Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1.Cl.[O-:12][C:13]#[N:14].[Na+].C(=O)([O-])[O-].[K+].[K+]>O>[NH:1]([CH2:2][C:3]1[N:10]2[C:6]([S:7][CH:8]=[CH:9]2)=[CH:5][N:4]=1)[C:13]([NH2:14])=[O:12]
Reactant: N#C[O-]
Reactant: NCc1ncc2sccn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)NCc1ncc2sccn12
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 57.4 %

Procedure:
To 220 mg (1.42 mmol) of 5-aminomethylimidazo[5,1-b]-thiazole and 0.3 mg of ice were added 1 ml of ice-cooled water and 1 ml of 5N hydrochloric acid, and the mixture was stirred at 80° C. for 5 minutes. To this mixture was added 111 mg of sodium cyanate, and the resulting mixture was stirred at the temperature for 2 hours. 123 mg of sodium cyanate was further added to the mixture, and the resulting mixture was stirred for one hour. 122 mg of sodium cyanate was added again to the mixture, and the stirring was continued for 2 hours. The mixture was cooled to room temperature, and then made alkali by the addition of potassium carbonate. This mixture was washed with methylene chloride. MeOH was added to the aqueous layer, and the mixture was thoroughly stirred. Insoluble matters were removed by filtration. The filtrate was concentrated under reduced pressure, and then allowed to stand at 0° C. overnight. The crystals precipitated were collected by filtration to obtain 160 mg (yield 57%) of 5-ureidomethyl-imidazo[5,1-b]thiazole.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>>[CH:1]([C:4]1[S:5][C:6]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)c1nccs1
Product: CC(C)c1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from 2-iso-propyl-thiazole and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][N:2]=[CH:1]3)=[CH:6][CH:7]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Oc1ccc2ccncc2c1)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3ccncc3c2)CC1

Procedure:
The product from step (a) above (300 mg, 1.1 mmol) and 1-BOC-piperazine (307 mg, 1.6 mmol, Aldrich) was reacted under the conditions of Example 132b to give the title compound as yellow amorphous solid, which was used for the next step. MS (ESI, pos. ion) m/z: 314 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[NH3:22]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12]([NH2:22])(=[O:14])=[O:13]
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Cc1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
2-Chloro-5-(2-oxopropyl)-benzenesulphonyl chloride (32a) (2.0 g, 7.5 mmol) is dissolved in dioxan (50 ml) with stirring. Sodium carbonate (7.5 ml, 2M solution, 2 eq.) is added followed by a solution of ammonia in dioxan (37.5 ml, 0.5 M). After 30 min the reaction mixture is poured onto water (250 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts are washed with water (2×100 ml) followed by brine (100 ml) and dried (MgSO4). After filtration the solvent is removed and the product is purified by chromatography on silica, eluting with ethyl acetate/hexane (1:2) to afford the titled compound.
Reaction SMILES: [F:1][C:2]([F:48])([C:44]([F:47])([F:46])[F:45])[CH2:3][CH2:4]/[CH:5]=[C:6](\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29]COC)=[CH:26][CH:27]=2)[O:22][CH2:21][C:20]1([C:34]1[CH:39]=[CH:38][C:37]([O:40]COC)=[CH:36][CH:35]=1)[CH3:33])/[C:7]([OH:9])=[O:8]>C(O)C.Cl.O>[F:48][C:2]([F:1])([C:44]([F:45])([F:46])[F:47])[CH2:3][CH2:4]/[CH:5]=[C:6](\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[C:28]2[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=2)[O:22][CH2:21][C:20]1([C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1)[CH3:33])/[C:7]([OH:9])=[O:8]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCC/C(=C\CCC(F)(F)C(F)(F)F)C(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC/C(=C\CCC(F)(F)C(F)(F)F)C(=O)O
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (E)-6,6,7,7,7-pentafluoro-2-{9-[(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman-4-yl]nonyl}-2-heptenoic acid (111 mg, 0.16 mmol) in ethyl alcohol (5 ml), was added 6 N aqueous solution of hydrochloric acid (30 drops) and the reaction mixture was stirred at 40° C. for 6 h. The reaction mixture was diluted with water and extracted with methylene chloride. Organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuum. Crude product was purified by flash chromatography on silica gel (hexane:ethyl acetate:methyl alcohol=10:10:1), and then additionally by preparative thin-layer chromatography on Merck Silica-gel 60 plates (hexane:ethyl acetate:methyl alcohol=5:5:1) to give (E)-6,6,7,7,7-pentafluoro-2-{9-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methychroman-4-yl]nonyl}-2-heptenoic acid as a colorless amorphous solid. yield: 47.4 mg (49%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[S:30]([CH3:29])(=[O:32])=[O:31])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1C1CCN(C(=O)c2cn(S(C)(=O)=O)c3cc(Cl)ccc23)CC1
Yield: 17.4 %

