Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([CH2:28][O:29][CH3:30])=[N:8][N:9]3[C:14]([C:15]4[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][O:24][CH3:25])=[CH:17][C:16]=4[O:26][CH3:27])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:31]1[CH2:35][CH2:34][CH:33]([CH:36]=O)[CH2:32]1.S(=O)(=O)(O)O.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([CH2:28][O:29][CH3:30])=[N:8][N:9]3[C:14]([C:15]4[C:16]([O:26][CH3:27])=[CH:17][C:18]([CH2:23][O:24][CH3:25])=[CH:19][C:20]=4[O:21][CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:36][CH:33]2[CH2:34][CH2:35][O:31][CH2:32]2)[CH2:3][CH2:2]1
Reactant: COCc1cc(OC)c(-c2cccc3c(NCC4CC4)c(COC)nn23)c(OC)c1
Reactant: O=CC1CCOC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1cc(OC)c(-c2cccc3c(N(CC4CC4)CC4CCOC4)c(COC)nn23)c(OC)c1
Reaction time: 1 h

Procedure:
To a solution of N-cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]amine (15 mg) dissolved in tetrahydrofuran (1 mL) was added tetrahydrofuran-3-carbaldehyde (50% aqueous solution; 0.022 mL), a 3M aqueous sulfuric acid solution (0.036 mL) and sodium borohydride (2.8 mg) while cooling with ice and the reaction mixture was stirred for 1 hour at the same temperature. Water and then saturated aqueous sodium bicarbonate were added to the obtained reaction mixture, extraction was performed with ethyl acetate, the organic extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (4.8 mg) was obtained as light yellow crystals from the n-hexane:ethyl acetate (1:2) fraction.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].O1CCCC1.C(N(CC)CC)C.[CH2:40]([NH:58]CCCCCCCCCCCCCCCCCC)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>>[CH2:40]([NH:58][C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH:8]1[C:12]2([CH3:27])[CH:11]([CH:16]3[CH:15]([CH2:14][CH2:13]2)[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([OH:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Yield: 172.2 %

Procedure:
Lithocholic acid (81) (9.78 g, 26 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) Isobutylchloroformate (3.55 g, 3.55 mL, 26 mmol) was added followed by the addition of triethylamine (5.26 g, 7.25 mL, 52 mmol) and dioctadecylamine (7 g, 26 g). The reaction mixture was brought to ambient temperature and allowed to stir over night. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (250 mL) The organic layer was washed with 5% sodium bicarbonate, 3% aqueous HCl and water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to afford amide 88 (14.5 g) in 89% yield. This was used as such for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)[CH3:2].Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:39][C:40]2[CH:41]=[N:42][C:43]([O:50][CH2:51][CH3:52])=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=2)=[O:38])=[C:32]([F:53])[CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:51]([O:50][C:43]1[N:42]=[CH:41][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:33]2[CH:34]=[CH:35][C:30]([C:8]3[CH:7]=[N:6][C:5]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=3)=[CH:31][C:32]=2[F:53])=[CH:45][C:44]=1[C:46]([F:47])([F:49])[F:48])[CH3:52]
Reactant: CCOc1ncc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cnc(OCC)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
To a mixture of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100 mg, 0.260 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added 2-(4-bromo-2-fluorophenyl)-N-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)acetamide (120 mg, 0.286 mmol), cesium carbonate (169 mg, 0.519 mmol) and PdCl2(dppf) (18.99 mg, 0.026 mmol). The mixture was stirred under a N2 atmosphere at 110° C. for 30 min under microwave. Then the reaction residue was filtered and the filtrate was concentrated to give the crude product, which was purified by preparative TLC (PE:EA=1:1, Rf=0.6) to yield a light yellow solid of N-(6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (50 mg, 0.071 mmol, 27.3% yield): 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J=2.5 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.52-7.35 (m, 6H), 6.93 (d, J=8.5 Hz, 2H), 5.39 (s, 2H), 4.47 (m, 2H), 4.17 (m, 2H), 3.78-3.85 (m, 5H), 1.42-1.47 (m, 3H), 1.38-1.42 (m, 3H); ES-LCMS m/z 600.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=1.[B:17]1(B2OC(C)(C)C(C)(C)O2)[O:21]C(C)(C)C(C)(C)[O:18]1.C([O-])(=O)C.[K+].C(OCC)(=O)C>O1CCOCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH2:13]([O:12][C:4]1[CH:3]=[C:2]([B:17]([OH:21])[OH:18])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:14]([CH3:16])[CH3:15]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: COC(=O)c1ccc(Br)cc1OCC(C)C
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(B(O)O)cc1OCC(C)C
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A mixture of methyl 4-bromo-2-isobutoxybenzoate (12.0 g), bis(pinacolato)diboron (12.2 g), dichloropalladium-triphenylphosphine (1:2, 2.05 g) and potassium acetate (12.3 g) in 1,4-dioxane (120 ml) was stirred at 90° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (500 ml) and water (500 ml) and the mixture was filtered through a Celite cake. The organic layer was separated and washed with water (500 ml) and brine (500 ml). The separated organic layer was concentrated under reduced pressure to ca. 150 ml. To the solution were added water (150 ml), acetic acid ammoniate (14.4 g) and sodium periodate (31.2 g) and the reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was extracted with ethyl acetate (twice) and the combined organic layer was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave a crude product followed by purification by column chromatography on silica gel (eluent: chloroform/methanol=98/2) to give [3-isobutoxy-4-(methoxycarbonyl)phenyl]boronic acid (7.58 g) as a purple solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[Cl:13][C:4]1[CH:3]=[C:2]([NH:17][CH:14]([CH3:16])[CH3:15])[C:7]([CH:8]=[O:10])=[CH:6][N:5]=1
Reactant: CC(C)N
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Product: CC(C)Nc1cc(Cl)ncc1C=O
Yield: 88.5 %

