Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.C(NC(C)C)(C)C.[Li].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[C:25]([C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=1>C1COCC1>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([CH:4]2[CH2:5][CH2:6][CH2:7][N:8]=[C:3]2[O:2][CH3:1])[CH:25]([C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:23]=1
Reactant: COC1=NCCCC1
Reactant: COC(=O)C(=Cc1ccc(F)cc1)C(=O)C(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C(=O)C(C)C)C(c1ccc(F)cc1)C1CCCN=C1OC
Temperature: -60 °C
Yield: 106.5 %

Procedure:
6-Methoxy-2,3,4,5-tetrahydropyridine (102.7 g, 0.91 mole) was added over 25 min to a solution of lithium diisopropylamine (1.8 M, 505 mL, 0.91 mole) in THF (1.2 L) stirring at −60° C. under nitrogen. After stirring at −60° C. for 1 h, methyl 3-(4-fluorophenyl)-2-isobutyrylacrylate (175 g, 0.70 mole) was added over 75 min keeping the temperature below −50° C. The reaction was quenched with saturated ammonium chloride (750 mL) after the reaction had stirred at −60° C. for 35 min. After the reaction mixture had warmed to room temperature, ethyl acetate was added and the mixture transferred to a separatory funnel. The mixture was extracted with ethyl acetate (2×1 L). The combined organic layers were washed with 50% saturated ammonium chloride solution, water, and brine; dried over magnesium sulfate; and concentrated in vacuo to afford methyl 2-[(4-fluorophenyl)-(2-methoxy-3,4,5,6-tetrahydro-pyridin-3-yl)-methyl]-4-methyl-3-oxo-pentanoate (271 g).
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:11][CH:12]1[CH2:17][CH2:16][N:15](C)[CH2:14][CH2:13]1>C(Cl)Cl>[Cl:11][CH:12]1[CH2:17][CH2:16][N:15]([C:1]([O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:9])[CH2:14][CH2:13]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC(Cl)CC1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC(Cl)CC1
Reaction time: 6 h
Yield: 71.3 %

Procedure:
A solution of phenyl chlorocarbonate (17.3 g) in dry methylene chloride (40 ml) was dropwise added to a stirred solution of 4-chloro-1-methylpiperidine (13.3 g) in dry methylene chloride (60 ml) under ice-cooling over a period of 5 minutes. The resultant mixture was stirred at the same temperature for 30 minutes and then at room temperature for 6 hours. The mixture was washed with water, dried over magnesium sulfate, and concentrated in vacuo to give an oil, which was distilled to give phenyl 4-chloro-1-piperidine-carboxylate (17.0 g) as a colourless oil.
Reaction SMILES: [CH2:1]([C:6]1([CH3:17])[O:11][C:10](=[O:12])[CH:9]([CH2:13][C:14]([OH:16])=[O:15])[S:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[N+](=[CH2:20])=[N-]>C(OCC)C>[CH3:20][O:15][C:14](=[O:16])[CH2:13][CH:9]1[S:8][CH2:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])([CH3:17])[O:11][C:10]1=[O:12]
Reactant: C=[N+]=[N-]
Reactant: CCCCCC1(C)CSC(CC(=O)O)C(=O)O1
Solvent: CCOCC
Product: CCCCCC1(C)CSC(CC(=O)OC)C(=O)O1

Procedure:
To 4.7 g of 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid, dissolved in 50 ml of diethyl ether, there is added dropwise, with stirring and ice cooling, ethereal diazomethane solution, until a pale yellow color just remained. After the usual working up, 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid methyl ester is obtained:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[N:18]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-].O>[Fe].CO>[N:18]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[O:11][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3ccncc3o2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2nc3ccncc3o2)cc1
Yield: 64.4 %

