Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.C[O:22][C:23](=[O:37])[C@@H:24]([CH3:36])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[C:29]([F:35])[CH:28]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[Li+]>CN(C)C=O.C(OCC)(=O)C.CO.C(N(CC)CC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:12]([C:13]([NH:34][CH2:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH2:25][C@H:24]([CH3:36])[C:23]([OH:37])=[O:22])=[CH:28][C:29]=4[F:35])=[O:15])=[CH:16][CH:17]=[CH:18][N:19]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@@H](C)COc1ccc(CN)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](COc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Temperature: 25 °C

Procedure:
2-(Benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid (0.168 g, 0.65 mmol), (S)-3-(4-aminomethyl-3-fluoro-phenoxy)-2-methyl-propionic acid methyl ester hydrochloride (0.18 g, 0.65 mmol), 1-hydroxybenzotriazole hydrate (0.097 g, 0.72 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.138 g, 0.72 mmol) and triethylamine were dissolved in N, N-dimethylformamide (6 mL) and stirred at room temperature over night. The reaction was diluted in ethyl acetate and washed successively with dilute aqueous hydrochloric acid, dilute aqueous sodium hydroxide, and brine, and dried (Na2SO4). The product was purified by flash column chromatography (20% ethyl acetate/hexane). The residue was taken up in tetrahydrofuran (10 mL) and methanol (2 mL) and aqueous lithium hydroxide (2 mL, 1 M, 2 mmol). The reaction was stirred at room temperature 1 h. The solvents were stripped in vacuo and the residue partitioned between dilute aqueous hydrochloric acid and ethyl acetate. The aqueous was extracted with 2 aliquots ethyl acetate and the pooled organics were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford a white solid (0.12 g, 39% yeild).
Reaction SMILES: [H-].[Na+].CS([O:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)(=O)=O.[OH2:21]>CN(C)C=O>[CH3:17][C:18]1[CH:19]=[C:20]([O:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[CH:11]=[CH:12][C:13]=1[C:14](=[O:21])[CH3:15]
Reactant: O
Reactant: CS(=O)(=O)OCCOc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of 4-hydroxy-2-methylacetophonone (2 g) in dimethylformamide (30 mL) under argon was treated with 55% sodium hydride (0.58 g), stirred for 30 minutes and treated with 2-(2-naphthalenyloxy)ethyl methanesulfonate (3.65 g). The mixture was heated at 60° C. for 2 hours, cooled, diluted with water and filtered. The damp solids were mixed with water and excess sodium hydroxide solution, the product was extracted twice with dichloromethane, and the organic layers were washed with water. The combined organic layers were dried (Na2SO4), filtered, and evaporated to give crude material which was crystallized from dichloromethane-diethyl ether to provide 3.5 g of 1-[2-methyl-4-[2-(2-naphthalenyloxy)ethoxy]phenyl]ethanone as a colorless solid, mp 128°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Cl:12][C:13]1[N:14]=[C:15]([NH:11][C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH3:10])[CH:16]=[N:17][CH:18]=1
Reactant: C[C@H](N)c1ccc(F)c(F)c1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1cncc(Cl)n1)c1ccc(F)c(F)c1
Temperature: 110 °C
Yield: 35.1 %

