Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1Br)=[O:14].CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.[Zn].Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:14]
Reactant: COC(=O)c1ccncc1Br
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccncc1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-cyanobenzyl bromide (625 mg, 3.27 mmol) in dry THF (4 mL) was added slowly over ~3 min. to a suspension of activated Zn (dust; 250 mg) in dry THF (2 mL) at 0° under an argon atmosphere. The ice-bath was removed and the slurry was stirred at room temperature for a further 30 min. Then 3-bromopyridin-4-carboxylic acid methyl ester (540 mg. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant reddish-brown mixture was stirred for 3 h at ~40°-45° C. The mixture was cooled and distributed between EtOAc (100 ml,) and 5% aqueous citric acid (50 mL). The organic layer was washed with H2O(2×50 mL), dried with Na2SO4. After evaporation of the solvent the residue was purified on silica gel, eluting with 35% EtOAc in hexane to give 420 mg as a clear gum. FAB ms (M+1)253.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31].C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN1C(=O)CCC1>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH:18]1[N:26]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[C:27]1=[O:31]
Reactant: O=C1NCCN1C1Cc2ccccc2C1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1N(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CCN1C1Cc2ccccc2C1
Yield: 10.3 %

Procedure:
Synthesized according to general procedure 43. The reaction was set up with 4-iodo-N-(thiazol-2-yl)benzenesulfonamide (250 mg, 0.68 mmol), 1-(2,3-dihydro-1H-inden-2-yl)imidazolidin-2-one (138 mg, 0.68 mmol), copper(I) iodide (267 mg, 1.4 mmol), potassium carbonate (282 mg, 2.0 mmol), and NMP (1.7 mL). The dark mixture was purified via silica gel chromatography using 5% MeOH in CH2Cl2 followed by trituration with 50% Et2O in CH2Cl2 to obtain the desired urea as a white solid (32 mg, 0.07 mmol, 10% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 7.75-7.69 (m, 4H), 7.26-7.24 (m, 3H), 7.19-7.17 (m, 2H), 6.81 (d, J=4.5 Hz, 1H), 4.74 (dd, J=1.3, 14.2 Hz, 1H), 3.81-3.77 (m, 2H), 3.34-3.27 (m, 2H), 3.12 (dd, J=7.9, 16.1 Hz, 2H), 3.00 (dd, J=6.2, 16.1 Hz, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=441.2; tR=1.45 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C@H:12]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C@H:12]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:10]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccccc1F
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Nc3ccccc3F)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1-fluoro-2-isocyanatobenzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 517.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3]1.[Li]CCCC.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](Cl)=[O:25])=[CH:16]1>C1COCC1.CCCCCC>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([O:9][CH2:8][CH2:7][CH:6]2[CH2:5][CH2:4][CH2:3][N:2]2[CH3:1])=[O:25])=[CH:16]1
Reactant: CN1CCCC1CCO
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCCC1CCOC(=O)c1c[nH]c2ccccc12
Reaction time: 0.5 h

Procedure:
To a dry THF solution (30 ml) of 2-(1-methyl-2-pyrrolidine)ethanol at -10° to 5° C. was dropwise added a 1.5M hexane solution of n-BuLi (16.0 ml, 24.0 mmol) over a period of 10 min. Stirring was continued for 30 min. To a mixture was then dropwise added at -5° to 5° C. a dry THF solution (20 ml) of indole-3-carboxylic acid chloride (4.20 g, 24.0 mmol) over a period of 45 min. The cooling bath was removed. After stirring overnight at room temperature, a reaction solution was poured onto a cold diluted hydrochloric acid, and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted with saturated aqueous sodium bicarbonate to a pH of >10 and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.91 g of the title compound as a yellow viscous material. A foamy solid;