Procedure:
Using the three-step procedure of Example C5, ethyl 4,6-dichloronicotinate (20 g, 91 mmol) and isopropylamine (60% in water, 18 g, 182 mmol) were converted to 6-chloro-4-(isopropylamino)nicotinaldehyde (16 g, 81% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1 H), 8.43-8.39 (m, 2 H), 6.83 (s, 1 H), 3.84 (m, 1 H), 1.17 (d, J=6.4 Hz, 6 H).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[N:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[S:27][CH:28]=[C:29]([CH:31]=O)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:31][C:29]3[N:30]=[C:26]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[S:27][CH:28]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[N:14]=[CH:13][N:12]=1
Reactant: COC(=O)CCCC(N)c1c(OC)ncnc1OC
Reactant: O=Cc1csc(-c2ccccc2)n1
Product: COc1ncnc(OC)c1C1CCCC(=O)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(4,6-dimethoxypyrimidin-5-yl)pentanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 410.79 g/mol.
Reaction SMILES: C([O:8][C:9]1[C:24](=[O:25])[N:13]2[CH2:14][CH2:15][O:16][CH2:17][C:18]3([CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:12]2=[N:11][C:10]=1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[N:37]1[C:41](=[O:42])[N:40]([CH3:43])[CH:39]=[N:38]1)=[O:27])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:26]([C:10]2[N:11]=[C:12]3[C:18]4([CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[CH2:17][O:16][CH2:15][CH2:14][N:13]3[C:24](=[O:25])[C:9]=2[OH:8])=[O:27])=[C:31]([N:37]2[C:41](=[O:42])[N:40]([CH3:43])[CH:39]=[N:38]2)[CH:32]=1
Reactant: Cn1cnn(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOCC32CCOCC2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1cnn(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2O)CCOCC32CCOCC2)c1=O
Yield: 60.9 %

