Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:10]=1[O:11][CH2:12][C@H:13]1[CH2:15][O:14]1)C1C=CC=CC=1.C([O-])=O.[Na+].C(O)=O.[OH-].[Na+]>[Pd].C(O)C>[N+:20]([C:18]1[CH:17]=[CH:16][C:10]2[O:11][CH2:12][C@H:13]([CH2:15][OH:14])[O:8][C:9]=2[CH:19]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=CO
Product: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CO)CO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1 L three necked flask equipped with a mechanical stirrer, thermocouple and heating mantle is charged with (2R)-2-{[2-(benzyloxy)-4-nitrophenoxy]methyl}oxirane (50.00 g, 0.17 mol), ethanol (400 mL) N-methyl-2-pyrrolidone (100 mL) and palladium (5% on carbon, 50% water, 7.5 g). The mixture is heated to an internal temperature of 45° C., at which point a solution of sodium formate (1.40 g, 0.022 mol) in 95% formic acid (8.40 mL, 0.208 mol) is added over 5 min. The reaction is monitored by LCMS, and no starting material remained after 4 h. The pH of the reaction mixture is found to be about 2. 1 N NaOH (16 mL, 16 mmol) is added to achieve a pH of 9. Heating is discontinued, and the solution is allowed to cool to room temperature overnight. The catalyst is removed by filtration through celite, and the ethanol is removed by rotary evaporation. The flask containing the product in NMP is equipped with a magnetic stirrer and an addition funnel. Water (150 mL) is added via addition funnel over 15 min, followed by seed crystals, and the resulting suspension is stirred for 15 min. Additional water (250 mL) is added over 30 min, during which time more precipitate forms. The suspension is stirred for 2 h and the solid is collected by vacuum filtration. The filter cake is washed with water (200 mL) and suction dried under nitrogen. The title compound is obtained as a red/brown solid (24.54 g, 70%, 94% ee); m.p. 110° C. LCMS (Basic Method): 2.13 min, 212 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 7.81-7.76 (m, 2H), 6.96 (d, J=8.5 Hz, 1H), 4.42 (dd, J=2.1, 11.2 Hz, 1H), 4.32-4.18 (m, 2H), 3.98-3.85 (m, 2H), 2.03 (br s, 1H).
Reaction SMILES: C[O-].[Na+:3].[Na].O.[CH3:6][O:7][Si:8]([O:13]C)([O:11][CH3:12])[O:9][CH3:10]>CO>[CH3:6][O:7][Si:8]([O:11][CH3:12])([O:9][CH3:10])[O-:13].[Na+:3]
Reactant: CO[Si](OC)(OC)OC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: CO[Si]([O-])(OC)OC
Yield: 96.4 %

Procedure:
A solution of 81.0 gm (1.5 mols) of sodium methylate in methanol, prepared by reacting 34.0 gm (1.5 mols) of sodium with 500 ml of methanol, was first mixed with 27.0 gm (1.5 mols) of water, then with 1000 gm (6.6 mols) of tetramethoxy-silane. The mixture was heated for about 15 minutes under reflux. Methanol and the unreacted tetramethoxy-silane were then distilled off under a water jet vacuum. Instead of the theoretically expected 240.3 gm (1.5 mols) of sodium trimethoxy-silanolate, 231.5 gm of sodium trimethoxy-silanolate were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:14]1([CH2:13][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OCC1CC1

Procedure:
A solution of 3-hydroxy-4-methoxybenzaldehyde (400 g, 2.63 mole)and bromomethylcyclopropane (426 g, 3.2 mole) in 1 L dimethylformamide (DMF) was stirred with potassium carbonate (K2CO3) (483 g, 3.5 mole) at 55° C. for 3.5 h. Then, 1 L of water was added, the mixture chilled on ice, and Intermediate 1 filtered as a white solid, (535 g, 99%). m/z 207 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].[CH:11]1[CH:16]=[C:15]([CH:17](O)[C:18](O)=[O:19])[C:14]([Cl:22])=[CH:13][CH:12]=1>>[Cl:22][C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][C:15]=1[CH:17]1[C:9]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:10]=2)[NH:8][C:18]1=[O:19]
Reactant: CCOc1ccc(N)cc1
Reactant: O=C(O)C(O)c1ccccc1Cl
Product: CCOc1ccc2c(c1)C(c1ccccc1Cl)C(=O)N2

