Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:11]([OH:13])=O)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.S(Cl)([Cl:16])=O>>[CH3:1][C:2]1([C:11]([Cl:16])=[O:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: CC1(C(=O)O)Cc2ccccc2C1
Reactant: O=S(Cl)Cl
Product: CC1(C(=O)Cl)Cc2ccccc2C1

Procedure:
A stirred mixture of 2,3-dihydro-2-methyl-1H-indene-2-carboxylic acid (6.70 g) and thionyl chloride (70 ml) is heated under reflux for 14 hr. The ecess of thionyl chloride is removed and the acid chloride is distilled. Yield 5.35 g, 72%, bp. 93°-98° C./3 mmHg.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]([F:34])([F:33])[C:28]1[CH:32]=[CH:31][NH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:30]1[CH:31]=[CH:32][C:28]([C:27]([F:34])([F:33])[F:26])=[N:29]1)[C:11]([C@@H:12]([N:14]1[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]1=[O:23])[CH3:13])=[CH:10]2
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](c1cc2cccc(Cl)c2nc1-n1ccc(C(F)(F)F)n1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (0.2000 g, 0.539 mmol), 3-(trifluoromethyl)pyrazole (0.0733 g, 0.539 mmol), cesium carbonate (0.351 g, 1.08 mmol) and in DMF (1.80 mL, 0.539 mmol) was stirred at 100° C. After 2 h, The mixture was cooled to room temperature. To the cooled mixture was added water (30 mL). The mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL×1), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 10 min, then 10 to 50% gradient of EtOAc in hexane over 20 min, then 50% isocratic of EtOAc for 10 min as eluent to give 2-((S)-1-(8-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dione as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (1H, s), 8.51 (1H, d, J=2.2 Hz), 8.25 (1H, dd, J=8.4, 1.0 Hz), 8.08 (1H, dd, J=7.7, 0.9 Hz), 7.63-7.85 (5H, m), 6.92 (1H, d, J=2.7 Hz), 5.94-6.05 (1H, m), 1.83 (3H, d, J=7.0 Hz); LC-MS (ESI) m/z 471.1 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[CH2:31][N:32]([CH2:35]C)CC.[OH2:37]>C(#N)C.CN=C=O>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:31]([NH:32][CH3:35])=[O:37])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCN(CC)CC
Reactant: O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: CN=C=O
Agent: Cl
Solvent: CC#N
Product: CNC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
To a solution of the compound (0.20 g) obtained in Example 1 and Et3N (0.19 ml) in acetonitrile (5 ml), methyl isocyanate (0.050 ml) was added, and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, and then the product was. extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound as colorless oil (0.20 g, 95%).
Reaction SMILES: N.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=CC=1.[NH2:13][CH:14]([C:17]#[N:18])[C:15]#[N:16].C(OC)(OC)(OC)CCCC.[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>C(#N)C>[NH2:16][C:15]1[N:34]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:5]([CH2:6][CH2:7][CH2:2][CH3:12])=[N:13][C:14]=1[C:17]#[N:18]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#CC(N)C#N
Reactant: CC(C)CN
Agent: CCCCC(OC)(OC)OC
Agent: N
Solvent: CC#N
Product: CCCCc1nc(C#N)c(N)n1CC(C)C
Temperature: 25 °C
Yield: 62.1 %

Procedure:
Dry ammonia was bubbled through a stirred solution of aminomalononitrile p-toluenesulfonate (25.0 g, 98.7 mmol) in anhydrous acetonitrile (1 L). The reaction warmed slightly, and precipitate formed. The precipitate was removed by filtration, and the filtrate was concentrated to a volume of about 500 mL. Trimethyl orthovalerate (17.0 mL, 98.7 mmol) was added, and the resulting solution was heated at reflux for 30 minutes and then allowed to cool to room temperature. Isobutylamine (9.8 mL, 99 mmol) was added, and the reaction was complete in minutes as evidenced by thin layer chromatography (TLC). The volatiles were removed under reduced pressure, and the residue was dissolved in ethyl acetate (400 mL). The resulting solution was washed sequentially with aqueous sodium hydroxide (75 mL of 2 M), water, and brine; dried over magnesium sulfate, and concentrated under reduced pressure to provide a dark solid. The crude product was purified by column chromatography on silica gel (eluting with 50/50 ethyl acetate/hexane) to provide 13.50 g (62%) of 5-amino-2-butyl-1-(2-methylpropyl)-1H-imidazole-4-carbonitrile as a brown solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1.O>C(O)(=O)C>[N:18]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)[CH:21]=[CH:25][CH:24]=[CH:23]1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1-n1cccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
Compound 2 (0.060 g, 0.25 mmol) was dissolved in acetic acid (1.0 mL) and the solution was added with 2,5-dimethoxytetrahydrofuran (99 μL, 0.77 mmol), followed by stirring at room temperature for 2 hours. Then, to the reaction mixture, water was added and the precipitated solid was filtered. The solid was recrystallized from ethanol to obtain Compound 162 (14 mg, 20%).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH:7]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:8][NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[OH:22][C:21]1[C:20]2[C:15](=[CH:16][C:17]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:18][CH:19]=2)[CH:14]=[N:13][C:12]=1[C:10]([NH:9][CH2:8][CH:7]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]([OH:36])=[O:5])=[O:11]
Reactant: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(NCC(C(=O)O)c1ccccc1)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
A mixture of 3-[(4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-2-phenyl-propionic acid tert-butyl ester (50 mg) and TFA (2 mL) in DCM (2 mL) was stirred at rt for 3 h; then the mixture was concentrated and resulting residue was treated with water; the solids were collected via filtration and air dried to give desired product as white solids (35 mg). LC-MS ESI+: 429 (M+1)+.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[CH3:7][N:8]([O:17][CH3:18])[C:9]([C:11](N(C)OC)=[O:12])=[O:10]>Cl>[CH3:7][N:8]([O:17][CH3:18])[C:9](=[O:10])[C:11](=[O:12])[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1
Reactant: CON(C)C(=O)C(=O)N(C)OC
Reactant: BrCC1CCC1
Agent: Cl
Product: CON(C)C(=O)C(=O)CC1CCC1
Temperature: 0 °C
Yield: 80.3 %

Procedure:
The finely divided Mg was treated with 22.5 mL (0.20 mol) of bromomethylcyclobutane maintaining the internal temperature at <5° C. The resulting mixture was stirred cold for I h, then was treated with 26.40 g (0.15 mol) of N,N′-dimethyl-N,N′-dimethoxy oxamide (from Step A) in portions as a solid. The resulting mixture was stirred at 0° C. for 16 h. The reaction was poured onto a mixture of 100 mL conc. HCl and 500 g of ice under N2 atmosphere. The quenched mixture was extracted with 1.5 L of EtOAc. The extract was washed with 500 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 500 g of silica gel using 3:1 v/v hexanes/EtOAc as the eluant afforded 22.3 g (80%) of the title compound: 1H NMR (500 MHz) δ 1.66-1.76 (m, 2H), 1.82-1.98 (m, 2H), 2.12-2.22 (m, 2H), 2.74-2.84 (3H), 3.20 (s, 3H), 3.66 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.Br[CH2:18][CH2:19][CH3:20].CC(C)([O-])C.[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:16][CH2:18][CH2:19][CH3:20])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: CCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(Br)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 58.1 %

