Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=2)[C:9](OC)=[O:10])[CH:5]=[CH:4][CH:3]=[N:2]1.[BH4-].[Na+]>CCO>[N:1]1([C:6]2[CH:7]=[C:8]([CH2:9][OH:10])[CH:13]=[CH:14][N:15]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1ccnc(-n2cccn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccnc(-n2cccn2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl 2-(1H-pyrazol-1-yl)isonicotinate (399 mg; 1.96 mmol) in anh. EtOH (8 ml) was treated with NaBH4 (371 mg; 9.83 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 17 h. After concentration to dryness under reduced pressure, the resulting residue was treated with water, and extracted with DCM. The organic layer was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded (2-(1H-pyrazol-1-yl)pyridin-4-yl)methanol as a colorless solid. LC-MS (conditions A): tR=0.44 min.; [M+H]+: 176.10 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:17][C:18]2[CH:19]=[N:20][C:21]([CH2:24][O:25][CH3:26])=[CH:22][CH:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:17][C:18]2[CH:19]=[N:20][C:21]([CH2:24][O:25][CH3:26])=[CH:22][CH:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(COC)nc3)cc(OC)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCc1ccc(Oc2cc(OC)c3[nH]c(C(=O)O)cc3c2)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To a solution of ethyl 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (2.39 g) in a mixture of tetrahydrofuran (15 mL) and ethanol (10 mL) was added 1M aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 50° C. for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1M hydrochloric acid (10 mL) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (2.28 g, 100%) as a pale yellow amorphous solid. MS 329 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:8]1[CH:9]=[N:10][C:5]([NH:4][CH2:3][C:2]([F:15])([F:14])[F:1])=[CH:6][CH:7]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(=O)c1ccc(NCC(F)(F)F)nc1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(NCC(F)(F)F)nc1
Yield: 28 %

Procedure:
The title compound is prepared in 28% yield (180 mg, colorless oil) from 1-(6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethanone (441 mg, 2.02 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(#N)C>[S:21]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:23])(=[O:22])[CH3:20]
Reactant: COc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(COS(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
Combine 4-methoxybenzyl alcohol (45.4 mmol), N,N-diisopropylethylamine (12.9 g, 100 mmol), and acetonitrile (60 mL). Cool in an ice bath. Add methanesulfonyl chloride (6.76 , 49.0 mmol). After 2 hours, partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the organic layer with 1 M hydrochloric acid solution and then a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:10][CH2:11][OH:12])[C:6]([CH3:9])=[CH:7][CH:8]=1.Cl[CH2:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>O1CCCC1.O>[CH3:3][C:4]1[N:5]([CH2:10][CH2:11][O:12][CH2:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1ccc(C)n1CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)COCCn1c(C)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
32 g of sodiumhydride (60% oil dispersion) was added to 500 ml of tetrahydrofuran, and 56 g (0.4 mol) of 2-(2,5-dimethylpyrrole-1-yl)ethanol obtained in Preparation Example 1 was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was cooled to 0° C., and a solution obtained by dissolving 65.84 g (0.4 mol) of ethyl 4-chloroacetoacetate in 200 ml of tetrahydrofuran was added thereto dropwise over 2 hours. The mixture was stirred at room temperature for 16 hours and then adjusted to pH 6 to 7 with 3N hydrochloric acid. A sufficient amount of water was added to dissolve solid precipitates formed, and the reaction mixture was extracted two times with 600 ml and 100 ml of ethyl acetate, respectively. Combined ethyl acetate extract was dried over anhydrous magnesium sulfate, treated with decolorizing carbon, and then, the solvent was distilled off under a reduced pressure, to obtain 96.2 g of the titled compound as a pale yellow oil (yield: 90%).
Reaction SMILES: [N:1]1([CH2:6][C:7]([O:9][CH2:10]C)=[O:8])[CH:5]=[CH:4][N:3]=[N:2]1.[CH2:12](N(CC)CC)C>CO>[N:1]1([C:6](=[CH2:12])[C:7]([O:9][CH3:10])=[O:8])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CCOC(=O)Cn1ccnn1
Reactant: CCN(CC)CC
Solvent: CO
Product: C=C(C(=O)OC)n1ccnn1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
450 g of ethyl 2-(1H-1,2,3-triazol-1-yl)acetate were dissolved in 3.5 1 of methanol, 30 g of triethylamine were added and the mixture was stirred at 22° C. for 16 h. All solvents were then distilled off under reduced pressure. This gave 410 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:13][OH:14])[C:9]([O:11][CH3:12])=[O:10].[H-].[Na+].[CH3:17]I.O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[CH:13]/[O:14][CH3:17])/[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=CO)c1ccccc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO/C=C(\C(=O)OC)c1ccccc1C
Reaction time: 1 h

