Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:24]2[C:23](=[O:29])[CH2:22][C@@:21]2([CH3:30])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:20])[CH:13]([CH2:15][O:16][C:17](=[O:19])[CH3:18])I)[CH2:3]1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>ClCCl>[CH2:31]([N:33]([CH2:18][C:17]([O:16][CH2:15][CH2:13][C:12](=[O:20])[C@@H:11]1[C@:21]2([CH3:30])[C@H:8]([C@H:7]3[C@H:24]([C:23](=[O:29])[CH2:22]2)[C@:25]2([CH3:28])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:27][CH2:26]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)=[O:19])[CH2:34][CH3:35])[CH3:32]
Reactant: CCNCC
Reactant: CC(=O)OCC(I)C(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: ClCCl
Product: CCN(CC)CC(=O)OCCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
3α-hydroxy-21-iodo-acetoxymethyl-5α-pregnane-11,20-dione (235 mg) in dry dichloromethane (25 ml) was treated with diethylamine (1 ml) in similar manner to that described in Example 35 to give title compound (89 mg)[αD ] + 73° (c 0.42).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C@@H:22]1[CH2:27][N:26]([CH3:28])[C:25](=[O:29])[CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C@@H:22]2[CH2:27][N:26]([CH3:28])[C:25](=[O:29])[CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CN1C[C@@H](N)CCC1=O
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1C[C@@H](Nc2nc(Cl)nc3c2SCC3)CCC1=O
Temperature: 130 °C

Procedure:
0.27 g (II) are placed in 3 ml dioxane, then 0.45 ml diisopropylethylamine and 0.25 g (S)-5-amino-1-methylpiperidin-2-one are added. The reaction mixture is heated to 130° C. until there is no further reaction, then cooled and evaporated down. The product is extracted with dichloromethane and purified by chromatography (preparative HPLC, method B). 0.26 g (III-5) are obtained in the form of a solid. Analytical HPLC-MS (method A): RT=1.06 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)CCC>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>[CH3:8][C:5]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:3][CH:2]=[CH:7][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccnc1-c1ccccn1
Temperature: 110 °C
Reaction time: 48 h
Yield: 76.2 %

Procedure:
A mixture of 2-bromo-5-methylpyridine (5.0 g, 29 mmol), 2-tributylstannylpyridine (10 g, 27 mmol) and Pd(PPh3)4 (2.0 g, 1.7 mmol) in dry toluene (250 mL) was stirred for 48 h at 110° C. The reaction mixture was filtered over Celite and evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. Flash column chromatography (0.5% MeOH in CH2Cl2) afforded methyl-2,2′-bipyridine (3.5 g, 75%) as a colorless oil. 1H-NMR (500 MHz, CDCl3): 2.47 (s, 3H), 7.35 (dd, 1H), 7.70 (dd, 1H), 7.87 (m, 1H), 8.36 (d, 1H), 8.43 (d, 1H), 8.58 (d, 1H), 8.74 (dd, 1H).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1)[CH2:7][CH2:8]C.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([N:15]2[CH:11]([O:10][CH2:6][CH2:7][CH3:8])[CH2:12][CH2:13][C:14]2=[O:16])=[O:26])=[CH:19][CH:20]=1
Reactant: CCCCOC1CCC(=O)N1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCOC1CCC(=O)N1C(=O)c1ccc(OC)cc1
Reaction time: 2 h

Procedure:
11.2 cm3 of a 1.6M solution of n-butyllithium in n-hexane is added at -40° C. to a solution, cooled to -45° C., of 2.8 g of 5-n-butyloxy pyrrolidin-2-one in 70 cm3 of tetrahydrofuran with agitation for 30 minutes. Under the same conditions, a solution of 5.24 g of anisoyl chloride (at 58% in toluene) in 6 cm3 of tetrahydrofuran is added. After agitation for 2 hours, allowing to return to ambient temperature, the mixture is evaporated to dryness. The oil obtained is chromato-graphed on silica (eluent: toluene-ethyl acetate 8-2) and 2 g of the product sought is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[CH:26]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cccc(-c2cc(CCl)ccn2)c1
Product: COc1ccc(N(Cc2ccnc(-c3cccc(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(3-methoxyphenyl)pyridine (234 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10]2[CH2:11][N:12]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[C:9]=2[CH:8]=[N:7]1)C.[NH3:28]>>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]2[C:9]3[CH:8]=[N:7][N:6]([CH2:5][C:4]([NH2:28])=[O:3])[C:10]=3[CH2:11][N:12]=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14]=2[CH:19]=1
Reactant: N
Reactant: CCOC(=O)Cn1ncc2c1CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Product: NC(=O)Cn1ncc2c1CN=C(c1ccccc1)c1cc(Cl)ccc1-2