Procedure:
(1S)-1-(3,4-Difluorophenyl)ethanamine (977 mg, 6.2 mmol) and 2,6-dichloropyrazine (1.236 g, 8.3 mmol, 1.3 eq) was dissolved in dioxane (5 mL) and potassium carbonate (1.73 g, 2.0 eq) added to the solution. The mixture was then heated at reflux (110° C.) under a nitrogen atmosphere for 65 hours. The crude reaction mixture was then poured onto cold water (30 mL) and extracted with diethyl ether (3×30 mL). The combined organic extracts were concentrated and subjected to flashmaster chromatography (20 g silica cartridge (8:2 petroleum spirits:ethyl acetate, followed by ethyl acetate flush) to afford the desired pyrazine-adduct as an off-white solid (587 mg, 35%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[C:7]1[NH:8][C:9]3[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[C:14]=3[C:6]=1[CH2:5]2.[OH-].[Na+].I[CH3:23]>C1C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[C:7]1[N:8]([CH3:23])[C:9]3[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[C:14]=3[C:6]=1[CH2:5]2
Reactant: Cc1cc(C)c2c3c([nH]c2c1)-c1ccc(F)cc1C3
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C)c2c3c(n(C)c2c1)-c1ccc(F)cc1C3
Temperature: 40 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
To a solution of 47b (2.74 g, 10.9 mmol) in benzene (59 mL) was added aqueous sodium hydroxide (50% by mass, 5.9 mL), tetrabutylammonium iodide (289 mg, 0.78 mmol), and iodomethane (5.42 mL, 87.1 mmol). The reaction mixture was stirred vigorously at 40° C. for 16 hours and then cooled to room temperature. The mixture was diluted with benzene (20 mL) and H2O (20 mL), and the aqueous layer was extracted 2×20 mL ethyl acetate. Organic layers were combined, washed 1×25 mL H2O, dried over anhydrous magnesium sulfate and concentrated to yield a brown solid. Crude product was purified by flash column chromatography (15:1 hexanes-ethyl acetate followed by a second column 40:1 to 26:1 hexanes-ethyl acetate) to give 48b in 39% yield (1.12 g, 4.24 mmol). 1H NMR (400 MHz, CDCl3): δ 7.51-7.53 (dd, 1H, J=8.2, 5.2 Hz), 7.237-7.260 (m, 1H), 7.99-7.06 (td, 1H, J=9.2, 2.4 Hz), 6.99 (s, 1H), 6.78(s, 1H), 3.97 (s, 3H), 3.80 (s, 2H), 2.60 (s, 3H), 2.46 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 160.5 (d, J=361.5 Hz), 150.4 (d, J=13.5 Hz), 142.42, 141.72, 131.6 (d, J=3.0 Hz), 131.3, 129.0, 121.9, 121.6, 119.5 (d, J=4.5 Hz), 117.1 (d, J=13.5 Hz), 113.2 (d, J=34.5 Hz), 113.5 (d, J=34.1 Hz), 107.1, 31.2 (d, J=2.9 Hz), 30.8, 21.8, 19.0; 19F NMR (CD3CD, 376 MHz): δ −118.0 (m); FTIR: cm−1 3011, 2917, 1588, 1527, 1449, 1417, 1360, 1267, 1212.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[N:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[CH:9]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(O)c1cc(COc2ccc(Br)cc2)n(-c2c(Cl)cccc2Cl)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(COc2ccc(Br)cc2)n(-c2c(Cl)cccc2Cl)n1

Procedure:
Into a 25 mL flask was added 527 mg (1.16 mmol) of 2-[5-(4-bromophenoxymethyl)-1 (2,6-dichlorophenyl)-1H-pyrazol-3-yl]-propan-2-ol, 278 μL (1.74 mmol) Triethylsilane and 2 mL of Trifluoroacetic acid. After 1 h the crude reaction was concentrated in vacuo, washed into a separatory funnel with ethyl acetate and NaHCO3. The ethyl acetate was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to afford 5-(4-bromophenoxymethyl)-1-(2,6-dichlorophenyl)-3-isopropyl-1H-pyrazole as an off white solid (450 mg, 99%); 1H NMR (400 MHz, CDCl3): δ 7.42 (m, 1H), 7.41 (s, 1H), 7.33 (m, 1H), 7.31 (d J=9.1 Hz 2H), 6.67 (d J=9.1 Hz 2H), 6.36 (s, 1H), 4.82 (s, 2H), 4.43 (q, J=7.07 Hz 2H), 1.58 (s, 6H), MS (ES): 439 [M+H]+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)=[O:7].O1CCCC1>O>[O:14]=[C:11]1[N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:13]=[CH:12]1
Reactant: COC(=O)c1ccc(=O)n(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(=O)n(-c2ccccc2)c1
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Lithium hydroxide monohydrate (0.366 g, 8.73 mmol) was added to a mixture of methyl-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate (1.0 g, 4.37 mmol), tetrahydrofuran (9 mL) and water (6 mL) at 0° C. The mixture was stirred for 1 hour, diluted with water and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 2 using 2 N hydrochloric acid and the precipitate was filtered to give the title compound as a brown solid (0.740 g, 79%). m.p. 256-263° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.53 (d, J=9.4 Hz, 1H), 7.40-7.49 (m, 5H), 7.87 (dd, J=2.5, 9.8 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H); IR (KBr) υ 3446, 1708, 1645, 1577, 1263, 1228 cm−1; MS 214 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14]>>[OH:1][C:2]1[C:7]([CH2:12][CH2:13][CH3:14])=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1ccc(O)cc1OC
Reactant: C=CCBr
Product: CCCc1cc(OC)c(OC)cc1O

Procedure:
Following the procedure as in Example 3B, the same product can be obtained starting from 1-hydroxy-3,4-dimethoxybenzene and allyl bromide, Claisen rearrangement and hydrogenation
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[O:14]1[CH2:17][CH:16]([NH2:18])[CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C>[N+:11]([C:6]1[CH:7]=[C:8]2[CH2:9][N:18]([CH:16]3[CH2:17][O:14][CH2:15]3)[CH2:2][CH2:3][N:4]2[N:5]=1)([O-:13])=[O:12]
Reactant: NC1COC1
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc2n(n1)CCN(C1COC1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
To a solution of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (500 mg, 1.6 mmol) in acetonitrile (20 mL) was added oxetan-3-amine (140 mg, 1.92 mmol) and diisopropylethyl amine (372 mg, 0.50 ml, 2.88 mmol) drop wise and the resulting mixture was stirred at room temperature for 24 h. The solution was concentrated and the residue dissolved in ethyl acetate (50 mL), washed with water (50 mL) and dried over magnesium sulfate. The resulting mixture was filtered and evaporated and the residue purified by flash chromatography (SF25-40 g, 50% to 100% ethyl acetate in hexanes) to give 2-nitro-5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (255 mg, 71%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:16]([O:17][Si](C(C)(C)C)(C)C)[CH2:15][N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:16]([OH:17])[CH2:15][N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.3 %