Procedure:
A solution of 44 g of the product of Step B in 400 ml of tetrahydrofuran was introduced at 20°-25° C. into a solution of 700 ml of tetrahydrofuran and 11 g of sodium hydride (50% in oil). The reaction mixture was stirred for one hour and 150 ml of methyl iodide were added. The mixture was stirred for 5 hours and poured into water. Extraction was carried out with methylene chloride and the extracts were dried and brought to dryness to obtain 47.2 g of product which was chromatographed on silica and eluted with hexane-ethyl acetate mixture (7-3) to obtain the following:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18]Br.Cl>CN(C)C=O.O>[CH3:15][C:16]([CH3:20])=[CH:17][CH2:18][S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Sc1cccc(Br)c1
Reactant: CC(C)=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
36 g of 3-bromothiophenol were dissolved in 400 ml of dimethylformamide. After the addition of 27 g of finely powdered potassium carbonate and 29 g of 3,3-dimethylallyl bromide, the mixture was stirred at room temperature for 1 hour, diluted with 500 ml of water, acidified with 3N hydrochloric acid while cooling and extracted with ether. The yellow-brown oil obtained after evaporation was distilled in a high vacuum. There were obtained 48 g of m-bromophenyl 3-methyl-2-butenyl sulfide as a colorless liquid, boiling point 85° C./13.3 Pa.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:16])[C@:9]([OH:15])([CH3:14])[C:10]([F:13])([F:12])[F:11])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)#[N:25]>CCOC(C)=O>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8](=[O:16])[C@:9]([OH:15])([CH3:14])[C:10]([F:12])([F:13])[F:11])[CH2:4][CH2:3]2)=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: C[C@@](O)(C(=O)N1CCC(N)CC1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@](O)(C(=O)N1CCC(NC(=O)c2ccc(C#N)cc2)CC1)C(F)(F)F
Yield: 36.6 %

Procedure:
To a solution of (R)-[4-amino-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperidine] (Example 21, 170 mg, 0.71 mmol) and triethylamine (0.12 mg, 0.86 mmol) in EtOAc (15 ml) was added a solution of 4-cyanobenzoylchloride (130 mg, 0.78 mmol) in EtOAc (10 ml). The resultant mixture was stirred at ambient temperature for 4 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with 50% EtOAc/DCM as eluent to give the title compound as a solid (97 mg, 0.26 mmol). NMR: 1.45 (m, 2H), 1.65 (s, 3H), 2.1 (m, 2H), 3.05 (m, 2H), 4.2 (m, 1H), 4.4-4.6 (m, 2H), 5.1 (s, 1H), 6.2 (d, 1H), 7.65 (d, 2H), 7.8 (d, 2H); m/z 368.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH:12]1([N:15]=[C:16]=[O:17])[CH2:14][CH2:13]1>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH:7][C:16]([NH:15][CH:12]1[CH2:14][CH2:13]1)=[O:17])=[O:5]
Reactant: NNC(=O)c1ccccc1Cl
Reactant: O=C=NC1CC1
Solvent: C1CCOC1
Product: O=C(NNC(=O)c1ccccc1Cl)NC1CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 10.0 g (58.6 mmol) of 2-chlorobenzoic acid hydrazide is placed in 50 ml tetrahydrofuran. 4.87 g (58.6 mmol) of cyclopropyl isocyanate, dissolved in 50 ml tetrahydrofuran, are added dropwise at 50° C., and the mixture further stirred overnight at 50° C. The resulting precipitate is filtered off after cooling to room temperature and then washed with diethyl ether. 13.9 g (93% of theory) of the target compound are thus obtained.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7](=[N:14][NH:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH3:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:2]=[N-:3].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>N1C=CC=CC=1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:15]=[C:16]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[CH3:24])[O:25]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(Cl)cc1C(=O)NN=C(CCCN=[N+]=[N-])c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(Cl)cc1C1=NN(C(=O)C(C)(C)C)C(CCCN=[N+]=[N-])(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of N′-(4-azido-1-phenylbutylidene)-5-chloro-2-methyl benzohydrazide (100 mg, 0.28 mmol) in pyridine (1 mL) was added pivaloyl chloride (70 μL, 0.56 mmol). After stirring at room temperature for 16 hours the heterogeneous mixture was treated with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed successively with 10% NaHSO4 (2×10 mL), NaHCO3 (10 mL) and brine (10 mL) then dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (9:1 hexanes/EtOAc) to afford the product (62 mg, 50%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4](O)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Product: Cc1nc(Cl)nc(C)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A mixture of Compound 1 (500 mg) and phosphorus oxychloride (3.89 g) was stirred for 3 hours under reflux. After the reaction was completed, the mixture was concentrated under reduced pressure. To the resulting residue, chloroform and water were added and the mixture was cooled and neutralized with a 2N aqueous sodium hydroxide solution to a pH of 5 to 7. The mixture was then extracted with chloroform and the organic layer was concentrated under reduced pressure to obtain 411 mg of the desired product. When necessary, some of the product was purified by silica gel column chromatography (ethyl acetate: hexane=1:1) to give a purified product.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22].O[C:34]1[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37].C1CCC(N=C=NC2CCCCC2)CC1>CC#N.C1COCC1.CN(C1C=CN=CC=1)C>[C:1]([NH:24][CH:25]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:26]([O:28][C:41]1[CH:42]=[CH:43][CH:44]=[CH:34][C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22]
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)O
Reactant: CCOC(=O)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)Oc1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoic acid (50 mg, 0.11 mmol) and ethyl 2-hydroxybenzoate (19 mg, 0.11 mmol) in CH3CN/THF (1:1, 0.5 mL) at −10° C. was added DCC (12 mg, 0.11 mmol) and DMAP (1 mg). The mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (EtOAc-PE, 0-20%) to afford ethyl 2-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate (40 mg, 67%) as colorless oil. Mass calculated for C37H51NO5=589.80; found: [M+H]+=590.4.
Reaction SMILES: C([O:3][C:4](=[O:25])/[CH:5]=[CH:6]\[CH:7]=[C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)C.[OH-].[Na+]>CO>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:7]/[CH:6]=[CH:5]\[C:4]([OH:25])=[O:3])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)/C=C\C=C(c1cccc(OC)c1)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C(=C/C=C\C(=O)O)c2cccc(OC)c2)c1
Yield: 99.1 %