Procedure:
To a solution of 3′-(benzyloxy)-N-(4-fluoro-2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-4′-oxo-2,3,4′,5,6,6′,7′,9′-octahydrospiro[pyran-4,10′-pyrimido[1,2-d][1,4]oxazepine]-2′-carboxamide (0.093 g, 0.174 mmol) in ethyl acetate (5 mL) was added palladium on activated carbon (10%) (0.050 g) and the resulting mixture allowed to react under one atmosphere of hydrogen for 6 hours. The catalyst was removed by filtration and the filtrate was evaporated under reduce pressure to give a white solid. Recrystallization from hot ethanol afforded the title compound as a white solid (0.053 g, 68% yield): 1H NMR (400 MHz, CDCl3) δ 12.28 (1H, s), 8.95 (1H, brt), 7.66 (1H, dd, J=8.6, 6.1 Hz), 7.63 (1H, s), 7.22 (2H, dd, J=9.2, 2.8 Hz), 7.12 (2H, td, J=8.2, 2.8 Hz), 4.53 (2H, brs), 3.7-3.90 (10H, m), 3.43 (3H, s), 2.2-2.5 (2H, brm), 1.5-2.0 (2H, brm); LCMS (+ESI, M+H+) m/z 501.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20][CH3:21])=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:22]([NH2:24])=O.C[O-].[Na+].Cl>CN(C)C=O.CO.O>[CH2:13]([O:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:5])[NH:24][CH:22]=[N:1]2)=[CH:8][C:9]=1[O:20][CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC=O
Reactant: COC(=O)c1cc(OC)c(OCc2ccccc2)cc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (650 mg) was dissolved in N,N-dimethylformamide (15 ml) and methanol (3 ml). Formamide (0.46 ml) and sodium methoxide (373 mg) were added to the solution. The mixture was heated to 100° C. and was stirred overnight. The reaction solution was cooled to room temperature, and 10 ml of water was then added to the cooled reaction solution. The reaction solution was neutralized with a 1 M aqueous hydrochloric acid solution to precipitate a solid. The solid was collected by filtration, was washed with water and ether, and was then dried through a vacuum pump to give 566 mg (yield 87%) of the title compound.
Reaction SMILES: N([O-])=O.[Na+].O.[CH2:6]([C:8]1[CH:14]=[CH:13][C:11](N)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])[CH3:7].[ClH:18]>[Cu]Cl>[Cl:18][C:11]1[CH:13]=[CH:14][C:8]([CH2:6][CH3:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: CCc1ccc(N)cc1[N+](=O)[O-]
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 56 %

Procedure:
A solution of sodium nitrite in water (4.2 g, 60 mmol, 5 M, 12 mL) was added drop wise to a cooled (0° C.) solution of 4-ethyl-3-nitroaniline (10 g, 60 mmol) in conc. HCl (200 mL) and the reaction mixture was stirred at the same temperature for 1.5 h. Copper (I) chloride (9.5 g, 96 mmol) was then added and the solution was stirred at room temperature for 1 h and then at 80° C. for an additional hour. After cooling down the reaction mixture was extracted with DCM (3×100 mL) and the combined organic layers were dried over sodium sulfate. The crude was then purified by flash chromatography (hexane/EtOAc 9/1) to obtain the title compound as a yellow oil (6.28 g, 56%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][CH3:22])[CH:13]=1)(=[O:10])[O:6][CH2:7][CH2:8][OH:9].[H][H]>CCO.[Pd]>[OH:9][CH2:8][CH2:7][O:6][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:21][CH3:22])[CH:13]=1)(=[O:10])[O:4][CH2:3][CH2:2][OH:1]
Reactant: COc1cc(CP(=O)(OCCO)OCCO)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CP(=O)(OCCO)OCCO)ccc1N
Yield: 82.4 %

Procedure:
A mixture of bis(2-hydroxyethyl)(3-methoxy-4-nitrobenzyl)phosphonate (Compound 133B, 1.2 g, 3.58 mmol) and 5% Pd/C (0.2 g) in EtOH (80 mL) was hydrogenated under 50 psi hydrogen pressure at 40° C. for 6 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product (0.9 g, 82%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH2:10]([CH:12]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:13][NH:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:11]>[Hg]>[CH2:21]([CH:16]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][N:14]([CH2:13][CH:12]([CH2:10][CH3:11])[CH2:23][CH2:24][CH2:25][CH3:26])[C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9])[CH3:22]
Reactant: O=C(O)c1cnccn1
Reactant: CCCCC(CC)CNCC(CC)CCCC
Agent: [Hg]
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=O)c1cnccn1