Procedure:
This compound is prepared according to the procedure described in step B of Preparation 66 from N-4-ethoxyphenyl-DL-2-chloromandelamide (120°-130° C.), itself obtained according to the procedure described in step A of Preparation 2 from 4-ethoxyaniline and DL-2-chloromandelic acid. This gives the expected product. M.p.=176°-180° C.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[O:21][CH3:22].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:22][O:21][C:3]1[CH:4]=[C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])[CH:19]=[CH:20][C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1Br
Reactant: OB(O)c1ccccc1
Product: COc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1-c1ccccc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-3-methoxy-N-quinolin-7-ylbenzamide (D69) (76 mg, 0.21 mmol) and phenylboronic acid (28 mg, 0.23 mmol) as a white solid. MS(ES): MH+ 355, M-H+ 353.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=5)[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[CH3:6][CH:5]([CH3:7])[C@H:4]([NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=5)[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:3]([OH:43])=[O:2]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(-c5ccncc5)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2cccc(-c3ccncc3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 84.5 %

Procedure:
To 160 mg of (S)-3-methyl-2-{4′-[(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid methyl ester was added 1 mL of THF and 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 4 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The pH of the solution was adjusted to 7 and the resulting suspension was filtered. The solid product was dried under vacuum to give 132 mg of (S)-3-methyl-2-{4′-[(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid, obtained as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=21.5, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.2 (s, 3 H) 3.4 (s, 1 H) 7.3 (dd, J=7.3, 1.0 Hz, 1 H) 7.5 (m, 2 H) 7.6 (dd, J=8.3, 7.3 Hz, 1 H) 7.8 (m, 5 H) 7.9 (m, 2 H) 8.0 (d, J=8.8 Hz, 2 H) 8.7 (m, 2 H) 10.6 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].F[C:16](F)(F)[C:17](OC(=O)C(F)(F)F)=[O:18].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[C:17]([C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:18])[CH3:16]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(OC)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(C)=O)c(OC)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 1.00 g portion of methyl 2,4-dimethoxybenzoate was suspended in 0.58 ml of acetic acid, and 1.44 ml of dry trifluoroacetic acid anhydride was added under ice-cooling, followed by stirring at room temperature for 12 hours. Under ice-cooling, a saturated sodium bicarbonate aqueous solution and ethyl acetate were added, and then insoluble matter was removed by celite filtration. The thus obtained filtrate was extracted with ethyl acetate, washed with water and saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1-80:1) to give 0.99 g of methyl 5-acetyl-2,4-dimethoxybenzoate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>CO.CCOCC>[ClH:29].[ClH:29].[N:11]1([C:14]2[CH:15]=[C:16]([C:20]3[NH:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nc4ccccc4[nH]3)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: c1cc(-c2nc3ccccc3[nH]2)cc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[3-(1H-benzoimidazol-2-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (1.80 g, 4.76 mmol) in MeOH (2 mL), 2M HCl in Et2O (8 mL) was added and the resulting mixture was stirred for 6 h at room temperature.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3](=[O:12])[CH:4]=[CH:5][C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH3:11].CO>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][CH:2]([CH3:13])[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH3:11]
Reactant: Cc1ncsc1C=CC(=O)C(C)C
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ncsc1CCC(=O)C(C)C