Procedure:
A mixture of (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.150 g, 0.528 mmol), 1-bromopropane (0.240 mL, 2.64 mmol), and potassium tert-butoxide (0.296 g, 2.64 mmol) in DMF (3.0 mL) was heated at 80° C. After 24 h, additional 1-bromopropane (0.240 mL, 2.64 mmol) was added and mixture stirred at 70° C. for 16 h. The reaction was incomplete, so 1-bromopropane (0.240 mL, 2.64 mmol) and potassium tert-butoxide (0.296 g, 2.64 mmol) were added, and the mixture was stirred at 100° C. After 24 h, the reaction mixture was cooled to rt and water was added. The mixture was extracted with dichloromethane and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.100 g, 58%) as a colorless oil. MS (ESI, pos. ion) m/z 326, 328 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=[CH:30][C:31]2[N:36]([OH:37])N=[N:34][C:32]=2[CH:33]=1.CC1C(N)=CON=1>CN(C)C=O.O>[CH3:30][C:31]1[C:32]([NH:34][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][C:9]=2[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:33][O:37][N:36]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: Cc1nocc1N
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: Cc1nocc1NC(=O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 0.12 g, 0.36 mmol), EDC (0.14 g, 0.72 mmol) and HOBT (0.11 g, 0.72 mmol) in N,N-dimethylformamide (2 ml) was stirred in air at room temperature for 1 h, then 3-methyl-4-isoxazolamine (may be prepared as described in Description 91; 100 mg, 1.02 mmol) was added in one charge. The reaction mixture was stirred at 25° C. overnight. The reaction mixture was diluted with water (25 ml). The solid was filtered, washed with water (30 ml) and methanol (5 ml×2), and dried in vacuo to yield the title compound as a grey solid. 72 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:16]([Li])[CH2:17][CH2:18]C.C(Br)CC>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2=CCN(C)CC2)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCCBr
Product: CCCC1(c2cccc(OC)c2)C=CN(C)CC1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
A solution of 900 g (4.43 mol) of 1,2,3,6-tetrahydro-4-(3-methoxyphenyl)-1-methylpyridine dissolved in 10.8 liters of dry THF was added to a dry, nitrogen purged 22 liter reaction flask equipped with a stirrer, low temperature thermometer, and addition funnel. The temperature of the reaction mixture was lowered to approximately -10° C. whereupon 3.04 liters of 1.6 molar n-butyllithium in hexane was added at a rate so as to maintain the temperature below -5° C. The resulting deep red solution was stirred for 15 minutes at -5° C. and 572 g (4.65 mol) of n-propylbromide in 2.4 liters of dry tetrahydrofuran were added at such a rate so that the temperature remained below -5° C. The reaction mixture was stirred for 10 minutes at -5° C. and then carefully quenched by the addition of 1.5 liters of water to destroy any excess n-butyllithium. The organic phase was separated, washed with 1.5 liters of water, 1.5 liters of saturated sodium chloride solution and dried over 500 g of anhydrous sodium sulfate. Evaporation of the solvent gave 1126 g of crude 1,2,3,4-tetrahydro-4-(3-methoxyphenyl)-1-methyl-4-propylpyridine (75% pure).