Procedure:
In a similar fashion, (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid ethyl ester (2.2 g) in methanol (15 mL) was hydrolyzed using 2N sodium hydroxide solution (5 mL). The usual work up furnished 2.0 g of (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid. Crystallization of a portion from ether furnished the analytically pure acid, mp 178°-180° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 77.9 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine (9.2 g, 0.028 mol) in THF (100 ml) was added a solution of K2CO3 (7.91 g, 0.057 mol) in H2O (35 ml). After 10 minutes, ethyl chloroformate (2.86 ml, 0.030 mol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (100 ml) and a solution of borane in THF (1M) was added (114.5 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (100 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (100 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 7.31 g (76%) of the title compound as a colorless oil. ES-MS m/e: 335.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH:10]=[C:9](I)[CH:8]=[N:7]1)[CH3:2].C([Mg]Cl)(C)C.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C>C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)[CH:8]=[N:7]1)[CH3:2]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCOCCn1cc(I)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 85.1 %

Procedure:
A 22 L 4-neck flask equipped with a mechanical stirrer, thermowell, addition funnel, and N2 inlet was charged with 1-(ethoxyethyl)-4-iodo-1H-pyrazole (20, 700.0 g, 2.63 mol) and THF (5.5 L). The resulting solution was cooled to between −12° C.-−15° C. A solution of 2 M i-PrMgCl in THF (1513 mL, 3.03 mol, 1.15 equiv) was added via an addition funnel over 30 min while maintaining the reaction temperature at <−5° C. and the tan suspension was stirred at <−5° C. for 0.75 hr. The resulting reaction mixture was further cooled to −15° C. and 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (16, 734 g, 805 mL, 3.95 mol, 1.5 equiv) was added rapidly via an addition funnel with the reaction temperature increasing to ˜−5°. [Note: previous work with the analogous TMS-protected pyrazole has shown that slow addition of 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane results in a lower yield.] A nearly clear light brown solution was developed followed by reformation of grayish light suspension. The cooling bath was then removed and the reaction mixture was allowed to warm to 16° C. over 0.75 hr. The mixture was poured into 50 L reparatory funnel containing a stirred saturated aqueous NH4Cl solution (4 L). The mixture was diluted with toluene (8 L), heptane (8 L) and H2O (2 L). The aqueous phase was removed and the organic phase was washed with warm (30° C.) H2O (4×3 L) and saturated brine (2×3 L). The organic phase was dried over Na2SO4, and the solvents weree removed under reduced pressure. The residual toluene was further removed by co-evaporation with heptane (2 L). The residual oil was transferred to a 4 L beaker using a minimum amount of heptane (100 mL) and scratched to induce crystallization. The solid was filtered, washed with heptane (200 mL) and dried overnight in a vacuum oven at 30-40° C. The filtrate was concentrated under reduced pressure and the residue was allowed to stand overnight. The resulting solid was filtered, washed with heptane (100 mL) and dried overnight in a vacuum oven at 30-40° C. The two crops were combined to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19, 596 g, 700 g theoretical, 85.1%) as a white to off-white solid. For 