Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]([C:17]1[C:22]2[C@@H:23]3[C@H:28]([CH2:29][CH2:30][C:21]=2[CH:20]=[CH:19][CH:18]=1)[NH:27][CH2:26][CH2:25][CH2:24]3)=[O:16]>C(Cl)Cl.CO>[CH3:13][O:14][C:15]([C:17]1[C:22]2[C@@H:23]3[C@H:28]([CH2:29][CH2:30][C:21]=2[CH:20]=[CH:19][CH:18]=1)[N:27]([C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12])[CH2:26][CH2:25][CH2:24]3)=[O:16]
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COC(=O)c1cccc2c1[C@H]1CCCN[C@H]1CC2
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 43 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-10-carboxylic acid methyl ester following a procedure analogous to that described in Example 1. Yield: 43% of theory; TLC: rf=0.30 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=390 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.CN(C)C1C=CN=CC=1>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1C(CO)CCC1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCC(CO)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl 2,5-bis(hydroxymethyl)-1-pyrrolidinecarboxylate (commercially available, for example from J&W Pharmlab, 7.57 g, 32.7 mmol) in dichloromethane (200 mL) was added triethylamine (4.79 mL, 34.4 mmol), 4-dimethylaminopyridine (0.20 g, 1.64 mmol) and p-toluenesulfonyl chloride (6.55 g, 34.4 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was diluted with DCM (200 mL) and the solution washed with water (200 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum. The residue was purified by silica chromatography (Biotage SP4, eluting 30% EtOAc in iso-hexane (3 column volumes), a gradient from 30-50% (over 6 column volumes) then 50% EtOAc (3 column volumes)) to yield the title compound as a colourless gum (2.28 g).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[F:23])[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:24])[CH:7]=1.[Br:30]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>>[Br:30][C:7]1[C:8](=[O:24])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[F:23])[C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoate (7.3 g, 18 mmol) and N-methyl-2-pyrrolidine (20 mL). N-Bromo succinimide (3.5 g, 19.8 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The mixture poured into saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, and concentrated in vacuo. The residue was triturated with diethyl ether and filtered to give the title compound as a white powder (3.49 g). 1H NMR (400 MHz, CD3OD) δ 8.16 (qd, J=3, 6.8 and 15.6 Hz, 1H), 7.84 (d, J=2.12 Hz, 1H), 7.64 (q, J=8.4 and 14.8 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.04 (m, 2H), 6.60 (s, 1H), 5.34 (s, 2H), 3.87 (s, 3H), 2.00 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ−111.51 (1 F), −115.98 (1 F), −117.43 (1 F) ppm. ES-HRMS m/z 494.0387(M+H calcd for C22H19BrF2NO5 requires 494.0409). Step 2 Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid
Reaction SMILES: O.[C:2]([O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:6])[C:3]([CH3:5])=[CH2:4].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>CC(O)C>[CH3:5][C:3]([C:2]([O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])=[O:6])=[CH2:4].[CH3:14][C:13](=[O:16])[O:17][CH2:18][CH3:19]
Reactant: C=CC(=O)OCC
Agent: C=C(C)C(=O)OCCN(C)C
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCOC(C)=O