Procedure:
t-Butyl (3R,4S)-3-benzyloxycarbonylamino-4-(t-butyldimethylsilanoxy)pyrrolidine-1-carboxylate (54 g) was dissolved in THF (400 mL), followed by addition of a solution (167 mL) of 1 M tetrabutyl ammonium fluoride in THF with ice cooling, and the mixture was stirred at room temperature for 3.5 h. Water was added, then the mixture was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=1:1-1:2) to obtain t-butyl (3R,4S)-3-benzyloxycarbonylamino-4-hydroxypyrrolidine-1-carboxylate (38 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[N:11]1([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=3)[N:18]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(C(=O)O)cc3)cs2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2csc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[4-(4-Carboxy-phenyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.0 mmol) was dissolved in hydrochloric acid in dioxane (4N, 25 ml) and the reaction stirred at RT for 2 h. The reaction was concentrated in vacuo to yield 4-(2-piperazin-1-yl-thiazol-4-yl)-benzoic acid. Trimethoxyethane (6.5 mmol) was dissolved in aqueous hydrochloric acid (1N, 10 ml) and the reaction heated at 50° C. for 1.5 h. The reaction was allowed to cool to RT and was then added to a suspension of 4-(2-piperazin-1-yl-thiazol-4-yl)-benzoic acid (5.0 mmol) in acetonitrile (25 ml) and sodium acetate buffer (1N, pH 5.5, 10 ml). The reaction was stirred at RT for 1.5 h. Sodium cyanoborohydride (6.5 mol) was added and the reaction stirred at RT for 16 h. The reaction was concentrated in vacuo and the product purified by flash chromatography (silica gel, 10% methanol in dichloromethane) to give the title product as a colourless oil (0.9 g). m/z=348 (100% M+H) in MS ES+.
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[OH:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:5]
Reactant: Oc1ccc(F)cc1F
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1Oc1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (30 mg, 0.1 mmol) in DMF (1 mL) was added 2,4-difluorophenol (130 mg, 1.0 mmol) and Cs2CO3 (325.8 mg, 1.0 mmol) and the reaction mixture was stirred at 100° C. for 1 hour. The reaction was cooled to 25° C., filtered and purified by reverse phase chromatography using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (16). ESI-MS m/z calc. 410.07, found 411.2 (M+1)+; Retention time: 1.55 minutes (3 minutes run).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH2:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH:56][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (84 mg) was prepared from (3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (100 mg) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride following general procedure A.
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:8][C:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=O)=O.[NH2:28][CH3:29]>CO>[C:9]12([CH2:8][CH:7]([NH:17][C:18](=[O:19])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:6][NH:28][CH3:29])[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][CH2:10]2
Reactant: CS(=O)(=O)OCC(CC12CCC(CC1)CC2)NC(=O)OCc1ccccc1
Reactant: CN
Solvent: CO
Product: CNCC(CC12CCC(CC1)CC2)NC(=O)OCc1ccccc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
2-(benzyloxycarbonylamino)-3-(bicyclo[2.2.2]octan-1-yl)propyl methanesulfonate (830 mg, 2.1 mmol) was dissolved in 15 mL of NH2Me in MeOH and stirred at 30-40° C. overnight. The mixture was concentrated to give benzyl 1-(bicyclo[2.2.2]octan-1-yl)-3-(methylamino)propan-2-ylcarbamate (1.0 g, crude) as an oil, which was used in the next step without further purification. MS ESI +ve m/z 331 (M+H).
Reaction SMILES: [CH2:1]([OH:12])[C:2]([C@@H:4]([OH:11])[C@H:5]([OH:10])[C@@H:6]([OH:9])[CH:7]=O)=O.[CH:13]([NH2:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:7]1[N:26]([CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:2]([CH2:1][OH:12])[C@@H:4]([OH:11])[C@H:5]([OH:10])[C@H:6]1[OH:9]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)C(=O)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a -78° C. solution of 5-keto-D-glucose (Formula V, 4.00 g, 0.0225 mol) in 100 mL of methanol was added a cooled solution (-78° C.) of benzhydrylamine (3.29 g, 0.018 mol) and acetic acid (1.08 g, 0.018 mol) in 100 mL of methanol. Sodium cyanoborohydride (2.82 g, 0.0449 mole) was added, and the mixture was stirred at -78° C. for 2 h and then slowly warmed to ambient temperature. After 18 h, the solution was concentrated, saturated aqueous sodium carbonate was added, and the product was extracted into chloroform. The chloroform extracts were combined, dried (sodium sulfate), and concentrated to afford a yellow foam. Chromatographic purification on flash silica gel (5-10% gradient of methanol in chloroform) afforded 4.06 g (69%) of the title compound as a very pale yellow foam. 1H NMR and reversed-phase analytical HPLC showed that this substance was >95% stereochemically pure (ca. 4.5% of the iditol isomer). Recrystallization from MEOH afforded white needles, mp 101°-104° C. (corrected). Both 1H and 13C NMR in CDCl3 and D3CC(O)CD3 confirmed the structure.
Reaction SMILES: C(Cl)(=O)OCC.[CH2:7]([C:11]1[C:12](=[O:23])[NH:13][C:14]([C:20](O)=[O:21])=[C:15]([O:18][CH3:19])[N+:16]=1[O-:17])[CH:8]([CH3:10])[CH3:9].[BH4-].[Li+].Cl>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[OH:21][CH2:20][C:14]1[NH:13][C:12](=[O:23])[C:11]([CH2:7][CH:8]([CH3:10])[CH3:9])=[N+:16]([O-:17])[C:15]=1[O:18][CH3:19]
Reactant: COc1c(C(=O)O)[nH]c(=O)c(CC(C)C)[n+]1[O-]
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1c(CO)[nH]c(=O)c(CC(C)C)[n+]1[O-]
Reaction time: 2 h
Yield: 67.9 %