Reaction SMILES: [I:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+].CO.Cl>C1COCC1>[I:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1scc(C)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1csc(C(=O)O)c1I
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of methyl 3-iodo-4-methylthiophene-2-carboxylate [Oakwood Product Inc.] (10 g, 35.4 mmol) in THF (200 mL) was added a solution of 2N NaOH (19.50 mL, 39.0 mmol). MeOH was added to the reaction mixture until a homogeneous solution was obtained. After about 4 h, concentrated HCl was added until a pH of about 1 was obtained. The reaction mixture was partially concentrated under reduced pressure and the resulting solid was collected by filtration and dried under reduced pressure to provide the title compound as a brown solid (9.50 g, 100%): LC/MS (Table 1, Method a) Rt=2.55 min; m/z: 267 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[NH2:23])=[CH:5][CH:4]=1)#[N:2].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[NH:23][S:36]([C:27]2[CH:28]=[CH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)(=[O:38])=[O:37])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)c2)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)c(Oc3ccc(C#N)cc3)c2)cc1
Yield: 68 %

Procedure:
1,5-Bis-(4-cyano-phenoxy)-2-aminobenzene 0.175 g (0.54 mmol), 2-naphthalene-sulfonyl chloride 0.148 g (0.65 mmol) and N,N-diisopropylethylamine (DIPEA) 0.85 g (0.65 mmol) were dissolved in 5 ml of dry toluene and refluxed for 8 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate after the pH was adjusted to 2 with 6 N HCl. The organic phase was washed with 1 M Na2CO3 (5×100 ml) and saturated brine solution. The solution was dried over sodium sulphate and concentrated to afford an oily residue, which was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 0.190 g of the required product. 1H NMR (DMSO-d6): δ 6.45 (3H, m), 7.16 (5H, m), 7.42 (6H, m), 7.75 (2H, dd), 8.10 (2H, d), 8.35 (1H, s).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][C:5](=[NH:9])OCC.C(O)(=O)C.[CH:14]([NH2:16])=[NH:15].O.NN.[N:20]([O-])=O.[Na+].Cl>O>[N:15]1[CH:14]=[N:16][N:9]=[C:5]([CH2:4][CH2:3][OH:2])[N:20]=1
Reactant: N=CN
Reactant: O=N[O-]
Reactant: CCOC(=N)CCO
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: OCCc1nncnn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
To a mixture of ethyl 3-hydroxypropanimidate hydrochloride (1 mmol, 153 mg) and formamidine acetate (5 mmol, 521 mg) was added hydrazine hydrate (1 mL) under an atmosphere of argon. After stirring at room temperature for 2 hours, the mixture was diluted with water (10 mL) and sodium nitrite (12.5 mmol, 0.86 g) was added. To this solution was added 2% aqueous HCl dropwise on an ice bath until the now pink solution reached a pH of 3. The aqueous solution was extracted with methylene chloride (5×25 mL), dried with magnesium sulfate, the solvent was removed by rotary evaporation, and then dried under vacuum to afford the product, 2-(1,2,4,5-tetrazin-3-yl)ethanol (28 mg, 22%), as a pink oil. LRMS-ESI [M+H]+ calcd. for C4H7N4O+: 127.06, found: 126.7.
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])(=[O:7])=[O:6])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[N-:21]=[C:22]=[S:23].[K+]>ClCCCl>[CH2:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([N:21]=[C:22]=[S:23])=[O:12])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: [N-]=C=S
Agent: [K+]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: C=CCNS(=O)(=O)c1cccc(C(=O)N=C=S)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
To a suspension of 3-(N-allylsulfamoyl)benzoic acid (2 g, 8.29 mmol) in 1,2-dichloroethane (25 mL) was added thionyl chloride (1.271 mL, 17.41 mmol) dropwise. The suspension was stirred for 2 hours at 80° C. After 2 hours, the reaction mixture was concentrated to an off-white solid. The solid was redissolved in 25 mL acetone, and potassium isothiocyanate (0.967 g, 9.95 mmol) was added. A precipitate formed immediately upon addition. The reaction was stirred at 50° C. After 2 hours, the reaction was filtered, concentrated, and adsorbed onto a silca-gel pre column. The residue was purified by column chromatography, eluting with 20-100% EtOAc in hexanes, to provide 3-(N-allylsulfamoyl)benzoyl isothiocyanate as an off-white solid (0.71 g, 30.3% yield). MS, m/z (C11H10N2O3S2): calcd, 282.0. found, 282.9 [M+H].
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][N:21]=[CH:22]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH:22]1[C:23]2[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH2:13][CH2:12][O:11][C:8]3[CH:7]=[CH:6][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:10][CH:9]=3)[CH:24]=2)[CH:19]=[CH:20][N:21]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccncc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccncc3c2)cc1
Yield: 93.7 %

Procedure:
A mixture of 4-[[2-(7-isoquinolyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in hot methanol (5 mL) and tetrahydrofuran (5 mL) was treated with 1N sodium hydroxide (2.0 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was dissolved in hot water. Cold 2N hydrochloric acid (1.0 mL) was added dropwise and the product was allowed to crystallize and was filtered, washed with water and dried to give 0.45 g of 4-[[2-(7-isoquinolyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 260° C. with decomposition.