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][N:13]([CH:15]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:12]2=[O:33])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].C1(OC)C=CC=CC=1>C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][N:13]([CH:15]([C:23]([OH:25])=[O:24])[C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[C:12]2=[O:33])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1CN(C(C(=O)OCc2ccccc2)c2ccc(O)cc2)C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC1CN(C(C(=O)O)c2ccc(O)cc2)C1=O
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A mixture of 3-phenylacetamido-1-(α-carbobenzoxy-p-hydroxybenzyl) azetidin-2-one (15 mg), methylene chloride (0.5 ml), aluminum chloride (12 mg) and anisole (0.2 ml) is kept at -20° C. for 8 hours. The reaction mixture is diluted with ethyl acetate, washed with dilute hydrochloric acid and water, dried, and concentrated in vacuo. Crystallizing the residue from a mixture of ethyl acetate and ether gives 3-phenylacetamido-1-(α-carboxy-p-hydroxybenzyl)azetidin-2-one (9 mg) melting at 134°-141° C. Yield: 75%.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1([NH:24][C:25]([C:27]2[N:28]=[CH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:26])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:6]1=[O:23])#N.Cl.[OH2:38].[CH3:39][OH:40]>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([N:7]2[C:8]3[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[C:5]([CH2:4][CH2:3][C:1]([O:40][CH3:39])=[O:38])([NH:24][C:25]([C:27]3[N:28]=[CH:29][C:30]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:26])[C:6]2=[O:23])=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)C(CCC#N)(NC(=O)c1cc3ccccc3cn1)C(=O)N2c1ccc(F)cc1
Reactant: O
Reactant: CO
Agent: Cl
Product: COC(=O)CCC1(NC(=O)c2cc3ccccc3cn2)C(=O)N(c2ccc(F)cc2)c2ccc(OC)cc21

Procedure:
160 g of (+)-N-[3-(2-cyanoethyl)-1-(4-fluorophenyl)-2,3-dihydro-5-methoxy-2-oxo-1H-indol-3-yl]-3-isoquinolinecarboxamide was dissolved in 770 ml of methyl alcohol, and under ice cooling, a hydrochloric acid gas was passed through the solution for about 2 hours. Then, 6.6 ml of water was added, and the whole mixture was refluxed under heating for 1 hour. After returning to room temperature, the reaction mixture was concentrated under reduced pressure and diluted with an aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was collected by separation. This organic layer was washed with water with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered, and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane =1:2 to 1:1) to afford (+)-methyl 3-[l-(4-fluorophenyl)-2,3-dihydro-3-(3-isoquinolinyl)carbonylamino-5-methoxy-2-oxo-1H-indol-3-yl]propionate as an amorphous substance. [α]D25 : +7.25° (c=0.248, methanol).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][OH:29])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=O)(C)(C)C.C(Cl)[Cl:31]>FC(F)(F)C(O)=O.O>[ClH:31].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][OH:29])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CO)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cl
Product: OCc1cccc(CCc2cncc(OC[C@@H]3CCN3)c2)c1

Procedure:
3-[2-[5-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]ethyl]phenylmethanol is dissolved in a mixture of trifluoroacetic acid, CH2Cl2, and water. The reaction is allowed to proceed at room temperature until the starting material is no longer detected by TLC. The solvent is evaporated, and the residue is purified by preparative HPLC (for example, acetonitrile/water gradient on C18). The product-containing fraction is partially evaporated to remove CH3CN, and the product is extracted into CH2Cl2. The organic phase is dried over MgSO4 and evaporated. The residue is taken up in methanol and