Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(=O)=O.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([NH:20][CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CS(=O)(=O)OCCCC#Cc1cccs1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCCCC#Cc1cccs1
Reaction time: 96 h

Procedure:
A mixture of 210 mg of 2b and 5 ml of tert-butyl amine was stirred for 4 days. The reaction mixture was concentrated and the residue was treated with 20 ml of 1M K2CO3 and the product was extracted into ethyl acetate. The organic layer was washed once with water, dried and concentrated, to provide 250 mg of 2c as a colorless oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:15][C:16](=[O:18])[CH3:17]>CN(C=O)C>[C:7]1([S:13][CH2:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)CCl
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CSc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
13.8 g (100.0 mmol) of K2CO3 were added to a solution of 5.1 ml (50.0 mmol) of thiophenol and 4.22 ml (52.5 mmol) of chloroacetone in DMF (30 ml), and the mixture was stirred for 2 h at RT. Concentration in vacuo was then carried out. The residue was purified by means of CC (EA/hex 15:85), yielding 7.7 g (46.3 mmol, 93%) of 1-(phenylthio)propan-2-one.
Reaction SMILES: [Na+].[O:2]=[C:3]1[NH:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O-:23])=[O:22].[CH3:24]C(C)=O.[OH-].[K+].CI>O>[CH3:24][N:7]1[CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:3]1=[O:2]
Reactant: O=C([O-])CCCCCCCn1c(-c2ccccc2)c[nH]c1=O
Reactant: CC(C)=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: Cn1cc(-c2ccccc2)n(CCCCCCCC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.2 g of 8-(2-oxo-5-phenyl-4-imidazolin-1-yl) caprylic acid sodium salt (preparation see German patent application No. P 29 34 746.4) are suspended in 20 cc. of acetone together with 2.8 g of pulverized potassium hydroxide. The mixture is refluxed and converted into a homogenous solution by the addition of some drops of water. Thereafter, 2.8 g of methyliodide are added at boiling temperature, the mixture is refluxed for 30 minutes and cooled to room temperature. After cooling, so much of water is added that precipitated solids are dissolved. The solution is stirred at room temperature for 4 hours, is acidified and diluted with water until the crude acid is separated as oil. The oil is dissolved in a small amount of chloroform, the chloroform phase is washed with water several times and is finally extracted with 5% soda lye. The soda lye extract is washed with chloroform, the aqueous solution is acidified with dilute hydrochloric acid and is separated from the acid precipitated as an oil. Purification occurs by chromatography on silicic acid gel using a mixture of chloroform and methanol as eluant.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]2[N:11]([CH3:22])[N:12]=[C:13]([C:14]3[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C:3]=12.ClC1N=C[N:27]=C2N(C)N=C(C3OC([N+]([O-])=O)=CC=3)C=12>>[NH2:27][C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]2[N:11]([CH3:22])[N:12]=[C:13]([C:14]3[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C:3]=12
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Reactant: CC(C)c1nc(Cl)c2c(-c3ccc([N+](=O)[O-])o3)nn(C)c2n1
Product: CC(C)c1nc(N)c2c(-c3ccc([N+](=O)[O-])o3)nn(C)c2n1

Procedure:
The procedure described in Example 3b was repeated using 4-chloro-6-isopropyl-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine as starting material instead of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, the reaction conditions being the same. The crystalline product was recrystallised from dimethylformamide to give 4-amino-6-isopropyl-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine having decomposition point 230° C.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8](O)[C:6]=2[N:7]=1)[CH3:2].[NH:19]1[CH:26]=[CH:25][C:23](=[O:24])[NH:22][C:20]1=[O:21]>C(O)(=O)C>[CH2:1]([C:3]1[S:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:25]3[C:23](=[O:24])[NH:22][C:20](=[O:21])[NH:19][CH:26]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: CCc1nc2c(s1)C=Cc1cc(C)ccc1C2O
Solvent: CC(=O)O
Product: CCc1nc2c(s1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O