Procedure:
A mixture of 2-(4-nitrophenyl)oxazolo[5,4-c]pyridine (610 mg, 2.5 mmol), NH4Cl (1.2 g, 22.4 mmol), iron powder (0.76 g, 13.6 mmol), H2O (13 mL) and methanol (51 mL) was heated to reflux for 6 h under N2. The mixture was concentrated in vacuo and purified by chromatography on silica gel (eluted with EA/PE=3:1) to give 4-(oxazolo[5,4-c]pyridin-2-yl)benzenamine as light brown powder (340 mg, yield 64%). 1H NMR (400MHz, DMSO-d6) δ:8.95 (1H, s); 8.46 (1H, d, J=5.2); 7.92 (2H, d, J=8.8); 7.69 (1H,d, J=5.6), 6.71 (2H,d, J=8.8), 6.19 (2H, s); MS(ESI) calcd for C12H9N3O (m/z): 211, found: 212 [M+H]+.
Reaction SMILES: C1C2C3C=CC(C2C=C1)C3.C(/C(/C([O-])=O)=C(/C(C)C)\C([O-])=O)(C)C.[CH:25]([O:28][C:29]([CH:31]1[CH:36]([C:37]([O:39]C(C)C)=[O:38])[CH:35]2[CH2:43][CH:32]1[CH:33]=[CH:34]2)=[O:30])([CH3:27])[CH3:26]>>[CH:25]([O:28][C:29]([CH:31]1[CH:36]([C:37]([OH:39])=[O:38])[CH:35]2[CH2:43][CH:32]1[CH:33]=[CH:34]2)=[O:30])([CH3:27])[CH3:26]
Reactant: CC(C)OC(=O)C1C2C=CC(C2)C1C(=O)OC(C)C
Agent: CC(C)/C(C(=O)[O-])=C(\C(=O)[O-])C(C)C
Solvent: C1=CC2C3C=CC(C3)C2C1
Product: CC(C)OC(=O)C1C2C=CC(C2)C1C(=O)O
Reaction time: 5 h
Yield: 83 %

Procedure:
27.1 g (0.2 mol) of dicyclopentadiene and 80.4 g (0.4 mol) of diisopropylfumarate were charged in a 200 ml autoclave, and after sufficiently replacing with nitrogen, reaction was conducted at 170° C. for 5 hours. The reaction liquid was distilled under reduced pressure of 0.4 kPa to obtain 88 g of a fraction of 124-126° C. It was confirmed by 1H-NMR spectrum and GC-MS that this fraction is 5-norbornene-2,3-dicarboxylic acid diisopropyl ester. Yield: 83%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:10]1[N:11]=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:39]=[CH:38][CH:37]=[CH:36][C:27]=4[O:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30]([NH2:32])=O)=[CH:20][C:18]=3[CH:19]=2)[S:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7]>CN(C)C=O>[C:6]([C:10]1[N:11]=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:39]=[CH:38][CH:37]=[CH:36][C:27]=4[O:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30]#[N:32])=[CH:20][C:18]=3[CH:19]=2)[S:13][CH:14]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCC(C#N)Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Phosphorus oxychloride (245 mg) was dissolved in dimethylformamide (2 ml) and the solution was ice-cooled. To this solution was added 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy]pentanamide (510 mg), and the mixture was stirred for two hours at room temperature. The reaction mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanenitrile (453 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[S:21][C:20]([N:22](CC2C=CC(OC)=CC=2OC)[S:23]([C:26]2[CH:31]=[CH:30][C:29](F)=[C:28]([C:33]#[N:34])[CH:27]=2)(=[O:25])=[O:24])=[N:19][CH:18]=1.[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:29]2[CH:30]=[CH:31][C:26]([S:23]([NH:22][C:20]3[S:21][C:17]([Cl:16])=[CH:18][N:19]=3)(=[O:24])=[O:25])=[CH:27][C:28]=2[C:33]#[N:34])=[C:4]([I:9])[CH:3]=1
Reactant: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Oc1ccc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a stirred suspension of 4-chloro-2-iodophenol (305 mg, 1.20 mmol) and potassium carbonate (207 mg, 1.5 mmol) in dimethyl sulphoxide (5.0 ml) was added N-(5-chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4-dimethoxybenzyl)-4-fluorobenzenesulfonamide (Preparation 207, 468 mg, 1.00 mmol). Suspension stirred at room temperature for 18 hours. The reaction mixture was poured into ethyl acetate (20 ml) and saturated aqueous ammonium chloride solution (20 ml) and the aqueous layer extracted with ethyl acetate (3×20 ml). Combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude residue was dissolved in dichloromethane (5 ml), trifluoroacetic acid (5 ml) was added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was concentrated in vacuo and purified by ISCO™ preparative system eluting with dichloromethane:ethyl acetate (gradient 1:0 to 6:4, by volume) to afford the title compound as a solid, 396 mg, 72% yield.
Reaction SMILES: C([C:5]1[CH:6]=[C:7](C2OC=C(CCO)N=2)[CH:8]=[C:9](C(C)(C)C)[C:10]=1[OH:11])(C)(C)C.C(N(C(=O)CC)CC[C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:29]1([O:11][C:10]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)c1cc(-c2nc(CCO)co2)cc(C(C)(C)C)c1O
Reactant: CCC(=O)N(CC)CCc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 109.7 %