Procedure:
The title compound was prepared as described in General Method 3 using 1.73 g (8.86 mmol) of 4-methyl-1-(4-methyl-thiazol-5-yl)-pent-1-en-3-one (prepared in Example B-1) and 0.4 g of 5% Pd/BaSO4 in THF:MeOH (25 mL:25 mL). The crude product was chromatographed on silica gel, eluting with 2:1 hexane:EtOAc, to give the title compound. 1H NMR (CDCl3): δ1.03 (d, 6 H), 2.35 (s, 3 H), 2.49-2.56 (m, 1 H), 2.72 (t, 2 H), 2.98 (t, 2 H), 8.49 (s, 1 H).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25](O)([CH3:27])[CH3:26])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[F:29][C:30]([F:41])([F:40])C1(COS(C)(=O)=O)CC1.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN1CCCC1=O.O.C(OCC)(=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3([C:30]([F:41])([F:40])[F:29])[CH2:27][CH2:26]3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: CC(C)(O)CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(CC2(C(F)(F)F)CC2)CC1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of N-cyclopropyl-N-[1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide (80 mg), methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester (269 mg), K2CO3 (81 mg), and potassium iodide (38 mg) in N-methyl-2-pyrrolidone (3 mL) is stirred at 100° C. for two days. After cooling to room temperature, ethyl acetate and water are added to the mixture. The organic phase is separated, dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel [dichloromethane/7 M ammonia in methanol 9:1→7:3] and the crude product is purified by preparative HPLC to give the title compound. LC (method 3): tR=1.22 min; Mass spectrum (ESI+): m/z=434 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:25][CH:26]([F:28])[F:27])=[C:11]([CH:13]2[C:15]3([C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[O:17][C:16]3([CH3:24])[CH3:23])[O:14]2)[CH:12]=1>ClCCCl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:25][CH:26]([F:27])[F:28])=[C:11]([CH:13]2[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[O:17][C:16]([CH3:24])([CH3:23])[C:15]2=[O:14])[CH:12]=1
Reactant: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2OC(F)F)C1=O
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(Br)ccc2OC(F)F)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
To an ice-cold solution of concentrated sulphuric acid (12 ml) is added a second solution of 2-(5-bromo-2-difluoromethoxyphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (7.22 g, 18.00 mmol) in 1,2-dichloroethane (12 ml) dropwise over 5 minutes. This biphasic mixture is stirred vigorously for 2 hours at 0° C., then allowed to stand at room temperature overnight. The reaction mixture is poured into ice-water, rinsing with a small amount of additional 1,2-dichloroethane/water, then concentrated under vacuum to remove all organic solvents. The crude product is next extracted into ethyl acetate (×3), than all organics are combined, washed with brine, and dried over magnesium sulfate. The suspension is filtered and the filtrate is concentrated in vacuo then purified by flash column chromatography (10% to 25% ethyl acetate in hexane as eluant) to give an oil which is triturated with hexanes to afford 4-(5-bromo-2-difluoromethoxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (2.08 g) as a white solid.
Reaction SMILES: [Cl:1]C1C(N(C)S(C)(=O)=O)=NC([NH:18][C@H:19]([C:21]2[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=2)[CH3:20])=NC=1NC1C=C(OC(C)C)NN=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[F:27][C:24]1[CH:23]=[N:22][C:21]([C@@H:19]([NH2:18])[CH3:20])=[N:26][CH:25]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)nc(N(C)S(C)(=O)=O)c2Cl)n[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](N)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-tert-butyl-1-(5-fluoropyrimidin-2-yl)ethylcarbamate (Method 10, 0.21 g, 0.87 mmol) in DCM (5 ml) was added HCl (1.3 ml, 5.2 mmol) in dioxane. The reaction was stirred at room temperature for 3 hours. The solvent was removed give the title compound as white solid (quantitative). MS: Calcd.: 141. Found: [M+H]+ 142.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[CH2:15]([S:17][C:18]1([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([OH:31])[CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH3:16]>>[CH2:15]([S:17][C:18]1([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:25]=2)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[CH3:16]
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: CCSC1(c2cc(O)cc(F)c2)CCOCC1
Product: CCSC1(c2cc(F)cc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOCC1
Yield: 40 %