Procedure:
A solution of the product from step (iii) (785 mg) in acetic acid (5 ml) was added to a suspension of uracil (0.673 g) in acetic acid (25 ml) at 90° C. over 3 min. After 1.5 h the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with ethyl acetate.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][N:13]3[CH:16]=[CH:17][N:18]=[C:12]3[CH:11]=2)=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:16]1[N:13]2[N:14]=[CH:15][C:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)=[CH:11][C:12]2=[N:18][CH:17]=1
Reactant: Fc1ccc(-c2cnn3ccnc3c2)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Fc1ccc(-c2cnn3c(Br)cnc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (0.12 mL, 2.34 mmol) was added dropwise to a stirred mixture of 7-(4-fluorophenyl)imidazo[1,2-b]pyridazine (500 mg, 2.34 mmol) and sodium acetate (289 mg, 3.52 mmol) in Acetic Acid (12 mL) and the mixture was stirred at room temperature for 1 h. The mixture was poured into ethyl acetate and aqueous sodium hydrogen carbonate (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were washed with water, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound as a white solid. 1H NMR (500 MHz, CD3SOCD3) δ 9.10 (d, 1H); 8.49 (d, 1H); 7.98 (dd, 2H); 7.96 (s, 1H); 7.38 (t, 2H). LRMS (APCI) calc'd for (C12H8BrFN3) [M+H]+, 292.0. found 292.0.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[O:28][CH3:29])[N:13]=2)=[CH:8][CH:7]=1.Cl.C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:29][O:28][C:18]1[N:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]=[O:1])=[CH:7][CH:8]=1)=[N:13]2
Reactant: COc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nccc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cc12
Reaction time: 3 h

Procedure:
To a solution of 2-[4-(1,3-dioxolan-2-yl)phenyl]-5-methoxy-3-phenyl-1,6-naphthyridine (760 mg, 1.98 mmol) in THF (8 mL) was added 1 N HCl (6 mL) and the solution was stirred for three hours. Ethyl acetate was added and the mixture was made basic with aqueous Na2CO3. The organic layer was dried (Na2SO4), filtered and the solvent evaporated. The residue was triturated with diethyl ether to give pure product. The mother liquors were purified by column chromatography on silica gel and elution with 10-30% ethyl acetate/hexane gave additional product. 1H-NMR (500 MHz, CDCl3): δ 10.10 (1H, s), 8.60 (1H, s), 8.26 (1H, d, J=6 Hz), 7.81 (2H, d, J=8.3 Hz), 7.62 (2H, d, J=8.3 Hz), 7.56 (1H, d, J=6.1 Hz), 7.30-7.32 (3H, m), 7.21-7.23 (2H, m), 4.17 (3H, s). m/e (m+1): 341.1.
Reaction SMILES: Cl.[N:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([OH:11])=[CH:8][CH:7]=[N:6]2.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:11][C:9]2[C:10]3[N:5]([CH:4]=[CH:3][N:2]=3)[N:6]=[CH:7][CH:8]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Oc1ccnn2ccnc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccnn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of imidazo[1,2-b]pyridazin-8-ol hydrochloride (D-5) (4 g, 23.3 mmol, 1.0 eq) and triethylamine (7.1 g, 70.0 mmol, 3.0 eq) in DCM (50 mL), 4-toluenesulfonyl chloride (5.3 g, 28.0 mmol, 1.2 eq) is added in portions and the resulting mixture is stirred at RT for 1 h. The mixture is washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (10-50% ethyl acetate-petro ether) to afford the product, imidazo[1,2-b]pyridazin-8-yl 4-methylbenzenesulfonate (D-6).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:9][NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:10])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1c(Cl)cccc1NN
Product: CCOC(=O)C(C)=NNc1cccc(Cl)c1C