Procedure:
To a stirred solution of 2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-hydroxyethyl)oxazole (5.51 g, 17.38 mmole) in tetrahydrofuran (47 ml) was added N-ethyl,N-propionyl tyramine (3.5 g, 15.8 mmole) and triphenylphosphine (4.55 g, 17.38 mmole). After cooling to 0° C., a solution of diethylazodicarboxylate (2.73 ml, 17.38 mmole) in tetrahydrofuran (16 ml) was added dropwise over 10 minutes. The reaction was allowed to warm to room temperature and stir for 22 hours, evaporated, and triturated with methylene chloride (50 ml) and filtered The filtrate was chromatographed on silica gel twice using methylene chloride-ethyl acetate and hexane-acetone gradients to give the intermediate phenyl ether (2.95 g, 36%):
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:12]#[N:13])=[CH:7][CH:6]=1>[Ni].CO.[H][H]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][NH2:13])=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: COCOc1ccc(C(C#N)Cc2cccnc2)cc1
Agent: [Ni]
Solvent: CO
Product: COCOc1ccc(C(CN)Cc2cccnc2)cc1
Yield: 84.6 %

Procedure:
An appropriate amount of Raney nickel was suspended in 30 ml of saturated ammonical methanol solution, followed by addition of 3.81 g of 2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propionitrile, and stirred for 72 hours in hydrogen atmosphere of 15 atm. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column, which was then eluted with aqueous ammonia-methanol-chloroform (1:10:100 v/v), and from the eluted fraction was obtained 3.27 g of 2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Ca+2].[OH-].[C:12](=O)([O-])[O-:13].[Na+].[Na+].Cl>O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][C:7]=1[CH:12]=[O:13]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(Cl)c1
Agent: Cl
Agent: [Ca+2]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1ccc(O)cc1Cl
Reaction time: 3 h
Yield: 16.3 %

Procedure:
3-Chlorophenol (CAS 108-43-0) (49.2 g, 0.380 mol), calcium hydroxide (122.0 g), and sodium carbonate (139.4 g) were suspended in water (872 mL). Chloroform (90.6 g, 0.760 mol) was added for 80 min, and the mixture was refluxed under vigorous stirring for 3 h. The reaction mixture was cooled on ice bath. Concentrated HCl (385 mL) and chloroform (300 mL) were added. The aqueous layer was discarded. The organic one was dried with anhydrous Na2SO4 (50 g) and evaporated in vacuo. The residue was purified by chromatography (silica gel 63-100 μm, 600 g, CCl4→CHCl3→CHCl3/EtOAc 93:7). Fractions containing the product were combined, evaporated, and coevaporated with dioxane to give the title compound (9.77 g, 0.062 mol, 16%) as a white powder. 1H NMR data (DMSO-d6): 11.06 (s, 1H, COH); 10.14 (s, 1H, OH); 7.75 (d, 1H, J=8.5 Hz, Ar—H); 6.92 (d, 1H, J=2 Hz, Ar—H); 6.85 (d.d., 1H, J1=8.5 Hz, J2=2 Hz, Ar—H).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]([OH:15])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:8][C:9]#[CH:10])([CH3:4])[CH3:3].N1C=CN=C1.CN(C)C=O.Cl[Si:27]([CH3:30])([CH3:29])[CH3:28]>CCCCCC>[CH3:28][Si:27]([O:15][C:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:1])[CH3:4])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:8][C:9]#[CH:10])([CH3:30])[CH3:29]
Reactant: C#CCC(O)(C#C[Si](C)(C)C)CCCC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CCC(C#C[Si](C)(C)C)(CCCC)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a stirred mixture of 8.5 g. of 4-trimethylsilylethynyl-1-octyn-4-ol and 6.2 g. of imidazole in 24 ml. of dry dimethylformamide is added,, under nitrogen, 5.7 ml. of chlorotrimethylsilane, in a slow stream, via a syringe. The mixture is stirred in an ice-bath for one hour and then at room temperature overnight. The mixture is poured into hexane, washed with saturated sodium bicarbonate solution, water and then brine and dried over sodium sulfate. The solvents are evaporated to dryness giving 11.1 g. of the desired product.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16](Cl)[CH:15]=2)[C:11]2[CH:10]=[C:9]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]1.O.NN.O.C(Cl)Cl>C(O)C.[Pd]>[ClH:20].[NH2:2][CH:3]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:10]=[C:9]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: CS(=O)(=O)NCCOc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N)CC2
Agent: [Pd]
Agent: Cl
Agent: NN
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)NCCOc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2
Reaction time: 4 h
Yield: 72.5 %