adsorbed on a cation exchange column. The column is first eluted with methanol to remove neutral or acidic impurities (including residual trifluoroacetic acid), then with methanolic ammonia to recover the product as free base. After evaporation, this material is dissolved in a small volume of methanol, neutralized with a small excess of hydrochloric acid, diluted with water, and lyophilized to yield the product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH2:14])([CH3:4])([CH3:3])[CH3:2].C[O:17][CH:18]1[CH:22]([CH:23]=O)[CH2:21][CH:20](OC)O1>N1C=CC=CC=1.C(O)(=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[N:14]1[CH:20]=[CH:21][C:22]([CH:18]=[O:17])=[CH:23]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Reactant: COC1CC(C=O)C(OC)O1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1n1ccc(C=O)c1
Yield: 61.1 %

Procedure:
A solution of trans-(2-amino-cyclohexyl)-carbamic acid tert-butyl ester (Tetrahedron Lett. 2000, 41, 9607; 400 mg, 1.87 mmol) and 2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde (365 mg, 2.05 mmol) in pyridine (0.5 mL) and acetic acid (0.82 mL) was heated at 100° C. for 4.5 h. After cooling, the reaction mixture was partitioned between ethyl acetate and 10% aq. citric acid solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) yielded the title compound (334 mg, 61%). Off-white solid, MS (ISP) 293.3 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[C:7]([O:10][CH2:11][CH:12]1[CH2:24][CH2:23][N:15]2[C:16]3[C:21]([CH:22]=[C:14]2[CH2:13]1)=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:9])[CH3:8].Cl[CH2:26][Cl:27]>>[C:7]([O:10][CH2:11][CH:12]1[CH2:24][CH2:23][N:15]2[C:16]3[C:21]([C:22]([C:8]4[C:7](=[O:9])[O:10][C:1](=[O:5])[C:2]=4[C:23]4[CH:24]=[CH:12][CH:13]=[CH:14][C:26]=4[Cl:27])=[C:14]2[CH2:13]1)=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:9])[CH3:8]
Reactant: CC(=O)OCC1CCn2c(cc3ccccc32)C1
Reactant: ClCCl
Reactant: O=C(Cl)C(=O)Cl
Product: CC(=O)OCC1CCn2c(c(C3=C(c4ccccc4Cl)C(=O)OC3=O)c3ccccc32)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.2 g of oxalyl chloride were added to an ice-cold solution of 4 g of 8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole in 50 ml of dichloromethane. After 2 hours, the solvent was evaporated and the residue was dissolved in dichloromethane. This solution was added to a solution of 3.0 g of 2-chlorophenylacetic acid and 4.0 g of triethylamine in dichloromethane. The mixture was stirred for 16 hours and then concentrated. Chromatography of the residue on silica gel with dichloromethane/methanol (95:5) yielded 0.9 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(2-chlorophenyl)furan-2,5-dione of melting point 168°-171° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:15][O:16]/[N:17]=[C:18](/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)\[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:15][O:16]/[N:17]=[C:18](/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)\[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)COc1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.3 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged 10 mL of Toluene. to the stirred solvent was added ethyl (4-hydroxyphenoxy)acetate (0.2 g, 1.030 mmol) and (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.22 g, 0.810 mmol) was added Tributyl phosphine (0.268 g, 1.32 mmol) and 1,1′(Azodicarbonyl)di-piperidene (0.33 g, 1.326 mmol). Then the reaction mixture was Stirred at RT for 3 hrs. After completion of the reaction (reaction monitored by TLC), reaction mixture was extracted with ethyl acetate. Then the organic layer was dried over anhydrous Na2SO4. Solvent was removed under reduced pressure, and the resulting crude compound was purified by column chromatography on silica gel using petroleum ether and ethyl acetate as eluent (0.13 g Yield: 28.3%): 1H NMR (300 MHz, CDCl3): δ 7.57-7.60 (m, 2H), 7.18-7.28 (m, 5H), 6.82-6.84 (d, 3H), 6.78-6.79 (d, 3H), 5.12 (s, 2H), 4.83 (s, 2H), 4.49 (s, 2H), 4.15-4.22 (m, 2H), 3.98 (s, 3H), 1.19-1.24 (t, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:12][N:11]([CH:10]=[N:9][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1)[CH3:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Solvent: c1ccncc1