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>C(OCC)C.C(O)C>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccncc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of potassium ethoxide (3.1 g, 36.2 mmol) in diethyl ether (70 mL) and ethanol (10 mL) under an argon atmosphere was added diethyl oxalate (4.9 mL, 36.2 mmol) and the reaction stirred at rt for 30 min. A solution of 4-methyl-3-nitropyridine (5.0 g, 36.2 mmol) in diethyl ether (20 mL) was added resulting in the immediate formation of a dark red precipitate. The reaction mixture was stirred at rt for 72 h, then cooled to 0° C. and filtered. The solid was dissolved in water (500 mL) acidified to pH 4 with acetic acid and the precipitate collected and dried to give the title compound as a red solid. δH (d6 DMSO): 1.27 (3H, t), 4.25 (2H, q), 6.74 (1H, s), 8.34 (1H, d), 8.43 (1H, d), 8.98 (1H, s); m/z (ES+)=239 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:20]([OH:22])=O.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[C:27]=1[OH:33])=[O:25]>>[C:24]([C:26]1[C:27]([OH:33])=[C:28]([NH:32][C:20]([C:3]2[CH:4]=[CH:5][C:6]3[O:10][CH:9]([CH2:11][CH2:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:8][C:7]=3[C:2]=2[Cl:1])=[O:22])[CH:29]=[CH:30][CH:31]=1)(=[O:25])[CH3:23]
Reactant: O=C(O)c1ccc2c(c1Cl)CC(CCCc1ccccc1)O2
Reactant: CC(=O)c1cccc(N)c1O
Product: CC(=O)c1cccc(NC(=O)c2ccc3c(c2Cl)CC(CCCc2ccccc2)O3)c1O
Yield: 93 %

Procedure:
Following the process described in example 1 (point K), starting from 4-chloro-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxylic acid and 3-amino-2-hydroxyacetophenone, the title compound was prepared (93% yield).
Reaction SMILES: [OH-:1].[K+].[NH:3]1[CH:10]=[CH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[CH2:11]=O>O>[OH:1][CH2:11][C:9]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[NH:3][CH:10]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: [OH-]
Reactant: C=O
Agent: [K+]
Solvent: O
Product: O=c1[nH]cc(CO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.4 %

Procedure:
To a 40 mL aqueous solution containing 0.60 gram of KOH were added 1.2 g of uracil and 5 mL of a 36.5% aqueous solution of formaldehyde. The resulting mixture was stirred in an oil bath set at 50° C. and the reaction was allowed to proceed until the complete disappearance of the starting uracil as observed by thin layer chromatography (TLC). The total reaction time was 72 hours under a nitrogen atmosphere. The reaction mixture was diluted with 80 mL of distilled water and vigorously stirred as 2.0 g of Amberlite resin IRC-50 (H) was added. The mixture was stirred for an extra 30-minute period and the pH was verified to ensure that the mixture was slightly acidic before proceeding. The resin was removed by filtration, and the filtrate was concentrated by vacuum distillation to a volume of approximately 25 mL. The solution was allowed to cool to room temperature, then further cooled in an ice bath to precipitate the product as a white solid. Recrystallization of the product was performed from water-methanol (volume ratio 1:2) and the product was filtered out, washed with cold methanol and dried under high vacuum to yield 827 mg of a fine white powder (54.4% yield) showing a single on TLC, with the Rf value 0.69 (methanol solvent) and properties given below.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[F:30])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[F:30])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:2]2[CH:12]=[C:6]3[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:13])[N:3]=2)=[CH:21][CH:20]=1
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)cc1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-(3,4-difluorophenoxy)phenyl)methanol.