Procedure:
N-(2-(7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)methanesulfonamide hydrochloride (50.0 mg, 0.104 mmol), Pd—C 10% (1.10 mg), and hydrazine monohydrate (522 mg, 10.4 mmol) were suspended in ethanol (5 ml) and stirred for 4 h under reflux. Water and CH2Cl2 were added, the mixture filtered, and the filtrate was extracted with CH2Cl2. The combined organic layers were washed with water, saturated NaCl solution, dried over Na2SO4, and concentrated to afford a residue that was purified by precipitation from diisopropylether. The residue was transferred to an HCl salt and finally gave the product as a white solid (31 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:14]>CO>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH2:12][O:10][C:3]2[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Cc1cc(C)c(C)c(O)c1
Solvent: CO
Product: Cc1ccc(C(=O)COc2cc(C)cc(C)c2C)cc1
Yield: 75 %

Procedure:
Using 2,3,5-trimethylphenol and 2-bromo-1-(4-methylphenyl)ethanone, the title compound was synthesized in the same manner as in Reference Example 159. Yield 75%. Melting point: 94-95° C. (methanol).
Reaction SMILES: C([O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]([C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[C:16]([Br:23])[N:15]=2)[C:11](=O)[CH3:12])=[C:7]([Cl:26])[CH:6]=1)(=O)C.C(O)(=O)C.C(Cl)(Cl)Cl.CO>C(O)C>[Br:23][C:16]1[N:15]=[C:14]2[N:10]([CH2:9][C:8]3[CH:24]=[CH:25][C:5]([OH:4])=[CH:6][C:7]=3[Cl:26])[C:11]([CH3:12])=[N:20][C:19]2=[CH:18][CH:17]=1
Reactant: CC(=O)Oc1ccc(CN(C(C)=O)c2nc(Br)ccc2[N+](=O)[O-])c(Cl)c1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: Cc1nc2ccc(Br)nc2n1Cc1ccc(O)cc1Cl
Temperature: 110 °C
Yield: 102 %

Procedure:
To a solution of 2-[N-(4-acetoxy-2-chlorobenzyl)acetamido]-6-bromo-3-nitropyridine (1.28 g) in ethanol (13 ml) were added acetic acid (1.5 ml) and reduced iron powder (646 mg), and the mixture was refluxed under heating at 110° C. for 15 hr. After allowing to cool, chloroform/methanol=10/1 (15 ml) was added and the mixture was stirred under ice-cooling. The insoluble matter was filtered off and the filtrate was concentrated. A saturated aqueous sodium hydrogen carbonate solution (5 ml) and chloroform/methanol=10/1 (15 ml) were added to make the mixture alkaline, and the precipitated insoluble matter was filtered off. The residue was repeatedly eluted with chloroform/methanol=5/1-2/1-1/1. The organic layer of the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. To the resulting crystals was added ethyl acetate (8 ml), and the mixture was heated and stirred at room temperature. The crystals were collected by filtration and dried under reduced pressure to give 5-bromo-3-(2-chloro-4-hydroxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine as colorless crystals (1.04 g).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccccn2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccccn2)ccc1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.9 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate (0.038 g) in ethyl acetate (2 mL) and methanol (4 mL), 10% palladium-carbon (20 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 45 minutes. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-70% hexane/ethyl acetate] to obtain 0.021 g of tert-butyl 2-(2-hydroxy-5-(pyridin-2-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22].O>CS(C)=O>[CH3:3][N:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[N:7]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14])[C:5]1=[O:6]
Reactant: Cc1cn(C)c(=O)[nH]c1=O
Reactant: C=CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCn1c(=O)c(C)cn(C)c1=O
Reaction time: 0.25 h
Yield: 74.6 %