Product: CN(C)C=Nc1nc(OC(=O)c2ccccc2)ncc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
To a suspension of N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (0.10 g, 0.54 mmol) in pyridine (2 mL) was added benzoyl chloride (0.084 g, 0.60 mmol), and the mixture was agitated on an orbital shaker for 16 h at RT. The reaction mixture was partitioned between EtOAc and saturated aq NaHCO3, and the organic phase was dried over solid MgSO4, filtered, and evaporated to give the title compound (0.147 g 94%) as a white solid: mp 136-138° C.; 1H NMR (300 MHz, CDCl3) δ 8.69 (s, 1H), 8.27 (d, J=2.4 Hz, 2H), 8.25-8.20 (m, 2H), 7.69-7.63 (m, 1H), 7.56-7.49 (m, 2H), 3.23 (s, 3H), 3.20 (s, 3H); HPLC-MS (ESI) m/z 289 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][NH2:26].[O:27]1CC[O:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:29](=[O:30])[C:28]([NH:26][CH2:25][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)=[O:27]
Reactant: NCCc1ccccn1
Reactant: C1COCCO1
Reactant: COc1ccccc1CN
Solvent: CCN(CC)CC
Product: COc1ccccc1CNC(=O)C(=O)NCCc1ccccn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 70 %

Procedure:
2-Methoxybenzyl amine (5 mmol) was mixed with triethylamine (2 equiv.) in anhydrous Dioxane. Ethyl oxalyl chloride (1 equiv.) was added and the mixture was shaken at room temperature for 0.5-2 hours. Then 2-(2-pyridinyl)ethyl amine (1 equiv.) was added and the suspension was heated at 80° C. overnight. The solution was concentrated and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried by sodium sulfate and solvent was evaporated to give the crude product, which was purified by flash column chromatography to afford the title compound: yield 70%, m.p. 118-119° C.; m/e=314 [M+1]; 1H NMR (CDCl3): 3.02 (t, 2H), 3.76 (dt, 2H), 3.86 (s, 3H), 4.47 (d, 2H), 6.80-6.90 (m, 2H), 7.14-7.18 (m, 2H), 7.20-7.30 (m, 2H), 7.55-7.62 (m, 1H), 7.75-7.83 (m, 1H), 8.05-8.12 (m, 1H), 8.55-8.63 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[C:15]1[NH:16][C:17](=[O:28])[C:18]2[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=2[N:20]=1)[CH3:2].C(OCC)(=O)C.O>CO.[Pd]>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[C:15]1[NH:16][C:17](=[O:28])[C:18]2[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=2[N:20]=1)[CH3:2]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(/C=C/C(=O)O)ccc3OCC)nc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(CCC(=O)O)ccc3OCC)nc12
Reaction time: 3 h
Yield: 54.4 %

Procedure:
A solution of (E)-4-Ethoxy-3-(1-methyl-7-oxo-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-5-yl)cinnamic acid (0.426 g, 0.0011 mol) in a mixture of methanol (28.5 ml), ethyl acetate (100 ml) and water (1.5 ml), was stirred with 5% palladium on charcoal catalyst (0.05 g) under a hydrogen atmosphere at room temperature and pressure for 3 hours. The catalyst was removed by filtration and the solvent removed by evaporation under vacuum. Crystallisation of the residue from ethyl acetate-hexane gave the title compound as beige crystals (0.23 g, 54%), m.p. 165°-167° C. Found: C,62.25; H,6.17; N,14.09. C20H24N4O4 requires C,62.39; H,6.33; N,14.41%
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][C:11]([CH3:18])=[CH:12][C:13](OCC)=[O:14].S(=O)(=O)(O)O.CCOCC>C1C=CC=CC=1>[CH3:10][C:11]1([CH3:18])[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=2[CH3:8])[O:9][C:13](=[O:14])[CH2:12]1
Reactant: CCOC(=O)C=C(C)C
Reactant: Cc1cc(C)cc(O)c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: c1ccccc1
Product: Cc1cc(C)c2c(c1)OC(=O)CC2(C)C