Procedure:
To a 2 liter glass vessel equipped with; reflux condenser, stirrer, means of temperature control, 300 g deionized water and 300 g propan-2-ol were charged then heated to a gentle reflux. A monomer mixture of dimethylaminoethyl methacrylate (134.6 g) and ethyl acrylate (200 g) was fed into the reactor over an approximate time frame of 3 hours. Sodium persulphate solution (3.4 g in 125 g of water) was fed concurrently with the monomer over a similar time period. When feeds were a propan-2-ol azeotrope was then distilled from the reactor, followed by neutralization with acetic acid (41.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([O:13][CH3:14])=[N:7][C:8](Cl)=[N:9][C:10]=1[CH3:11])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[C:24]=1B(O)O)[CH3:22]>COCCOC.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:13][CH3:14])=[N:7][C:8]([C:24]2[C:25]([CH2:29][CH3:30])=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:21][CH3:22])=[N:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)c1c(C)nc(Cl)nc1OC
Reactant: CCc1cccc(CC)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCc1cccc(CC)c1-c1nc(C)c(C(=O)OC)c(OC)n1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-4-methoxy-6-methyl-pyrimidine-5-carboxylic acid methyl ester (4.1 g, 19.0 mmol) in DME (100 mL) is added potassium carbonate (10.5 g, 76 mmol, 4 eq) in water (40 mL) followed by 2,6-diethylphenylboronic acid (6.77 g, 38 mmol, 2 eq). The resulting mixture is degassed by bubbling with argon for 20 min. Pd(PPh3)4 (5 mol %) is added and the resulting yellow biphasic solution is heated at 95° C. in a sealed tube with magnetic stirring for 18 h. The reaction mixture is cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (75 mL×3). The combined organic layers are washed with brine (75 mL), dried over magnesium sulfate, filtered and evaporated at reduced pressure. The resulting orange oil is purified by chromatography on silica gel (1:2 ether/hexanes) to afford the title compound as a colorless oil. 1H NMR (CDCl3) δ=7.29 (dd, 1H), 7.14 (d, 2H), 4.00 (s, 3H), 3.98 (s, 3H), 2.55 (s, 3H), 2.39 (q, 4H), 1.10 (t, 6H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+].Cl>O.CC(C)=O>[C:1]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
17.3 ml (20.90 g, 149 mmol) of benzoyl chloride (Aldrich, purity 99%) are added dropwise over a period of 30 minutes with vigorous stirring to an ice-cooled solution of 20.00 g (145 mmol) of 4-hydroxybenzoic acid (Aldrich, purity 99%) and 12.00 g (300 mmol) of sodium hydroxide in 300 ml of distilled water and 30 ml of acetone. After a further 30 minutes, the mixture is acidified using concentrated hydrochloric acid and diluted with 750 ml of distilled water. The resultant white precipitate is filtered off and recrystallized from methanol/ethanol/ethyl acetate (450 ml+225 ml+300 ml).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.N([O-])=O.[Na+].[ClH:16]>O>[Cl:16][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: Nc1cccc2ccncc12
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cccc2ccncc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 8-aminoisoquinoline (J. Med. Chem., 2005, 48, 744-52) (1 mmol) in concentrated hydrochloric acid was added a solution of sodium nitrite (1.2 mmol) in water. The diazotization was carried out at 0° C. The cold diazonium salt solution was added to a solution of cuprous chloride in concentrated hydrochloric acid at 0° C. The cold solution was warmed to room temperature and stirred at room temperature for 3 hours. After 3 hours, the solution was heated at 60° C. for 30 min. Reaction mixture was basified and extracted with diethyl ether. Ether was washed with cold concentrated sulfuric acid, brine. Ether was dried over anhydrous sodium sulfate and evaporated under vacuum. Crude residue was column purified to afford a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:24]=[N:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cncc(OC)c3)cccc2c1N
Yield: 76.8 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.324 mmol) and 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (160 mg, 0.68 mmol) were reacted to afford the title compound (84 mg, 77% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.49-8.60 (m, 2H), 8.39 (m, 1H), 7.93 (dd, J=8.2, 1.6 Hz, 1H), 7.73-7.84 (m, 2H), 7.66 (m, 1H), 3.93 (s, 3H), 3.47 (apparent q, J=6.7 Hz, 2H), 1.68 (apparent sextet, J=7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). MS APCI, m/z=338 (M+H) HPLC 1.52 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:16]=[N:17][CH:18]=[C:19]([OH:21])[CH:20]=1)[CH2:8][CH2:7]2.[C:22]([O:26][C:27](=[O:30])[CH2:28]Br)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([O:26][C:27](=[O:30])[CH2:28][O:21][C:19]1[CH:18]=[N:17][CH:16]=[C:15]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([Cl:3])[CH:5]=3)[C:10]2=[O:14])[CH:20]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
NaH (38 mg, 1.5 mmol) was added to a solution of 6-chloro-2-(5-hydroxy-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (288 mg, 1.0 mmol, example 252) in dry DMF (5 mL) at 0° C. After stirred at RT for 10 minutes, bromo-acetic acid tert-butyl ester (234 mg, 1.2 mmol) was added and the reaction mixture was stirred at RT for 1 hour before it was poured into ice-water and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (320 mg, 82%) as a solid MS: 389.8 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH2:12].[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][CH2:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=Cc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Brc1ccc2[nH]cc(CCc3ccccn3)c2c1