Procedure:
A mixture of 0.4 g (1.05 mmol) of 8-chloro-6-phenyl-3H,4H-pyrazolo[3,4-d][2]benzazepine-3-acetic acid ethyl ester and 20 ml of methanolic ammonia (ca 20% v/v) was heated in an autoclave on the steam bath overnight. The solvent was evaporated and the residue was purified by chromatography over 15 g of silica gel using 5% (v/v) of ethanol in methylene chloride. Crystallization from ethyl acetate/ether gave colorless crystals with mp 218°-219°.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([NH:17][CH:5]=[N:4][C:3]#[N:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Solvent: ClC(Cl)Cl
Product: N#CN=CNc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 90 °C
Yield: 183.2 %

Procedure:
Cyanamide (8.00 g, 190.0 mmol) was stirred at reflux in triethylorthoformate (60 mL) for 2 h. The reaction was cooled to room temperature and distilled to provide ethyl-N-cyanoimidate (12.5 g, bp=110-112° C./45 mm Hg).* To this imidate (1 mL) was added 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.05 g, 0.2 mmol) and the mixture was heated at 90° C. for 4 h, cooled, diluted with chloroform, filtered, and evaporated. The crude product was purified by reverse phase chromatography to furnish 0.053 g (17%) of the title compound as an off white solid: mp 148-149° C.; 1H NMR (300 MHz, CDCl3) δ 9.45 and 9.33 (bd, bs, J=10 Hz, 1H), 8.33 and 8.25 (2d, J≈2 Hz, 1H), 7.46-7.38 (m, 2H), 7.11-7.01 (m, 2H), 5.35 and 5.33 (2s, 2H); HPLC-MS (ESI) m/z 290 (M+H)+, 288 (M−H)−. *Bridsen, Peter K., and Wang, Xiaodong, Synthesis, 1995, 855-8.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([O:33]CC)=[O:32])=[CH:27][CH:26]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:9][C:8]=1[C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:3])[CH3:2].[OH-].[Na+]>O1CCCC1.O>[C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:9][C:8]=1[C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc(NCCC(C)=O)c(C(C)(C)C)c3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)CCNc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCCCO)cc1C(C)(C)C
Yield: 76.2 %

Procedure:
In a manner similar to that of Example 3, by reacting 270 mg of ethyl 4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate with 0.8 mL and then 0.4 mL of aqueous 1N sodium hydroxide solution in a mixture of 8 mL of tetrahydrofuran and 2 mL of water. 195 mg of 4″-(acetylethylamino)-3″-tert-butyl-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid are obtained in the form of a white solid (yield=95%, m.p.=75° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](S(C)(=O)=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:20]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([O:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)nc(S(C)(=O)=O)n1
Reactant: O
Product: Cc1cc(OCc2ccccc2)nc(Oc2ccccc2)n1

Procedure:
4-Benzyloxy-6-methyl-2-(methylsulfonyl)pyrimidine (Compound II-4) (0.45 g, 0.00162 mol) was added thereto and the resulting solution was allowed to react for about 2 hours at room temperature. The reaction solution was poured into water and extracted with ethyl acetate to separate an organic phase. The obtained organic phase was washed successively with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, then dried over anhydrous sodium sulfate and thereafter concentrated. The concentrate was purified on silica gel column to obtain the end product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl[CH2:14]/[CH:15]=[C:16]1/[C:17]2[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[CH:28]=[CH:27][C:18]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]/1=2>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:14]/[CH:15]=[C:16]2/[C:17]3[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[CH:28]=[CH:27][C:18]=3[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]/2=3)[CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)/C(=C/CCl)c1ccccc1CO2
Reactant: c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)/C(=C/Cc1cccnc1)c1ccccc1CO2
Temperature: 25 °C