Procedure:
To a solution of 0.035 g (0.09 mmol) (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone in 2 ml N,N-dimethylformamide were added 0.005 g (0.10 mmol) sodium hydride (50% in oil). After 45′, 0.008 ml (0.10 mmol) methanesulfonyl chloride were added. The reaction mixture was quenched with water after 3 h and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30), dried over sodium sulfate and concentrated to dryness. The residue was chromatographed (loaded as a solution in toluene; Flashpac 5 g; n-heptane/ethyl acetate 100:0→75:25) to give the title compound (0.007 g; 17%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]2[CH2:18][CH:17]=[CH:16][CH:7]2[CH:8]([O:11][C:12](=[O:15])[NH:13][CH3:14])[O:9][CH:10]=1)=[O:4].[C:19](O)(=[O:26])C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:18][CH:17]=[C:16]([CH2:19][OH:26])[C@@H:7]2[C@H:8]([O:11][C:12](=[O:15])[NH:13][CH3:14])[O:9][CH:10]=1)=[O:4]
Reactant: CNC(=O)OC1OC=C(C(=O)OC)C2CC=CC12
Reactant: O=C(O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CO)[C@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.4 %

Procedure:
28.5 g of the above (1S, 4aS, 7aR )-7-(tert-butyldiemthylsilyloxymethyl)-1-(methylcarbamoyloxy)-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester were dissolved in tetrahydrofuran followed by addition of 35 g of benzoic acid. Next, 143 ml of tetra-n-butylammonium fluoride (1.0 M, tetrahydrofuran solution) were dropped in followed by stirring for 24 hours at room temperature. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with saturated aqueous sodium bicarbonate and brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the hexane-ether eluate in the form of (1S,4aS,7aR)-7-(hydroxy-methyl)-1-(methylcarbamoyloxy)-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (20.0 g, yield: 98.4%). The physicochemical properties of this compound are described in Table 66, Compound No. I-315.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]2[NH:25][CH:26]=[N:27][C:23]=2[CH:22]=1)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]2[N:25]([CH2:11][C:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]4[C:8]=3[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]4)[CH:26]=[N:27][C:23]=2[CH:22]=1)=[O:20]
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Reactant: COC(=O)c1ccc2[nH]cnc2c1
Product: COC(=O)c1ccc2c(c1)ncn2Cc1cc(Cl)cc2cnn(CC(C)C)c12
Yield: 40 %

Procedure:
Compound 34 was prepared following general method 3A, using compound 17 as a starting material and 1H-benzoimidazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 40%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH:14]=O)=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2.C([O-])(=O)C.[NH4+].[CH3:21][N+:22]([O-:24])=[O:23]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH:14]=[CH:21][N+:22]([O-:24])=[O:23])=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: COc1cc(C=O)c2c(c1OC)CCC2
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc(C=C[N+](=O)[O-])c2c(c1OC)CCC2
Temperature: 112 °C
Yield: 9.1 %

Procedure:
To a 100 ml 3-necked round bottom flask fitted with a condenser and thermometer and magnetically stirred, was added 12.97 g (0.063 mole) of 4,5-dimethoxy-7-indanaldehyde, 3.00 g (0.039 mole) of ammonium acetate, 13.0 ml (0.292 mole) of CH3NO2 and 40 ml of glacial acetic acid. This mixture was heated for 1 to 2 hours at 112° C. As the reaction solution began to cool the entire solution solidified. After cooling in an ice bath and removing the solvent by filtration, the solid 4,5-dimethoxy-7-nitrovinylindane was washed with a small volume of acetic acid giving fine yellow needles (9.55 g) after thorough drying. The filtrate was poured into 300 ml of ice and water from which precipitated a slightly gummy, yellow-brown solid. This gave an additional 1.43 g of crystalline solid after drying and crystallizing from methanol giving a total yield of 10.98 g (70 percent). An analytical sample melted at 128°- 130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:11][C:7]1[CH:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)O)cc1Br

Procedure:
Briefly described, p-toluic acid 2 is refluxed with N-bromo-succinimide and benzoyl peroxide in dry benzene to give a bromo-p-toluic acid 3 which, upon reaction with nitric acid, is converted to 3-nitro-4-bromomethyl benzoic acid 4. This is believed to be a new compound and represents a parent compound in the synthesis forming the subject matter of this invention. At slightly higher temperatures, above -10° C., the corresponding dinitro derivative 4a predominates.
Reaction SMILES: [CH2:1]([O:8][CH:9]([OH:14])[CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[CH3:18].O>O1CCCC1>[CH2:17]([O:14][CH:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH3:13])[CH3:18]
Reactant: CCBr
Reactant: CCCCC(O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(OCC)OCc1ccccc1
Yield: 86.4 %

