Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[NH:10][NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.[C:17]([O-:20])(=O)[CH3:18].[C:21]([O-])(=[O:23])[CH3:22].[Pb+2].C(OC(=O)C)(=O)C>C(Cl)(Cl)Cl>[CH3:22][C:21]([N:10]1[C:11](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:13])[N:9]1[C:17]([CH3:18])=[O:20])=[O:23]
Reactant: O=c1[nH][nH]c(=O)n1-c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)n1c(=O)n(-c2ccccc2)c(=O)n1C(C)=O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To a mixture of 5.3 g (30 mmol) of 4-phenyl-1,2,4-triazolidine-3,5-dione and 22.7 g (60 mmol) of lead diacetate trihydrate in 200 ml of chloroform was added dropwise over a 15 minute period 45.9 g (450 mmol) of acetic anhydride. The mixture was stirred at room temperature. After 25 hours the pale yellow solution was washed with three 100 ml portions of water and three 75 ml portions of 10% sodium carbonate. The carbonate washings were acidified with concentrated hydrochloric acid. No precipitate was produced. The chloroform solution was dried (Na2SO4) and evaporated under reduced pressure to give a solid-liquid residue. The residue was filtered and the filtered solid was washed with 25 ml of 95% ethanol to give 2.75 g (35.1%) of the 1,2,4-triazolidine-3,5-dione product as a white solid. An additional quantity of the product precipitated from the ethanol filtrate. This solid was filtered to give an additional 1.20 g (15.3%) of the 1,2,4=triazolidine-3,5-dione product (50.4% total yield). The solids were recrystallized from 95% ethanol to give pure 1,2-dimethylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione: m.p. 169°-170.5° C.; IR (Nujol) 1750, 1732 (shoulder), 1714 (shoulder) cm-1 (CO); 1H NMR (60 MHz, CDCl3)δ7.80(s, 5H), 2.55 (s, 6H); Found: C, 55.2; H, 4.45; N, 16.0; C12H11N3O4 requires C, 55.2; H, 4.2; N, 16.0.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[Cl:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][Cl:14])[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCc2ccsc2C1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCCc2cc(C(=O)CCCCl)sc2C1
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of 2.5 g of 7-acetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine and 2.7 g of 4-chlorobutyryl chloride in 25 ml of dichloromethane was added 6.0 g of aluminum chloride under ice-cooling. The mixture was stirred for 30 minutes, poured into water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel to give 2.9 g of 7-acetyl-2-(4-chlorobutyryl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[C:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[CH:21][CH:22]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]1[CH:79]=[CH:78][CH:77]=[C:76]([OH:80])[C:71]=1[C:72]([O:74][CH3:75])=[O:73].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(#N)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[C:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[CH:21][CH:22]=1)[C:13]([NH:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]1[CH:79]=[CH:78][CH:77]=[C:76]([OH:80])[C:71]=1[C:72]([O:74][CH3:75])=[O:73])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Reactant: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2-c2ccccc2)S(=O)(=O)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(-c2ccccc2)c1)NC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a solution of (2S)-2-[(benzyloxy)carbonyl]amino-3-[6-(1,1-dioxido-3-oxoisothiazolidin-5-yl)biphenyl-3-yl]propanoic acid (18.0 mg, 0.0354 mmol) in N,N-dimethylformamide (1.00 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16.4 mg, 0.0372 mmol) at 0° C. The reaction was stirred for 15 min and then methyl 2-(4-aminobutoxy)-6-hydroxybenzoate (9.32 mg, 0.0389 mmol) and N,N-diisopropylethylamine (18.5 μL, 0.106 mmol) was added. The resulting solution was stirred for 3 h and then diluted with acetonitrile and purified by preparative LCMS to afford a white solid (12.4 mg, 48%). 1H NMR (400 MHz, CD3OD): δ 8.07 (m, 1H), 7.56 (m, 1H), 7.29 (m, 13H), 6.46 (m, 2H), 5.05 (m, 3H), 4.35 (m, 1H), 3.94 (m, 2H), 3.84 (s, 3H), 3.19 (m, 5H), 2.96 (m, 1H), 1.60 (m, 4H). LCMS found for C38H40N3O10S (M+H)+: m/z=730.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH:10]=1)=[O:8])([O-:3])=[O:2].[OH-].[Na+]>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCn1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2ccccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.4 %