Procedure:
To 50 ml of pyridine was added to 2.0 g of lithium aluminum hydride, and the mixture was stirred at room temperature for one night. Then, 90 ml of tetrahydrofuran solution containing 5.0 g of Compound h was dropwise added thereto under ice-cooling. The mixture was stirred at room temperature for 5 hours, and the solvent was distilled off under reduced pressure. The residue was washed with tetrahydrofuran, and the washings were concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate:triethylamine=10:10:1) to give 1.7 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7]([CH2:15][CH2:16][NH:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:11](OC)=[O:12])[C:6]=2[CH:26]=1.C([N-]C(C)C)(C)C.[Li+].C(O)(=O)C>O1CCCC1>[CH2:19]([O:18][N:17]1[CH2:16][CH2:15][C:7]2([C:6]3[CH:26]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][CH2:8]2)[C:11]1=[O:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C1(CCNOCc2ccccc2)CCOc2ccc(F)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1N(OCc2ccccc2)CCC12CCOc1ccc(F)cc12

Procedure:
To a solution of methyl 2,3-dihydro-6-fluoro-4-(2-(benzyloxyamino)ethyl)-4H-1-benzopyran-4-carboxylate (3.1 g) in anhydrous tetrahydrofuran at -78° C. was added a solution of 1-M lithium diisopropylamide (9.0 mL) in tetrahydrofuran. After 1 hour acetic acid (1 mL) was added, and the solution concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N HCl, and organic layers washed with 1N HCl, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated to afford the title compound as an oil, 2.9 g. (1H NMR (CDCl3, 60 MHz): 1.9-2.5 (m, 4H), 3.2-4.6 (m, 4H), 5.0 (s, 2H), 6.3-6.8 (m, 3H), 7.3-7.5 (m, 5H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1cnn(CCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In flask were introduced 4-iodopyrazole (10 g, 51.6 mmol), cesium carbonate (20.16 g, 61.9 mmol) and anhydrous DMF (98 mL). The suspension was stirred at rt for 5 min, before adding 2-(2-bromoethoxy)tetrahydro-2H-pyran (9.74 mL, 61.9 mmol) and heating at 70° C. for 17 h. Then the RM was quenched with 100 mL water and extracted with 3×120 mL EtOAc. The combined organic layers were washed with 3×100 mL water and 1×100 mL brine, before being dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash chromatography (6×25 cm, Hexane/EtOAc 0%-30%) to afford the title compound as a colorless oil (tR 3.12 min (conditions 8), MH+=323).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]([C:19]1[N:20]([CH3:29])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH2:28])=[CH:23][CH:22]=2)=[O:18]>>[CH3:15][O:16][C:17]([C:19]1[N:20]([CH3:29])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH:28][C:12]([C:10]1[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=1)=[O:14])=[CH:23][CH:22]=2)=[O:18]
Reactant: COC(=O)c1cc2cc(N)ccc2n1C
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Product: COC(=O)c1cc2cc(NC(=O)c3ccc(-c4ccccc4)o3)ccc2n1C

Procedure:
Carboxylic acid (56) (23 mg, 0.12 mmol) was coupled to 5-amino-1-methyl-1H-indole-2-carboxylic acid methyl ester (25 mg, 0.12 mmol) using Method D to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[CH3:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH:18]=O>O.CO.[Pd]>[CH2:18]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])[CH2:17][C:16]([CH3:21])([CH3:20])[CH3:15]
Reactant: CC(C)(C)CC=O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)CCN[C@@H](CC(=O)O)C(=O)O
Reaction time: 48 h
Yield: 72.9 %