Procedure:
To 5-bromoindole (5.9 g) in acetic acid (10 ml) solution, 2-vinylpyridine (3.6 ml) was added and the mixture was heated and refluxed for 15 hours. The reaction solution was cooled, then was diluted with ethyl acetate, the aqueous layer was made alkaline with 4N-aqueous sodium hydroxide solution and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off in vacuo, and the residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to 17:33) to afford the above-identified compound (5.6 g).
Reaction SMILES: [CH3:1][C@H:2]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3](O)=[O:4].Cl.[O:21]=[C:22]1[CH2:27][CH2:26][C:25]([NH2:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.CCCC(C)C.CCO>>[CH3:1][C@H:2]([C:6]1[CH:7]=[C:8]([C:16]([F:17])([F:19])[F:18])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1)[C:3]([NH:34][C:25]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23][C:22](=[O:21])[CH2:27][CH2:26]1)=[O:4]
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Reactant: C[C@@H](C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCCC(C)C
Solvent: CCO
Product: C[C@@H](C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (R)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 41) and 4-oxo-1-phenylcyclohexylamine hydrochloride (Description 18) according to the method of Example 50. 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.72 (2H, s), 7.29 (5H, m), 5.71 (1H, s), 3.70 (1H, q, J 7.0 Hz), 2.81 (1H, m), 2.64 (1H, m), 2.47–2.04 (5H, m), 1.60 (1H, m), and 1.52 (3H, d, J 7.0 Hz). e.e. [Determined by chiral HPLC (Chiralcel OD-H 250×4.6 mm i.d.; isohexane/EtOH (96:4); 1 mL/min; 210 nm]>99%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C)C=O>[CH2:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH:25]=[CH2:24]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C

Procedure:
A solution of methyl 4-(4′-hydroxyphenyl)benzoate (5 g) in N,N-dimethylformamide (50 ml) was treated with potassium carbonate (6.06 g) and allyl bromide (2.46 ml), then heated at 60° C. for 3 hours. After cooling, the reaction mixture was poured into ice-water (˜200 ml) and the resulting precipitate was collected by filtration, washed with water, then isopropyl ether, then dried to give methyl 4-[4′-(allyloxy) phenyl]benzoate (5.55 g) as a solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])=[O:9])(=[O:3])[CH3:2].[Cl-].[C:27](OC1C(=CC=CC=1)C(O)=O)(=[O:29])[CH3:28].C(O)COCCOCCOCCO>C(N(CC)CC)C>[C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:28][CH2:27][OH:29])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC(=O)c1ccc(C(=O)OCCOCCOCCO)c(O)c1C(C)=O
Agent: [Cl-]
Solvent: OCCOCCOCCOCCO
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C(=O)OCCOCCOCCOCCO)c(O)c1C(C)=O

Procedure:
The compound (II) was prepared according to the procedure described for the synthesis of triethylenglycol bis-acetylsalicylate (XIX), starting from 2 g of the chloride of acetylsalicylic acid, 0.93 g of tetraethylenglycol and 1.5 ml of trietylamine. The product was purified on silica gel chromatography utilizing an eluent mix constituted by methylene chloride/ethyl acetate 1:1 (v/v). The intermediate fractions were collected, the solvent was evaporated under reduced pressure and 0.6 g of tetraethylenglycol bis-acetylsalicylate (II) were obtained.
Reaction SMILES: C[N:2]1[N:6](CCCCC2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)C=N[NH:3]1.[CH3:29][CH:30]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[N:53]=3)=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)[CH2:31][CH2:32][C:33]#[N:34].[Na].[Cl-].[NH4+]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:29][CH:30]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[N:53]=3)=[CH:46][CH:45]=2)=[CH:40][CH:41]=1)[CH2:31][CH2:32][C:33]1[NH:6][N:2]=[N:3][N:34]=1
Reactant: CN1NN=CN1CCCCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CC(CCC#N)Cc1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(CCc1nnn[nH]1)Cc1ccc(OCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 135 °C

Procedure:
5-(3-methyl-4-(4-(4-(2-quinolinylmethyloxy)phenyl)butyl)tetrazole. A mixture of 4-methyl-5-(4-(4-(2-quinolinylmethyloxy)benzyloxy)phenyl) valeronitrile (1.5 g.), sodium aside (3 g), ammonium chloride (1.9 g) in dimethylformamide (20 ml) is stirred and heated at 135° C. for 18 hours. After cooling, the reaction mixture is poured into ice water and the insoluble material is taken up by chloroform. The residue from the evaporation of chloroform is purified by silica gel dry column (5% methanol in chloroform as eluant) to yield 5-(3-methyl-4-(4-(4-(2-quinolinylmethyloxy)benzyloxy)-phenyl)butyl)tetrazole.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9].O>C(#N)C>[CH:11]1([N:10]2[CH2:4][CH2:5][CH2:6][CH2:7][C:8]2=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(CCCCCl)NC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CCCCN1C1CCCCC1
Yield: 59.1 %