Procedure:
A mixture of ethyl 4-[3-(3-nitrobenzoyl)indol-1-yl]butyrate (1.60 g), 1N aqueous sodium hydroxide (11 ml) and 1,4-dioxane (50 ml) was stirred at 25° C. for 14 hours. After evaporation of the organic solvent, 1N hydrochloric acid (20 ml) was added to the aqueous solution and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-[3-(3-nitrobenzoyl)indol-1-yl]butyric acid (1.28 g) as-colorless crystals.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([O-:24])=O)=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH3:38][C:39]1[C:47]2[C:46]([NH2:48])=[CH:45][CH:44]=[CH:43][C:42]=2[N:41]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][N:51]=2)[N:40]=1.O>CN1C(=O)CCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([NH:48][C:46]4[CH:45]=[CH:44][CH:43]=[C:42]5[C:47]=4[C:39]([CH3:38])=[N:40][N:41]5[CH2:49][C:50]4[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][N:51]=4)=[O:24])=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: Cc1nn(Cc2ccc(C(F)(F)F)cn2)c2cccc(N)c12
Reactant: CC(C)N1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nn(Cc2ccc(C(F)(F)F)cn2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C(C)C)CC5)ccn34)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
Lithium 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.746 g, 2.204 mmol) was dissolved in 16 mL of dry NMP. To this was added 2,4,6-trichlorobenzoyl chloride (0.538 g, 2.20 mmol) and this mixture was stirred at ambient temperature for 30 minutes. 3-Methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine (0.500 g, 1.63 mmol) was added and the mixture was warmed to 90° C. for 16 hours, then allowed to cool to ambient temperature. Water (50 mL) was added and the mixture extracted with EtOAc. The extracts were then washed with 10% aqueous potassium carbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography (7% MeOH/DCM/0.5% NH4OH) afforded 0.112 g (11%) of the final compound. MS (APCI), positive scan, m/z=622.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1.S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+].[CH2:31](O)[CH3:32]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH2:31][CH3:32])=[O:14])=[CH:8][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(Oc2ccc(F)c(F)c2)nc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccc(Oc2ccc(F)c(F)c2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 2-(6-(3,4-difluorophenoxy)pyridin-3-yl)acetic acid (10 g, 37.7 mmol) in ethanol (100 mL) was added sulfuric acid (20 ml, 375 mmol) in ethanol (100 mL). The reaction mixture was stirred at 80° C. for 3 hr. and then the reaction mixture was made alkali with Na2CO3, and then extracted with CH2Cl2. The organic layer was separated and dried over Na2SO4, and then concentrated under reduced pressure to provide ethyl 2-(6-(3,4-difluorophenoxy)pyridin-3-yl)acetate (10 g, 78%).
Reaction SMILES: [CH:1]1([NH:6][C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C@@H:9]([CH3:27])[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[CH:1]1([N:6]([C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C@@H:9]([CH3:27])[CH2:8]2)[C:37](=[O:39])[CH3:38])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](NC3CCCC3)C[C@@H]2C)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)C3CCCC3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution (2S,4R)-N-cyclopentyl-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (100 mg, 02.7 mmol) in methylene chloride (5 mL) was added diisopropylethylamine (120 uL, 0.70 mmol) followed by acetyl chloride (90 uL, 1.27 mmol). The mixture was stirred at r.t. for 4 h. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford pure N-cyclopentyl-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (100 mg, 91%).