Procedure:
Using a similar procedure to that described in Example 11, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-ethylthio-4-(5-fluoro-3-hydroxyphenyl)tetrahydropyran to give 4-ethylthio-4-[5-fluoro-3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 40% yield, m.p. 73°-75° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH:28](I)([CH3:30])[CH3:29]>CC(C)=O>[F:21][C:2]([F:20])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH:28]([CH3:30])[CH3:29])[C:6]([CH3:15])=[C:5]([C:16]([F:19])([F:18])[F:17])[N:4]=1
Reactant: CC(C)I
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C)c1OC(C)C
Yield: 21 %

Procedure:
A mixture of 15.1 g (0.209 mol) of product of Example 35, 6.6 g (0.2 mol) of potassium carbonate, 32 g of isopropyl iodide and 50 ml of acetone was held at reflux for 18 hours and concentrated. The residue was treated with water and filtered. The solid was dissolved in ether (100 ml) and the ether solution was washed with 50 ml of 10% NaOH, dried, and concentrated. The residue was recrystallized from hexane to give 14.2 g (83%) of product; mp 53°-55° C.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][O:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:22][C:23]#[N:24].[C:25](=O)([O:29]CC)[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1.C(O)C>[C:23]([CH:22]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:8]=1[O:7][CH3:6])[C:25]([O:26][CH2:27][CH3:28])=[O:29])#[N:24]
Reactant: COc1c(CC#N)cccc1Oc1ccccc1F
Reactant: CCOC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2F)c1OC
Yield: 109.4 %

Procedure:
A mixture of sodium ethoxide prepared from sodium metal (470 mg) and ethanol (20 ml), 2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetonitrile (5 g) and diethyl carbonate (9.2 g) in toluene (50 ml) was treated in a similar manner to that of Example 10-(4) to give oily ethyl 2-cyano-2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetate (7 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:13]=2)[N:6]=1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CCCCCCCCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.111 g, 0.401 mmol) was reacted with N-(2-azidoethyl)tetradecanamide (0.130 g, 0.401 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-tetradecanamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), δ 6.85 (s, 1H), δ 6.42 (s, 1H), δ 6.05 (s, 1H), δ 4.38 (s, 2H), δ 3.66 (s, 2H), δ 2.60 (s, 2H), δ 2.11 (s, 2H), δ 2.08 (t, 2H), δ 1.41 (m, 13H), δ 1.32 (s, 2H), δ 1.17 (s, 18H), δ 0.77 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 202.9, 174.3, 149.6, 148.3, 121.9, 100.1, 84.8, 49.5, 42.3, 39.5, 36.7, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 29.5, 29.3, 28.9, 28.1, 25.9, 25.6, 22.9, 14.3 ppm; HRMS (ESI) calcd for C31H55N7O3 (M+) 573.4366. found 573.4365, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)tetradecanamide hydrochloride (0.118 g, 87% yield). 1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), δ 6.53 (s, 1H), δ 4.71 (s, 2H), δ 3.75 (s, 2H), δ 2.89 (s, 2H), δ 2.54 (t, 2H), δ 2.17 (t, 2H), δ 1.80 (s, 2H), δ 1.69 (s, 2H), δ 1.54 (s, 2H), δ 1.48 (s, 2H), δ 1.28 (s, 20H), 0.88 (t, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 175.6, 161.8, 147.2, 127.6, 127.4, 108.5, 52.3, 38.8, 36.6, 35.8, 31.9, 30.6, 29.7, 29.6, 29.5, 29.4, 29.2, 28.0, 27.9, 27.7, 25.8, 24.1, 23.6, 23.4, 22.6, 13.4 ppm; HRMS (ESI) calcd for C26H47N7O (M+) 473.3842. found 473.3834.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([N:9]([CH3:11])[NH2:10])[N:3]=1.[C:12](OC)(=[O:16])[C:13]([CH3:15])=O>CO>[NH2:8][C:6]1[C:5]2[C:12](=[O:16])[C:13]([CH3:15])=[N:10][N:9]([CH3:11])[C:4]=2[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: COC(=O)C(C)=O
Reactant: CN(N)c1cc(N)nc(N)n1
Solvent: CO
Product: Cc1nn(C)c2nc(N)nc(N)c2c1=O
Reaction time: 5 h
Yield: 76 %