Procedure:
The title compound was prepared in accordance with the general method of example 25b) from a) (3-chloro-2-methyl-phenyl)-hydrazine and ethyl pyruvate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[Br:22][C:23]1[O:27][C:26]([CH2:28][OH:29])=[CH:25][CH:24]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Br:22][C:23]1[O:27][C:26]([CH2:28][O:29][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH2:17]5)[N:13]([CH3:19])[C:12]=4[CH:20]=3)[C:4](=[O:21])[CH:3]=2)=[CH:25][CH:24]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Reactant: OCc1ccc(Br)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Br)o4)cc3=O)cc21
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (150 mg) and (5-bromo-2-furyl)methanol (177 mg) in toluene (2.0 ml) was added potassium tert-butoxide (112 mg) at 100° C., and the mixture was stirred for 30 min. The mixture was quenched with water (2 ml), and the precipitate was collected. The resulting solid was recrystallized from EtOH—H2O to give the title compound (158 mg) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.C1N2CCN(CC2)C1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[S:27]>CN(C=O)C>[CH3:24][N:25]([CH3:29])[C:26]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2)=[S:27]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OC(=S)N(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of methyl 6-hydroxy-2-naphthoate [J. Med. Chem., 2001, 44, 2869-2878] (156) (5.95 g, 29.4 mmol), DABCO (6.61 g, 58.9 mmol) and dimethylthiocarbamoyl chloride (5.46 g, 44.2 mmol) in dry DMF (40 mL) was stirred at room temperature for 8 h. The precipitated solid was collected, washed with water and dissolved in CH2Cl2. The solution was filtered through a column of silica gel and the product was triturated with i-Pr2O and recrystallised from CH2Cl2/hexane to give methyl 6-{[(dimethylamino)carbothioyl]oxy}-2-naphthoate (157) (7.47 g, 88%) as a white solid: mp 144-147° C.; 1H NMR [(CD3)2SO] δ 8.66 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 8.00 (dd, J=−8.6, 1.5 Hz, 1H), 7.70 (d, J=−2.3 Hz, 1H), 7.389 (dd, J=8.9, 2.3 Hz, 1H), 3.93 (s, 3H), 3.40 (s, 3H), 3.38 (s, 3H). Anal. (C15H15NO3S) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[NH2:29][C:30]1[CH:31]=[C:32]([C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:45]#[N:46])[CH:43]=3)[N:38]([CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[N:37]=2)[CH:33]=[CH:34][CH:35]=1>ClCCl>[C:45]([C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][O:48]1)[N:37]=[C:36]2[C:32]1[CH:31]=[C:30]([NH:29][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH:35]=[CH:34][CH:33]=1)#[N:46]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3nn(C4CCCCO4)c4ccc(C#N)cc34)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1-[(tert-butyl)oxycarbonyl]piperidine-4-carboxylic acid (0.317 g, 1.38 mmol) in 12 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) (0.287 g, 1.5 mmol) The solution was stirred at room temperature for 10 min before 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.400 g, 1.25 mmol) was added as a solid. (A small volume of dichloromethane was used to rinse the flask containing the core). The reaction was stirred at room temperature for 12 hours. Even after addition of 0.5 equivalent of carboxylic acid and EDCI, the reaction could not be driven to completion. The crude mixture was partitioned between water and dichloromethane. The crude was isolated as a brown oil. The yield was not calculated.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH:15]([CH3:23])[C:16]([O:18]C(C)(C)C)=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[O:1][CH:15]([CH3:23])[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C(=O)O)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Methyl 4-hydroxy-3-methoxybenzoate (1.09 g, 5.98 mmol) and tert-butyl 2-bromopropanoate (1.25 g, 0.97 mL, 5.98 mmol) and cesium carbonate (1.95 g, 5.98 mmol) were added into DMF (10 mL) in a 20 mL microwave vial equipped with a stir bar and sealed. The mixture was heated in Biotage microwave synthesizer for 1 hour at 100° C. The solvent was removed and the remained sticky oil was dissolved in DCM (7 mL) and TFA (7 mL). The mixture was stirred overnight. The reaction mixture was neutralized with sodium bicarbonate and organic layer was separated from the mixture. The aqueous layer was washed with DCM (2×10 mL), combined organics and acidified to around pH5 with 2N HCl. Aqueous was extracted with DCM and then with ethyl acetate, dried with sodium sulfate and concentrated to an oil. The crude product was dissolved in DCM (4 mL) and a pure product (0.530 g) precipitate out from the solution by adding diethyl ether (4 mL).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]([CH2:15][CH2:16][O:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7].[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[CH:30]([C:12]1[CH:13]=[CH:14][C:9]([N:8]([CH2:6][CH3:7])[CH2:15][CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1)=[O:31]
Reactant: CCN(CCOC(=O)c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CCOC(=O)c1ccccc1)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
Phosphorous oxychloride (0.33mL, 3.5 mmol) was added to dry dimethylformamide (3 mL) at 0° C. for 15 minutes. After cooling to room temperature, N-ethyl-(2-benzoyloxyethyl)aniline (1 g, 3.5 mmol) was added followed by stirring at room temperature for 5 minutes and then at 90° C. for 30 minutes. The dark green solution was then cooled to room temperature and made basic to pH 8 by addition of 1 molar sodium hydroxide solution. Product was extracted into diethyl ether (3×20 mL). The combined ether extracts were washed with water (30 mL), saturated sodium chloride (30 mL), dried over magnesium sulfate and solvent removed under reduced pressure. Product was isolated as a clear yellow oil (0.90 g, 82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[N:6][CH:7]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cn1
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)nc1