19: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.09 (s, 1H), 8.58 (s,1H), 7.62 (s,1H), 5.55 (q, 1H, J=6.1 Hz), 3.37 (dq, 1H, J=7.1, 9.6 Hz), 3.12 (dq, 1H, J=7.0, 9.7 Hz), 1.56 (d, 3H, J=6.0 Hz), 1.24 (s, 12H), 1.00 (t, 3H, J=7.0 Hz); C13H23BN2O3 (MW, 266.14), LCMS (EI) m/e 267 (M++H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][O:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([Cl:27])[C:18]=1[C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:19](=[O:20])[C:18]1[C:22]([Cl:27])=[CH:23][CH:24]=[C:25]([Cl:26])[C:17]=1[O:16][CH3:15]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)Cl
Reactant: OCCNCCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1c(Cl)ccc(Cl)c1C(=O)N(CCO)CCO
Reaction time: 2 h
Yield: 76 %

Procedure:
Diethanolamine (11 grams; 0.105 mol), triethylamine (12 grams) and toluene (100 ml) were placed in a 250 ml, 3-necked glass reaction flask equipped with stirrer, thermometer and reflux condenser. 2-methoxy-3,6-dichlorobenzoic acid chloride (23.9 grams; 0.1 mol) in toluene (25 ml) were added to the reaction mixture by means of an addition funnel. The reaction mixture was stirred for two hours and then filtered. The recovered solid material was heated in ethyl acetate and filtered. Toluene was added to the oily residue, heated to dissolve the oil and cooled. The desired product first formed as an oil and then crystalized. The product weighed 23.6 grams representing a yield of 76%.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[O:32])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: O=C(Cl)c1ccccn1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)c3ccccn3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.55 g, 1.6 mmol) in acetonitrile (10 mL), was added picolinoyl chloride hydrogen chloride (0.32 g, 1.8 mmol) and N,N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give pyridine-2-carboxylic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-amide as an off-white solid (67 mg, 10% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.85 min (99.4%); mp, 261-263° C.; 1HNMR (DMSO-d6)2.08-2.27 (m, 1H, CHH), 2.64-2.93 (m, 6H, CHCH2, CH3), 4.91-5.05 (m, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.33-8.69 (m, 7H, Ar), 9.32 (t, J=6 Hz, 1H, CH2NH), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.73, 23.31, 30.62, 42.12, 56.57, 117.72, 121.86, 125.18, 125.76, 126.60, 134.05, 137.82, 140.30, 148.55, 149.77, 154.87, 161.17, 163.79, 169.47, 172.65. LCMS MH=406; Anal Calcd For C21H19N5O4+0.5H2O: C, 60.86; H, 4.86; N, 16.90. Found: C, 60.72; H, 4.62; N, 16.69.
Reaction SMILES: B(F)(F)F.[C:5]([OH:22])(=O)[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].[CH3:23][C:24]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:25]=1[OH:26].C([O-])(=O)C.[Na+]>O.C(Cl)Cl>[CH3:23][C:24]1[CH:30]=[C:29]([OH:31])[C:28]([C:5](=[O:22])[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:27][C:25]=1[OH:26]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: Cc1cc(O)ccc1O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)c1cc(O)c(C)cc1O
Reaction time: 8 h

Procedure:
Boron trifluoride was introduced with vigorous refluxing until saturation into a mixture of 27.2 g of palmitic acid, 13.7 g of 2-methylhydroquinone and 45 ml of methylene chloride. After standing overnight the mixture was refluxed for another hour and then decomposed with stirring in a solution of 25 g of sodium acetate in 220 ml of water. After 45 min the solution in methylene chloride was separated and evaporated. The residue was stirred with methanol, filtered with suction and recrystallized from n-chlorobutane.