S)-2-benzylcarbamoyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (2.23 g, 7.0 mmol, 17.5%).