Procedure:
A solution of 194 g (1 mol) of pentanediol monobenzyl ether in 1 L of tetrahydrofuran (hereinafter referred to THF) was added to a solution of 48 g (2 mol) of sodium hydride in 100 ml of THF under cooling. Then, the mixture was heated under reflux for 2 hours and cooled to the room temperature before 140 g (1.3 mol) of ethyl bromide in 300 ml of THF was added dropwise. The mixture was heated under reflux for 6 hours. 500 ml of water was added and extraction was carried out with 500 ml of diethyl ether. After the organic layer was neutralized and washed with water and dried over anhydrous magnesium sulfate and concentrated. The oily residue was purified by distillation under the reduced pressure, to obtain 192 g of pentanediol benzyl ethyl ether. Boiling point; 110-117° C. (1 mmHg).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)=[CH2:21]>C1C=CC=CC=1>[CH:20]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:30])=[O:29])=[CH:26][CH:27]=1)=[CH2:21]
Reactant: C=Cc1ccc2nnn(O)c2c1
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)On2nnc3ccc(C=C)cc32)cc1
Temperature: 10 °C
Yield: 44.2 %

Procedure:
In benzene (200 ml) are dissolved 1-hydroxy-6-vinyl-1,2,3-benzotriazole (31.2 g) and triethylamine (20 g) under stirring and thereto is added dropwise a solution of p-vinylbenzenesulfonyl chloride (39.2 g) in benzene (70 ml) under ice-cooling to 10° C. The mixture is stirred at room temperature for 3.5 hours. The reaction mixture is poured onto ice-water (1 liter) and the mixture is extracted with ethyl acetate (500 ml, three times). The combined extracts are washed with an aqueous sodium hydrogen carbonate and then water, dried over anhydrous magnesium sulfate, treated with charcoal, and then concentrated under a reduced pressure till about 150 ml. To the mixture is added n-hexane and the mixture is allowed to stand at a cooled place. The precipitated crystals are separated by filtration to give 1-(p-vinylbenzenesulfonyloxy)-6-vinyl-1,2,3-benzotriazole (28.0 g), melting point: 85°-87° C. To the filtrate is further added n-hexane and the mixture is allowed to stand at a cooled place to give additionally the desired product (11.7 g).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][N:18]3[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19]3)[CH2:13][O:14]2)=[C:9]([F:26])[CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:49][S:50]([NH2:53])(=[O:52])=[O:51].C1CCN2C(=NCCC2)CC1.[ClH:65].O1CCOCC1>CN(C=O)C.O1CCOCC1.CC(O)=O>[ClH:65].[F:36][C:2]([F:1])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:53][S:50]([CH3:49])(=[O:52])=[O:51])=[O:24])[CH2:19]3)[CH2:13][O:14]2)=[C:9]([F:26])[CH:8]=1
Reactant: O=C(O)C1CCN(CC2=Cc3c(F)cc(OCc4ccc(C(F)(F)F)cc4C(F)(F)F)cc3OC2)C1
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)C1CCN(CC2=Cc3c(F)cc(OCc4ccc(C(F)(F)F)cc4C(F)(F)F)cc3OC2)C1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a solution of 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]pyrrolidine-3-carboxylic acid (98 mg) in DMF (2 mL) was added CDI (46 mg), followed by stirring at 70° C. for 12 hours. To the reaction liquid were added methanesulfonamide (27 mg) and DBU (43 mg) in this order, followed by stirring for 12 hours. To the reaction liquid was added AcOH, followed by concentration under reduced pressure, and the residue was purified by reverse phase column chromatography (H2O:MeCN=100:0 to 90:10) to obtain a yellow amorphous substance (70 mg). This yellow amorphous substance was dissolved in dioxane (1 mL), and a 4 M HCl/dioxane solution (1 mL) was added thereto, followed by stirring and then concentrating under reduced pressure. The residue was washed with hexane to obtain 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-N-(methylsulfonyl)pyrrolidine-3-carboxamide hydrochloride (60 mg) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](C(O)=O)=[N:4][C:5]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:7]=1>ClC1C=CC=CC=1Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[N:4][CH:3]=1
Reactant: COc1ccc(-c2nc(N)c(C(=O)O)nc2-c2ccc(=O)n(C(C)C)c2)cc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(-c2nc(N)cnc2-c2ccc(=O)n(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspention of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-methoxyphenyl)-2-pyrazinecarboxylic acid in 1,2-dichlorobenzen (3 ml) was heated at 200° C. and stirred for 4 hours. This reaction mixture was cooled to room temperature. To this solution was added IPE and stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with IPE. The residual solid was placed on a column of silica-gel and eluted with CHCl3—MeOH (20:1). The eluent was evaporated and the residue was purified by recrystallization from EtOH—water to give 5-[5-amino-3-(4-methoxyphenyl)-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (88 mg) as a pale brown crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH2:26]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=1)=[O:14]
Reactant: NCc1ccccn1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCc1ccccn1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(pyridin-2-ylmethyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.46 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.78 mmol of pyridine-2-methylamine. LC/MS [8.33 min; 449 (M+1)]
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccc(-c2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ccc(Sc2ccc(-c3ccccc3)nn2)cc1
Yield: 82.6 %