Procedure:
0.70 Milliliters of ethyl chlorocarbonate was added, at -15° C., to a solution of 730 mg of 3-isobutyl-5-methoxy-1,2-dihydropyrazin-2-one-6-carboxylic acid 4-oxide and 1.0 ml of triethylamine dissolved in 20 ml of tetrahydrofuran, and the mixture was stirred for 2 hours at the same temperature. Thereto was added 330 mg of lithium borohydride, and the mixture was stirred for 18 hours at room temperature. To the reaction mixture was added 5 ml of 10% hydrochloric acid, and the mixture was diluted with ethyl acetate with stirring, and the resulting mixture was dried over magnesium sulfate, then the solvent was removed by evaporation. The residue was purified by a silica gel column chromatography (eluting solvent: 10% by volume of methanol-chloroform) to obtain 467 mg of 6-hydroxymethyl-3-isobutyl-5-methoxy-1,2-dihydropyrazin-2-one 4-oxide (Compound B-35) as a pale yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4](I)[CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O.C(COC)OC>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A suspension of 1-fluoro-3-iodo-5-nitrobenzene (11.0 g, 41.3 mmol), phenyl boronic acid (5.54 g, 45.4 mmol), tri-o-tolylphosphine (1.26 g, 4.13 mmol), Pd(OAc)2 (0.463 g, 2.07 mmol), and sodium carbonate (6.57 g, 62.0 mmol) in 4:1 dimethoxyethane:water (80 mL) was heated to 100° C. in a sealed tube for 6 hours. Upon cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (500 mL) and filtered through CELITE. The organic layer was washed with brine (500 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided 3-fluoro-5-nitrobiphenyl as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.93 (dt, J=8.1 Hz, 2.1 Hz, 1H), 7.72-7.60 (m, 3H), 7.51 (ddd, J=10.9, 9.9, 5.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([CH3:29])[CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](=O)[CH3:40])[N:34]=1)(=O)[CH3:31]>C1(C)C=CC=CC=1>[CH2:1]([O:21][C:22]1[CH:28]=[CH:27][C:25]([N:26]=[C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39](=[N:26][C:25]3[CH:27]=[CH:28][C:22]([O:21][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:23][C:24]=3[CH3:29])[CH3:40])[N:34]=2)[CH3:31])=[C:24]([CH3:29])[CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCCCCOc1ccc(N)c(C)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCOc1ccc(N=C(C)c2cccc(C(C)=Nc3ccc(OCCCCCCCCCCCCCCCCCCCC)cc3C)n2)c(C)c1
Yield: 69 %

Procedure:
10.0 g (25 mmol) 4-eicosanoxy-2-methylaniline was reacted under stirring with 2.3 g (14 mmol) 2,6-diacetylpyridine in the presence of 29 g 4 Å molecular sieves in 250 ml of refluxing toluene for 20 h. Subsequently the compound was filtered while hot, and volatiles removed from residue under reduced pressure. It was then washed with hot ethanol (300 ml) to give a yellow solid, which was dried in the vacuum oven (9.1 g, 69% yield).