Procedure:
To a refluxing solution of 2,4-diamino-6(1-methylhydrazino)pyrimidine (500 mg) in anhydrous methanol (15 ml) was added methyl pyruvate (496 mg) over a five minute period. Reflux was continued for 5 hours after which time the solid which had separated was collected by suction filtration of the hot mixture, washed with methanol, and dried under vacuum at 70° C. to yield tan crystals of 5,7-diamino-1,3-dimethylpyrimido(4,5-c)-pyridazine-4(1H)-one (508 mg; 76% of theoretical yield; m.p.>275° C.).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=1)[C:7]([O:9]CC)=[O:8].Cl>O>[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOC)c1csc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C(C(=O)O)c1csc(NC=O)n1
Yield: 40.4 %

Procedure:
A solution of sodium hydroxide (1.6 g.) in water (30 ml.) was dropwise added over 5 minutes with stirring and ice-cooling to a suspension of ethyl 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetate (syn isomer) (5.14 g.) in water (60 ml.), and the resulting mixture was stirred for 1.5 hours at 10° to 20° C. The reaction mixture was adjusted to pH 7 with 10% hydrochloric acid and washed twice with ethyl acetate (100 ml.). To the aqueous layer was added ethyl acetate (200 ml.), and the resulting mixture was adjusted to pH 1 with 10% hydrochloric acid and extracted with the ethyl acetate. The aqueous layer was further extracted with ethyl acetate (100 ml.). Both ethyl acetate extracts were combined, washed with a sodium chloride aqueous solution (100 ml.) and dried over magnesium sulfate. The solvent was distilled off to give 2-methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.85 g.), mp 152° C. (dec.), which was recrystallized from ethyl acetate to give a pure compound, mp 167° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([OH:17])=[O:16])[C:7]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:18][O:16][C:15]([C:6]1[C:7]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:17]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c1NCCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc([N+](=O)[O-])cc2c1NCCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-1-benzazepine-9-carboxylic acid (6.25 g) was dissolved into DMF (50 ml), to which then potassium carbonate (11 g) and methyl iodide (4.9 ml) were added, and was stirred for 2 hours at room temperature. After the insoluble matter was filtered off and the filtrate was concentrated, ethyl acetate (500 ml) was added to the residue, which was then washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to give the intended compound 6.65 g (quantitatively) as yellow crystal.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[CH2:21]([O:20][C:18]([C:14]1[S:13][C:12]([C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[CH:16][CH:15]=1)=[O:19])[CH3:22]
Reactant: c1ccc(-c2ccc(-c3cccs3)s2)cc1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(-c3ccccc3)s2)s1

Procedure:
This compound was prepared in a manner analogous to Example 69 using 2.0 grams (0.083 mole) of 5-phenyl-[2,2'-bithienyl], 3.2 ml (0.0083 mole) of n-buthyl-lithium (2.6M in hexanes), and 1.0 gram (0.0092 mole) of ethyl chloroformate in 50 ml of dry tetrahydrofuran The yield of 5'-(ethoxycarbonyl)-5-phenyl[2,2'-bithienyl]was 0.9 gram; m.p. 113-115° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[C:14]([O-])(=[O:16])[CH3:15].[Na+].C(C1C(=O)CC(C2C=CC(F)=CC=2)CC1=O)(=O)C>>[C:14]([CH:9]1[C:10](=[O:12])[CH2:11][CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH2:7][C:8]1=[O:13])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: O=C1CC(=O)CC(c2ccco2)C1
Agent: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Agent: [Na+]
Product: CC(=O)C1C(=O)CC(c2ccco2)CC1=O

Procedure:
The title compound was prepared from 5-(2-furyl)-cyclohexane-1,3-dione (500 mg, 2.8 mmol) and sodium acetate (229 mg, 2.8 mmol), following the procedure describing the synthesis of 2-acetyl-5-(4-fluoro-phenyl)-cyclohexane-1,3-dione (example 3/a stage 1).