Procedure:
N,N-bis(2'-ethylhexyl)pyrazine-2-carboxamide was prepared from pyrazine-2-carboxylic acid and bis(2-ethylhexyl)amine by the general method of Example 5, the amine being used in place of the alcohol. The compound had a boiling range of 155° to 160° C. at 0.2 mm pressure of mercury.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.N1C=CC=CC=1.[Br:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:31])=[C:26]([CH:30]=1)[C:27](O)=[O:28].CCCP(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC1CCCO1.CCOC(C)=O>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:31])=[C:26]([CH:30]=1)[C:27]([NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1)=[O:28]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Agent: CCCP(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC1CCCO1
Product: N#Cc1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Temperature: 85 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
To a solution of 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53, 400 mg, 2.17 mmol) in 2-methyltetrahydrofuran (12 mL) was added pyridine (524 uL, 6.51 mmol) and 5-bromo-2-chlorobenzoic acid (768 mg, 3.26 mmol). The mixture was heated to 85° C. and propylphosphonic anhydride (50% w/w in EtOAc, 3.10 mL, 4.34 mmol), was added dropwise. The reaction was heated at 85° C. for 16 hours, then stirred for 48 hours at room temperature. The reaction was quenched by the addition of 10% aqueous potassium carbonate solution (24 mL, 17.4 mmol) with stirring at room temperature for 1 hour. The reaction was diluted to 150 mL with EtOAc and washed with 10% aqueous solution of potassium carbonate (100 mL) followed by 2M aqueous HCl (100 mL). The organic layer was dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-1% methanol in dichloromethane to afford the title compound (640 mg, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([CH3:18])=[CH:16][C:15](=[O:19])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9]2)=[CH:4][CH:3]=1.O=C(C=CC)CC(OC)=O.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1.C(OC(=O)C)(=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([CH:18]=[CH:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[CH:16][C:15](=[O:19])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: COC(=O)c1cn(-c2ccc(F)cc2)c(C)cc1=O
Agent: CC=CC(=O)CC(=O)OC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1cn(-c2ccc(F)cc2)c(C=Cc2cccnc2)cc1=O
Temperature: 25 °C

Procedure:
In the same manner as in Example 4, methyl 1-(4-fluorophenyl)-6-methyl-4-oxo-1,4-dihydronicotinate (m.p. 190°-195° C.) was prepared from methyl 3-oxo-4-hexenoate and 4-flouoroaniline, and 0.7 g of this ester was mixed with 0.32 g of nicotinaldehyde and 0.58 g of acetic anhydride, and they were refluxed for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 20 ml of water was added thereto, after which the mixture was successively extracted with three 40-ml portions of chloroform. The chloroform layer was washed with 50 ml of a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform) to obtain 0.496 g of methyl 1-(4-fluorophenyl)-6-[2-(pyridin-3-yl)ethenyl]-4-oxo-1,4-dihydronicotinate having a melting point of 201°-204° C.
Reaction SMILES: C(OC(N[C@@H]([C@H]1CC[C@H](O)CC1)C(OC)=O)=O)(C)(C)C.[OH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([C@H:28]([NH:36]C(=O)OC(C)(C)C)[C:29](=[O:35])[N:30]2[CH2:34][CH2:33][S:32][CH2:31]2)[CH2:24][CH2:23]1>>[NH2:36][C@@H:28]([C@H:25]1[CH2:26][CH2:27][C@H:22]([OH:21])[CH2:23][CH2:24]1)[C:29](=[O:35])[N:30]1[CH2:34][CH2:33][S:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCSC1)[C@H]1CC[C@H](O)CC1
Agent: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Product: N[C@H](C(=O)N1CCSC1)[C@H]1CC[C@H](O)CC1

Procedure:
3.5 g (12.2 mmol) of methyl trans-(2S)-[(tert-butoxycarbonyl)-amino](4-hydroxycyclohexyl)-ethanoate was converted to 3.34 g of tert-butyl trans-(1S)-1-(4-hydroxycyclohexyl)-2-oxo-2-(1,3-thiazolidin-3-yl)ethyl-carbamate using the procedures outlined in Example 1, Step C. 1H NMR (400 MHz, CD3OD, mixture of rotamers) δ 4.65–4.47 (m, 1.5H), 4.19–4.05 (m, 1.5H), 3.55–3.40 (m, 1H), 3.17–3.03 (m, 2H), 2.00–1.83 (m, 3H), 1.70–1.58 (m, 2H), 1.45–1.38 (m, 9H), 1.30–1.08 (m, 4H). A portion of this material was deprotected as described in Example 1, Step D to give the title compound. 1H NMR (400 MHz, CD3OD, mixture of rotamers) δ 4.65–4.63 (m, 0.5H), 4.61–4.57 (m, 1H), 4.50–4.44 (m, 0.5H), 3.93–3.85 (m, 0.5H), 3.82–3.71 (m, 1.5H), 3.50–3.38 (m, 2H), 3.15–3.02 (m, 2H), 2.01–1.83 (m, 3H), 1.63–1.59 (m, 1H), 1.55–1.45 (m, 1H), 1.30–1.05 (m, 4H).