Procedure:
3-Chloro-6-phenylpyridazine (0.026 moles, 5.0 g), 4-aminothiophenol (0.026 moles, 3.3 g) and potassium carbonate (0.026 moles, 3.6 g) were stirred in 250 ml ethanol for 3 days. The reaction was filtered, concentrated, ethyl acetate added, washed with water and dried over sodium sulfate. The solution was concentrated and the product purified by HPLC over silica gel eluted with 50% ethyl acetate/hexane to yield 3-(4-aminophenylthio)-6-phenylpyridazine 6.0 g, 83%. Mass Spec (FD) 279. Calculated for C16H13N3S: C, 68.79; H, 4.69; N, 15.04. Found: C, 68.87; H, 4.43N, 15.31.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH2:11][CH:10]([C:14]([NH2:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:16][CH2:14][CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: NC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
1-Benzyl-5-oxo-pyrrolidine-3-carboxylic acid amide (22 g, 0.1 mol) was added portionwise to a stirred solution of lithium aluminum hydride (9.5 g, 0.25 mol, 2.5 equiv.) in dry tetrahydrofuran (600 mL). After the initial effervescence had subsided, the reaction mixture was heated at reflux at room temperature for 24 h, at which time analysis of the reaction mixture by LCMS showed there was no starting material. The reaction mixture was quenched by dropwise addition of saturated sodium sulphate solution with stirring until no further effervescence was observed. The suspension was filtered through a celite plug, eluting with diethyl ether (200 mL). The solvent was remove to afford 3-(RS)-aminomethyl-1-benzylpyrrolidine as an oil (14.7 g) which was used directly without further purification.
Reaction SMILES: CN(CCN(C)C)C.[Li]C(CC)C.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:24])[CH:16]=1.CI.C1C[O:30][CH2:29]C1>>[F:14][C:15]1[CH:16]=[C:17]([CH3:24])[C:18]([C:19]([OH:21])=[O:20])=[C:22]([O:30][CH3:29])[CH:23]=1
Reactant: C1CCOC1
Reactant: Cc1cc(F)ccc1C(=O)O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CI
Product: COc1cc(F)cc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of TMEDA (1.95 mL, 19.2 mmol) in anhydrous THF (8 mL) at −78° C. was slowly added a solution of sec-BuLi (1.4 M solution in cyclohexane, 18.5 mL, 25.8 mmol), followed by a solution of 4-fluoro-2-methyl-benzoic acid (44, 1.0 g, 5.88 mmol) in anhydrous THF (2 mL) at −78° C. under an atmosphere of N2. The mixture stirred at −78° C. for 2 h before a solution of methyl iodide (1.46 mL, 23.5 mmol) in anhydrous THF (2 mL) was added slowly. The mixture was stirred at same temperature for 1 h before it was warmed up to room temperature and quenched with H2O. The crude mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL). Aqueous layer was collected and acidified with 2 M HCl, followed by extraction by EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 40 g Redisep column, 20% to 50% EtOAc/hexane) to give 4-fluoro-2-methoxy-6-methyl benzoic acid as a white solid (45, 0.18 g, 16%): 1H NMR (300 MHz, CDCl3) δ 6.53-6.62 (m, 2H), 3.90 (s, 1H), 2.48 (s, 1H); MS (ESI+) m/z 185 (M+H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([N:18]=[C:19]=[O:20])[CH2:15][CH2:16][CH3:17]>C1(C)C(C)=CC=CC=1.P([O-])(OCCCC)(OCCCC)=O>[CH2:14]([NH:18][C:19]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:20])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN=C=O
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: CCCCOP(=O)([O-])OCCCC
Solvent: Cc1ccccc1C
Product: CCCCNC(=O)N(c1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 60 %

Procedure:
0.5 mole of diphenylamine was taken together with 0.53 mole of n-butyl isocyanate and 1 g of di-n-butyl phosphate in 150 ml of xylene. The mixture was heated at 120° C. for 24 hours, with stirring, and then cooled to room temperature. After the product had been filtered off, washed with 100 ml of cold xylene and dried, 0.3 mole of N-n-butyl-N',N'-diphenylurea was obtained. Melting point: 92° C./yield: 60% of theory.