Procedure:
L-aspartic acid (4 g, 0.03 mol) was added to a Parr bottle containing a solution of sodium bicarbonate (5.04 g, 0.06 mol) in water (50 mL) to form a clear solution, with effervescence. A solution of 3,3-dimethylbutyraldehyde (3 g, 0.03 mol) in methanol (50 mL) was then added to the Parr bottle, followed by Pd/C (4% palladium on carbon, 50% wet, 0.4 g). The mixture was hydrogenated at 50 psi/room temperature for 2 days. If the reaction was not complete, fresh Pd/C (0.2 g) would be added and hydrogenation continued for an additional 8 hrs. The mixture was filtered through a Celite® bed, and the bed was washed with methanol (20 mL). The filtrate and washings were combined and concentrated under reduced pressure at 40-50° C. The pH of the remaining aqueous solution was adjusted to 3 with concentrated hydrochloric acid. The precipitated solid was filtered and dried in a vacuum oven at 50° C. for 4 hrs to give 4.75 g (73%) of crude N-neohexyl-L-aspartic acid. The crude product was slurried with aqueous ethanol (47.5, 80% ethanol, 20% water) for 15 minutes and filtered to give 3.3 g (51%) of >98% pure N-neohexyl-L-aspartic acid. M.P. 184-186° C.; [α]D +12.35 (c=1, water); NMR (D2O) δ3.37(t, 3H); 2.25-2.65 (m, 4H); 1.27-1.47 (m, 2H); 0.89(s, 9H); Anal. Calc'd. for C10H19NO4 ; C, 55.28; H, 8.81; N, 6.45; Found: C, 55.35; H, 8.86; N, 6.50.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O-])=O>CCO.C1COCC1.[Zn]>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCC[N+](=O)[O-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCCCCCC(=O)OCCCCN

Procedure:
Hexadecanoic acid (4-nitrobutyl)ester was reduced with zinc in EtOH/THF/6 nHCl for 30 minutes at 35°-35°. Work up in the cold via basification with ammonia and extraction with methylene chloride yielded a crude residue. Crystallization from ether furnished off-white crystals, m.p. 59°-61°.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[C:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].O[ClH](O)(=O)=O>N1C=CC=CC=1>[C:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1)(=[O:16])[CH3:15]
Reactant: CC(=Cc1ccc(O)cc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=C(C)C(=O)O)cc1
Reaction time: 2 h
Yield: 89.9 %

Procedure:
In 100 ml of pyridine was dissolved 18 g of refined 4-hydroxy-α-methylcinnamic acid synthesized in Referential Example 1, 20 g of acetic anhydride was dropped into the solution, and the reaction was carried out at room temperature with stirring for 2 hours. Then, the liquid reaction mixture was dropped in a 1% by weight aqueous solution of hydroxychloric acid, and the precipitated reaction product was recovered by filtration, washed with water, and dried to obtain 20 g of 4-acetoxy-α-methylcinnamic acid.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][C:12](=[O:39])[CH2:13][CH2:14][C:15]([CH3:38])=[CH:16][CH2:17][C:18]1[C:19]([O:31]CC[Si](C)(C)C)=[C:20]2[C:24](=[C:25]([CH3:29])[C:26]=1[O:27][CH3:28])[CH2:23][O:22][C:21]2=[O:30])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[OH:31][C:19]1[C:18]([CH2:17][CH:16]=[C:15]([CH3:38])[CH2:14][CH2:13][C:12]([NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:39])=[C:26]([O:27][CH3:28])[C:25]([CH3:29])=[C:24]2[C:20]=1[C:21](=[O:30])[O:22][CH2:23]2
Reactant: CCOP(=O)(CCNC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COc1c(C)c2c(c(O)c1CC=C(C)CCC(=O)NCCP(=O)(O)O)C(=O)OC2
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a solution of (2-{6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-ethyl)-phosphonic acid diethyl ester (36.6 mg, 0.063 mmol) in acetonitrile (1 mL) was added TMSBr (81 μL, 0.63 mmol) followed by 2,6-lutidine (73 μL, 0.63 mmol). The reaction was allowed to proceed overnight when it was completed as judged by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by preparative reverse-phase HPLC to afford 5.8 mg (29%) of desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.80 (s, 3H), 2.14 (m, 5H), 2.25 (m, 4H), 3.35 (m, 2H), 3.38-3.38 (m, 2H), 3.75 (s, 3H), 5.23 (s, 3H) ppm; 31p (121.4 MHz, CD3OD) δ 26.03 ppm; MS (m/z) 426 [M−H]−, 428 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[N:7]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:17])[C:8]3=[N:9]2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][NH:18][C:16]([C:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:24])[N:7]2[CH:15]=[CH:14][CH:13]=1)=[CH:4][CH:3]=[C:2]([C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1)[CH:11]=3)=[O:17]
Reactant: OB(O)c1cccnc1
Reactant: CN(C)CCNC(=O)c1cccn2c(=O)c3ccc(Br)cc3nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCNC(=O)c1cccn2c(=O)c3ccc(-c4cccnc4)cc3nc12