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
3,5-Dimethylphenol (IIa) (3.2 g, 26.2 mmol), ethyl 3,3-dimethylacrylate (5 mL, 36 mmol, 1.4 eq.) and concentrated sulfuric acid (1.5 mL) were dissolved in anhydrous benzene (30 mL), and the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and washed successively with water (2×40 mL), 5% aqueous NaHCO3 solution (2×20 mL), brine (2×20 mL) and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under vacuum to obtain a dark brown gummy material. To this gummy material was added anhydrous ether (5 mL) and boiled for 2 min on a steam bath. The title compound, IIIa, (3.34 g, 16.4 mmol, Y: 62.4%) was crystallized out from the mixture upon cooling in an ice bath; mp, 95.8-96.3° C.; 1H-NMR (300 MHz, acetone-d6) δ ppm: 1.41 (6H, s, 4,4-Me2), 2.24 (3H, s, 5-Me), 2.46 (3H, s, 7-Me), 2.61 (2H, s, 3-H2), 6.68 (1H, s, Ar-H), 6.76 (1H, s, Ar-H); MS (Isobutane-DCI) m/e: 205 (M+H)+ ; IR (KBr) ν max: 1770, 1250, 1190, 870 cm-1.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:7][OH:8])[CH2:5][CH2:4]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][C:18]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>O1CCCC1>[CH:3]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:7][O:8][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[C:18]([O:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:19]=2)[CH2:5][CH2:4]1
Reactant: OCC(c1ccc(Cl)cc1)C1CC1
Reactant: Fc1ccc(CCl)cc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(COCC(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A stirred suspension of 0.1 gram (0.0044 mole) of sodium hydride in 5 mL of tetrahydrofuran was cooled to 0° C., and a solution of 0.8 gram (0.0041 mole) of 2-cyclopropyl-2-(4-chlorophenyl)ethanol in 2.5 mL of tetrahydrofuran was added via syringe during a two minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes and then was heated to 55° C. where it stirred for 1.5 hours. The reaction mixture was cooled to ambient temperature, and a solution of 1.0 gram (0.0043 mole) of (4-fluoro-3-phenoxyphenyl)methyl chloride in 2.5 mL of tetrahydrofuran was added via syringe. Upon completion of addition, the reaction mixture stirred at ambient temperature for 20 hours and then was warmed to 60° C. where it stirred for 30 minutes. The reaction mixture was cooled, and 15 mL of water was added. The aqueous layer was removed and extracted with three 25 mL portions of hexanes. The organic materials were combined and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual oil. The oil was purified by rotating disk thin layer chromatography using 5-10% ethyl acetate in hexanes for elution. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.65 gram of (4-fluoro3-phenoxyphenyl)methyl 2-cyclopropyl-2-(4-chlorophenyl)ethyl ether. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1OS(C(F)(F)F)(=O)=O)=[O:4].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][SH:34])=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[S:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)=[O:4]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)cnc2ccc(OC)cc12
Reactant: COc1ccc(CS)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1c(SCc2ccc(OC)cc2)cnc2ccc(OC)cc12
Yield: 88.4 %

Procedure:
A mixture of 6-methoxy-3-trifluoromethanesulfonyloxy-quinoline-4-carboxylic acid methyl ester (3.69 g, 10.10 mmol, 1.0 eq), (4-methoxy-phenyl)-methanethiol (3.43 g, 22.22 mmol, 2.2 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (409 mg, 0.71 mmol, 0.07 eq), tris(dibenzylideneacetone)dipalladium(0) (925 mg, 1.01 mmol, 0.1 eq) and N,N-diisopropylethylamine (3.46 mL, 20.20 mmol, 2.0 eq) in dioxane (40 mL) is heated under reflux for 16 hours, then filtered through decalite and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 6-methoxy-3-(4-methoxy-benzylsulfanyl)-quinoline-4-carboxylic acid methyl ester as an off-white solid (3.30 g, 88% yield).