Procedure:
Add NaH (550 g, 14 mmol) into a solution of 5-chloro-N-cyclohexylpentanamide (3 g, 14 mmol) in acetonitrile (100 mL). Stir the reaction at room temperature for 12 hours. Add NaH (1 g, 28 mmol) and continue to stir for 2 days. Pour the reaction into ice and water. Wash the reaction with brine, dry with sodium sulfate, filter and concentrate. Purify the residue by column chromatography to afford the title compound (1.5 g, 60%) as a white solid. 1H NMR (CDCl3): 4.44-4.54 (m, 1H), 3.14 (m, 2H), 2.36-2.42 (m, 2H), 1.70-1.84 (m, 6H), 1.60-1.70 (m, 4H), 1.32-1.48 (m, 4H), 1.00-1.12 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[N+:9]([C:12]1[C:17](Cl)=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:9]([C:12]1[C:17]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:11])=[O:10]
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(Sc2ccccc2Cl)c1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
A mixture of 2-chlorobenzenethiol (8.0 g.), ethyl 2-(2-nitro-3-chlorophenyl)acetate (12.2 g.), anhydrous potassium carbonate (7.5 g.) and dry dimethylformamide (50 ml.) was stirred for an hour at 85° C. The reaction mixture was poured into water (300 ml.) and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. The oily residue was pulverized and recrystallized from methanol (20 ml.) to give the captioned compound (11.6 g.). mp 78° to 80° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:14][C:15]=3[N:16]=[C:17]2[C:20]#[N:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].O>CN1CCCC1=O>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:14][C:15]=3[N:16]=[C:17]2[C:20]2[NH:29][N:28]=[N:27][N:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc(C[C@@H]2CN3C(c4nnn[nH]4)=Nc4nc(C5CCCC5)[nH]c4C3=N2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Compound 75 (69 mg, 0.200 mmol) obtained in Example 75 was dissolved in 1-methyl-2-pyrrolidinone (1 mL), to the solution were added sodium azide (52 mg, 0.800 mmol, 4.0 equivalents) and ammonium chloride (42 mg, 0.800 mmol, 4.0 equivalents), and the mixture was stirred at 120° C. for 2 hours. To the reaction mixture was added water, and the deposited crystals were collected by filtration to obtain the title compound (64 mg, 83%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH:9]([CH3:22])[CH2:10][C:11]1[CH:21]=[CH:20][C:14]2[O:15][CH:16]([CH2:18][NH2:19])[O:17][C:13]=2[CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:23])[N:7]([CH:9]([CH3:22])[CH2:10][C:11]1[CH:21]=[CH:20][C:14]2[O:15][CH:16]([CH2:18][NH:19][C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[O:17][C:13]=2[CH:12]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Cc1ccc2c(c1)OC(CN)O2)N(C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 0.31 g (0.96 mmol) of 1F in 5 mL of dichloromethane was added 0.2 mL (1.14 mmol) of N,N-diisopropylethylamine and 10 mg (0.08 mmol) of 4-dimethylaminopyridine (4-DMAP) followed by 0.15 mL of benzyl chloroformate (1.04 mmol) at room temperature. The mixture was allowed to stir for 1 hours and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash column chromatography using 40% ethyl acetate in hexane to give 0.41 g (0.89 mmol, 94%) of 1G as a thick colorless gum (M+Na, 479).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH3:25])[C:17]=2[O:16][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1cccc(N)c1OC
Product: COc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (4.78 g) and 2,3-dimethoxyaniline (3.68 g) were condensed in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1.[H-].[Na+].I[CH2:18][CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].O>CN(C=O)C>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])[C:8](=[O:14])[NH:9][C:10]1=[O:13])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1ccsc1-c1c[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccsc1-c1cn(CCCCO[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 24 h
Yield: 23.2 %

Procedure:
To a solution of 5-(3-methyl-thiophen-2-yl)-1H-pyrimidine-2,4-dione (Prep 26, 250 mg, 1.2 mmol) in DMF (10 mL), 60% NaH (58 mg, 1.44 mmol) was added portionwise. The reaction was then heated to 70° C. and this temperature was maintained for 1.5 hour. After cooling to room temperature, (4-iodo-butoxy)-tert-butyl-dimethyl-silane (452 mg, 1.44 mmol) was then added dropwise and the reaction was stirred for 24 hours. Water (30 mL) was added and the product was extracted with Et2O. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (15-85) followed by DCM/MeOH (70:30) to give the title compound as a yellow oil (110 mg, 23% yield).