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[F:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:19]1[CH2:18][CH2:17][CH2:16][C:15](=[O:32])[C:14]2=1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C1COCC1.CN(C=O)C>[F:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:32])[C:14]2=1
Reactant: O=C1CCCc2c1c1cc(F)ccc1n2Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Oc1cccc2c1c1cc(F)ccc1n2Cc1ccc(F)cc1
Temperature: 75 °C
Reaction time: 6.5 h
Yield: 51.5 %

Procedure:
Pyridinium bromide perbromide (0.7068 g, 0.0022 mol) is added to a mixture of 6-fluoro-9-(4-fluorobenzyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.5245 g, 0.0017 mol) in THF (4 mL) and DMF (4 mL) and the mixture is heated to 75° C. After stirring for 6.5 h, the mixture is stored in the freezer overnight. Heating is resumed for an additional 2.5 h, at which time THF is removed under reduced pressure and the residue is partitioned between dichloromethane and brine. The combined organic layers are washed with dilute sodium thiosulfate/brine and the aqueous layer is backwashed with dichloromethane. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue is heated to 120° C. in DMF (8 mL) with lithium bromide (0.3412 g, 0.0039 mol) and lithium carbonate (0.2548 g, 0.0035 mol). After 2 h, DMF is removed under high vacuum and the mixture is partitioned between dichloromethane and water. The combined organic layers are washed with water, dried over sodium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (100 mL) using dichloromethane/hexane (30/70 to 50/50) to give 0.2706 g (52%) of the title compound; MS (ESI−) for C19H13F2NO m/z 308.0 (M−H)−; IR (drift) 1511, 1483, 1465, 1450, 1336, 1222, 1215, 1172, 1157, 1138, 883, 858, 791, 777, 744 cm−1; 1H NMR (CDCl3) δ5.35, 5.44, 6.57, 6.95, 7.06-7.30, 8.01. Anal. Calcd for C19H13F2NO: C, 73.78; H, 4.24; N, 4.53. Found: C, 72.65; H, 4.20; N, 4.45.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[NH:5])#[N:2].[OH:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.Cl>C(#N)C.O>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][NH:6][C:4]([NH:3][C:1]1[O:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:2]=1)=[NH:5]
Reactant: O=C(CO)c1ccccc1
Reactant: COc1ccccc1CNC(=N)NC#N
Agent: Cl
Solvent: CC#N
Solvent: O
Product: COc1ccccc1CNC(=N)Nc1nc(-c2ccccc2)co1
Temperature: 45 °C
Yield: 10.6 %

Procedure:
The cyclization of 0.60 g (2.94 mmol) N-cyano-N′-(2-methoxybenzyl)guanidine with 0.44 g (2.94 mmol) 2-hydroxyacetophenone was performed in 20 ml acetonitrile and water (1:1). The pH value of the mixture was adjusted with 1 N hydrochloric acid to pH 1.5 and the mixture was then heated in the microwave at 45° C. (100 Watt) for 4.5 hours. After workup and purification, analogously to 190.2, 0.10 g of pure product was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].Cl>[OH-].[Na+]>[CH2:14]([O:13][C:11]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of L-leucine (0.400 g, 3.049*10−3 mol) in 2M NaOH aq. (3.75 ml) cooled to 0° C., benzyl chloroformate (3.5374*10−3 mol, 0.52 ml) was added dropwise over 15 min. The mixture was stirred at RT for another 2 h, and then acidified with HCl conc. The aqueous layer was extracted with AcOEt (3×10 ml) and the combined organic layers were dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give crude N-benzoxycarbonyl-L-leucine. (colourless oil) (76%).
Reaction SMILES: [OH:1][C:2]1[C:3]([S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:15]1[CH:20]=[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])[C:18]([F:34])=[CH:17][C:16]=1[N+:35]([O-:37])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:34][C:18]1[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]([O:1][C:2]2[C:3]([S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:16]([N+:35]([O-:37])=[O:36])[CH:17]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COC(=O)CSc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a mixture of 0.26 g of 3-hydroxy-2-(methoxycarbonyl)methylthiopyridine, 0.38 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene, and 2 ml of N,N-dimethylformamide was added 0.17 g of potassium carbonate, and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and then poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.49 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methylthiopyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]([C:20]1[C:21](=[O:31])[N:22]([CH3:30])[C:23](=[O:29])[N:24]([CH3:28])[C:25]=1[CH2:26]Br)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[N:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:20]2[C:25]([N:24]([CH3:28])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2=[O:31])=[CH:26]1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(-c3cc([N+](=O)[O-])ccc3N)cc2n(C)c1=O
Yield: 44.3 %

Procedure:
In a 25 mL round bottom flask 4-nitro 1,2-phenylenediamine (300 mg, 1.96 mmol), and 4a (330 mg, 979 mmol) (see Example 2 for synthesis of 4a) were combined in ethanol (10 mL). The stirred mixture was brought to reflux for 3 h during which a yellow precipitate formed. The mixture was then chilled in an ice bath, filtered, and the precipitate washed with cold ethanol to give 5b (340 mg, 88.7%) as a waxy shiny yellow solid; mp>300° C. 1H NMR (600 MHz, DMSO-d6) δ 7.97 (dd, J=2.7, 9.2, 1H), 7.86 (d, J=2.6, 1H), 7.37-7.32 (m, 2H), 7.28-7.24 (m, 4H), 7.05 (s, 1H), 6.75 (d, J=9.2, 1H), 6.65 (s, 2H), 3.35 (s, 3H), 3.21 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 159.06, 151.66, 150.89, 135.01, 133.84, 130.38, 129.34, 129.02; 128.32, 127.38, 126.19, 126.05, 121.34, 114.31, 105.49, 102.98, 31.59, 27.46. MS (ES+) (m/z): [M+1]+ calculated for C20H18N5O4, 392.135880. found 392.03.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)C#N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].CN(C=[O:31])C>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[C:17]([CH:18]([CH3:20])[CH3:19])=[C:16]([O:21][CH3:22])[N:15]=[C:14]([O:23][CH3:24])[N:13]=2)=[O:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C)cc(Br)c2)n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(Br)c2)n1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a stirred solution of (3-bromo-5-methyl-phenyl)-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-acetonitrile (40 g, 0.1M) in anhydrous DMF (300 ml) in a water bath under an atmosphere of nitrogen, was portionwise added 60% sodium hydride (4.92 g, 0.12M). After 30 min., oxygen gas was bubbled into the reaction mixture for 2 hr. The mixture was neutralized with aqueous saturated ammonium chloride solution. The crude product was extracted with ether and purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 34.6 g (89%) of a white solid. m.p. 122-123° C.; 1H NMR (200 MHz, CDCl3) δ 1.17 (6H, d, J=7.1 Hz), 2.36 (3H, s), 2.77 (1H, m), 3.92 (3H, s), 4.05 (3H, s), 7.54-7.56 (2H, m), 7.75 (1H, m).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[C:10]2/[C:11](=O)[CH2:12][CH2:13][C:14]3[C:19]/2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.[NH2:24][NH2:25]>C(O)(=O)C.C(O)C>[CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([C:9]2[NH:24][N:25]=[C:11]3[C:10]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(/C=C2/C(=O)CCc3ccccc32)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2[nH]nc3c2-c2ccccc2CC3)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one (50 mg, 0.16 mmol), hydrazine hydrate (0.0155 ml, 0.32 mmol) were added into ethanol (5.0 ml) and 1-2 drops of acetic acid was added properly. Then, the solution was stirred and refluxed for 48 hours and cooled to room temperature. Afterward, the resulting solution was concentrated under reduced pressure, diluted by adding dichloromethane (10 ml), and then washed with water and the saturated brine. The residue was purified through silica gel column chromatography (eluent: ethylacetate/n-hexane=1/1, v/v). As a result, 35 mg of the present compound (productive yield 68%) was obtained as a brown solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>Cl[Pd](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.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[N:22][CH:23]=[C:18]([S:17][CH3:16])[CH:19]=2)[C:11]=1[CH3:12]
Reactant: CSc1cncc(B(O)O)c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (600 mg, 2.419 mmol), 5-(methylthio)pyridin-3-ylboronic acid (429 mg, 2.54 mmol), PdCl2(PPh3)2 (170 mg, 0.242 mmol), sodium carbonate (769 mg, 7.26 mmol), 1,4-dioxane (6.5 mL), and water (1.6 mL) at 95° C. for 2 h. Purification by column chromatography (silica gel, 0-30% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-3-methyl-2-(5-(methylthio)pyridin-3-yl)quinoline. Mass Spectrum (ESI) m/e=337.0 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:14]=[C:15]([S:17][CH3:18])[N:16]=[C:4]2[N:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:18][S:17][C:15]1[N:16]=[C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH2:20][OH:19])=[CH:22][CH:23]=3)[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][N:5]2[N:14]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CSc1nc2nc(Cl)c(-c3ccccc3)cn2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CSc1nc2nc(-c3ccc(CO)cc3)c(-c3ccccc3)cn2n1
Temperature: 100 °C

Procedure:
A mixture of 5-chloro-2-methylsulfanyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine (310 mg, 1.12 mmol), [4-(hydroxymethyl)phenyl]boronic acid (187 mg, 1.23 mmol), 2.32 mL Na2CO3 solution (10%), 56 mg 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) and 3.6 mL DME was heated at 100° C. for 50 min under microwave irradiation. In parallel, a second reaction was performed with a 100 mg portion of 5-chloro-2-methylsulfanyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine. On cooling, both mixtures were combined, diluted with water and extracted with CH2Cl2. The combined organic extract was washed with brine, dried and concentrated in vacuo to give the crude title compound which was used without further purification in the next step.