Procedure:
To a solution of 5-bromopyridine-2-aldehyde (3.72 g, 20 mmol) in toluene (60 mL) was added TsOH monohydrate (190 mg, 1 mmol) and ethane-1,2-diol (2.48 g, 40 mmol). The mixture was heated to reflux for 6 hours. The solvent was removed, and the residue was dissolved in ethyl acetate and washed with sodium bicarbonate and brine. The organic layer was dried with sodium sulfate and concentrated to give the crude product. MS: calc'd 230 (MH+), exp 230 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=O>>[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:1][CH2:2][CH2:3][OH:4]
Reactant: NCCO
Reactant: O=Cc1ccccn1
Product: OCCNCc1ccccn1

Procedure:
prepared by reaction of 2-amino-ethanol with pyridine-2-carbaldehyde
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.O>[C:16]([O:15][C:13]([NH:1][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([O:12][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:11])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 95.8 %

Procedure:
To a stirred solution of Boc-Phe-OH (10 g, 37.7 mmoL) in DMF (50 mL) was added potassium carbonate (7.81 g, 56.5 mmol) followed by benzyl chloride (4.55 mL, 39.6 mmol) and the resulting suspension was stirred at 60° C. for 3 d. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (75 mL, 2×25 mL). The combined organics were washed with brine (200 mL), water (3×100 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated then chromatographed on silica gel eluting with 0%-20% ethyl acetate in hexanes. The product-containing fractions were concentrated in vacuo giving the title compound (12.84 g, 95%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[CH:4]=[CH:5][N:6]=1.[ClH:18].Cl.[NH2:20][CH2:21][CH2:22][O:23][NH2:24].N1C=CC=CC=1>C(O)C>[ClH:18].[ClH:18].[NH2:20][CH2:21][CH2:22][O:23][N:24]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][CH2:8][CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: NCCON
Reactant: Cc1nccn1CCCC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1nccn1CCCC(=NOCCN)c1ccccc1
Reaction time: 4 h
Yield: 109.4 %

Procedure:
A mixture of 4-(2-methyl-1-(1H)-imidazolyl)-1-phenyl-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.35 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for four hrs. The solvent was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol/ether to give 3.1 g (66%) of product, mp 153°-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH:10]=O.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:12]([NH:19][CH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Br:1])[C:6]#[N:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1ccc(Br)c(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(Br)c(CNCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-bromo-3-formyl-benzonitrile (2.42 g, 11.5 mmol) in MeOH (450 mL) was added benzylamine (1.88 mL, 17.3 mmol) and sodium cyanoborohydride (1.09 g, 17.3 mmol). Acetic acid (0.99 mL, 17.3 mmol) was added dropwise, and the reaction was stirred at room temperature overnight. The mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were dried, concentrated, and purified by silica gel chromatography (0-30% EtOAc in hexanes) to give 3-(benzylamino-methyl)-4-bromo-benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[CH2:14]([C:16]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH:31]=O)[CH:17]=1)[CH3:15]>C1COCC1.O>[CH2:14]([C:16]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18](/[CH:31]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])[CH:17]=1)[CH3:15]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CCOC(=O)c1c(C=O)cc(CC)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(/C=C/C(=O)OC)cc(CC)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a solution of trimethyl phosphonoacetate (1.60 mL, 9.90 mmol) in 100 mL of THF was added sodium hydride (0.24 g of 60% dispersion in mineral oil, 9.90 mmol) portionwise. The mixture was stirred at ambient temperature for 30 min and then ethyl 4-ethyl-2-formyl-6-(trifluoromethyl)benzoate (1.81 g, 6.60 mmol) as a solution in THF. The reaction mixture was allowed to stir at ambient temperature for 30 min and then was diluted with water. The mixture was extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 15% EtOAc/hexane) to afford 2.1 g (96%) of the title compound as an off-white solid. 1H NMR (CDCl3): δ 7.72 (d, 1H, J=15.9 Hz), 7.62 (s, 1H), 7.53 (s, 1H), 6.44 (d, 1H, J=15.9 Hz), 4.45 (q, 2H, J=7.2 Hz), 3.81 (s, 3H), 2.75 (q, 2H, J=7.6 Hz), 1.40 (t, 3H, J=7.2 Hz), 1.28 (t, 3H, J=7.4 Hz).