Procedure:
The procedure of Example 6 was used with the product of Example 14 (39 mg, 0.1 mmol), product of Example 4 (123 mg, 1.0 mmol), tetrakis(triphenylphospine)palladium(0) (29 mg, 0.025 mmol), 2 M sodium carbonate solution (0.5 ml, 1.0 mmol), and toluene (5 ml).
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([CH3:15])=[C:12]([CH3:16])[N:11]=[C:10]([NH2:17])[C:9]=2[N:8]=[C:7]1[CH2:18][CH2:19][CH3:20].[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)[CH3:22].Cl.N1C=CC=CC=1>CO>[NH2:17][C:10]1[C:9]2[N:8]=[C:7]([CH2:18][CH2:19][CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][O:2]/[N:1]=[C:21](/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)\[CH3:22])[C:14]=2[C:13]([CH3:15])=[C:12]([CH3:16])[N:11]=1
Reactant: CCCc1nc2c(N)nc(C)c(C)c2n1CCCON
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCO/N=C(\C)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A solution of 1-[3-(aminooxy)propyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine (0.64 g, 2.3 mmol) and acetophenone (325 μL, 2.76 mmol) in methanol (23 mL) was stirred overnight at room temperature, then heated at 50° C. for 4 hours. Pyridine hydrochloride (100 mg) was added to the solution and stirring was continued at 50° C. overnight. Additional pyridine hydrochloride was added and the solution was heated at reflux for 5 hours. The solvent was removed under reduced pressure and the resulting off-white solid was partitioned between chloroform (100 mL) and saturated aqueous sodium carbonate (30 mL). The aqueous layer was extracted with chloroform (3×30 mL). The combined organic layers were washed with saturated aqueous sodium carbonate (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 5-30% CMA in chloroform) to yield a solid that was triturated with acetonitrile and dried under vacuum at 70° C. overnight to provide 105 mg of (1E)-1-phenylethanone O-[3-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]oxime as a white powder, mp 125.0-127.0° C. Anal. Calcd for C22H29N5O: C, 69.63; H, 7.70; N, 18.45. Found: C, 69.41; H, 7.73; N, 18.36.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:15][C:16]#[N:17]>CN(C)C=O.C(OCC)(=O)C>[C:16]([CH2:15][N:6]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:17]
Reactant: N#CCBr
Reactant: CCOC(=O)c1ccc(C)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C)n1CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
A solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate (1 g, 6.53 mmol) in anhydrous N,N-dimethylformamide (20 mL) under nitrogen at 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (392 mg, 9.79 mmol). After effervescence ceased, the reaction was treated with a solution of 2-bromoacetonitrile (1.17 g, 9.79 mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. At this time, the reaction was diluted with ethyl acetate (200 mL), washed with water (2×100 mL) and a saturated aqueous sodium chloride solution (2×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (80 g silica gel column, 0-20% ethyl acetate/hexanes) afforded ethyl 1-(cyanomethyl)-5-methyl-1H-pyrrole-2-carboxylate (0.5 g, 39.8%). LC-MS calcd. for C10H13N2O2 [(M+H+] 193, obsd. 193.1.