Procedure:
This example illustrates a synthesis of 1-Methyl-3-(8,9-oxidononyl)thymine (inventive compound no. 1910). Sodium hydride (343 mg, 14 mmol) was added to a stirring solution of 1-methylthymine (2.00 g, 14 mmol) in dimethylsulfoxide (40 mL). After 15 minutes, 9-bromo-1-nonene (2.93 g, 14 mmol) was added and the mixture stirred for 20 hours. The reaction was poured into 40 mL water and extracted with dichloromethane (3×50 mL). The organic layers were combined, washed with water (40 mL), saturated aqueous salt solution (20 mL), and dried over sodium sulfate. The solvent was evaporated to yield 2.76 g (73% yield) 1-Methyl-3-(8-nonenyl)thymine (inventive compound no. 1917) as a colorless oil which solidified upon standing.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([CH3:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:27]4[CH:28]=[CH:29][C:24]([NH2:23])=[N:25][CH:26]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example E.62) (0.2 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.11 g, 54%). MS (ISP) 407.4 [(M+H)+]; mp 170.5° C.
Reaction SMILES: C[O-].[Na+].C[O:5][C:6]([C:8]1([NH:16][C:17](=[O:27])[CH2:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:13][CH2:12][N:11]([O:14][CH3:15])[CH2:10][CH2:9]1)=O>CN(C)C=O>[CH3:26][C:20]1[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=1[C:18]1[C:17](=[O:27])[NH:16][C:8]2([CH2:9][CH2:10][N:11]([O:14][CH3:15])[CH2:12][CH2:13]2)[C:6]=1[OH:5]
Reactant: COC(=O)C1(NC(=O)Cc2cc(C)ccc2C)CCN(OC)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON1CCC2(CC1)NC(=O)C(c1cc(C)ccc1C)=C2O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 0.82 g of sodium methylate in 20 ml of dimethylformamide was added a solution of 4-[2-(2,5-dimethyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester in 10 ml of dimethylformamide at a temperature of 60° C. After stirring for 3 hours at 60° C., the reaction mixture was evaporated. The residue was diluted with 10 ml of water, neutralized with 10% hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to yield 1.23 g of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound C1) as a light brown resin. This material was triturated with diethyl ether/hexane, filtered and dried to afford a solid, mp: 176-177° C.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([OH:15])(=[O:14])[CH:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10].CI>CCCCCC>[CH3:1][C:7]([CH2:11][CH2:12][CH3:13])([CH2:8][CH2:9][CH3:10])[C:6]([OH:15])=[O:14]
Reactant: [Li]CCCC
Reactant: CCCC(CCC)C(=O)O
Solvent: CI
Solvent: CCCCCC
Product: CCCC(C)(CCC)C(=O)O

Procedure:
The alkylation of the carboxylic acids at position 2 using alkyl halides is very generally possible with the aid of n-butyllithium at elevated temperature (Pfeffer et al., Alpha-anions of carboxylic acids. II. The formation and alkylation of alpha-metalated aliphatic acids. Journal of Organic Chemistry 37, 451-458 (1972). The methylation of the tertiary carbon atom of valproic acid is possible, for example, by deprotonation of the α-hydrogen atom at C-2 using n-butyllithium in hexane at 50° C. and subsequent methylation with methyl iodide at room temperature in a yield of 32%. The other 2-alkylated carboxylic acids can also be prepared in accordance with this method.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([O:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH2:25][CH2:24][N:23]([CH:26]5[CH2:31][O:30]C(C)(C)[O:28][CH2:27]5)[CH2:22][CH:21]=4)=[C:16]([F:34])[CH:15]=3)[CH2:9]2)=[N:2]1.Cl.N>C1COCC1>[O:1]1[CH:5]=[CH:4][C:3]([O:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH2:27][OH:28])[CH2:31][OH:30])[CH2:22][CH:21]=4)=[C:16]([F:34])[CH:15]=3)[CH2:9]2)=[N:2]1
Reactant: CC1(C)OCC(N2CC=C(c3ccc(N4C[C@H](COc5ccon5)OC4=O)cc3F)CC2)CO1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(C2=CCN(C(CO)CO)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.6 %

Procedure:
To a stirred solution of Example 59 (203 mg, 0.43 mmol) in THF (15 ml) was added 1N HCl (10 ml). The reaction was allowed to stir at ambient temperature for 18 hours. The reaction was basified with ammonia solution until aqueous layer was pH12. The reaction was extracted with EtOAc and the combined organic phases were washed with sat NaCl and then dried over MgSO4 and evaporated under reduced pressure. The resulting yellow oil was triturated with ether to give the title compound as a pale yellow solid (167 mg, 90%). MS: ESP+ (M+H)+=434.