Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]([NH2:19])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.O>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]#[N:19])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(C(N)=O)c1-c1ccc(F)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1ncc(C#N)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 92.7 %

Procedure:
To a solution of 1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (500 mg, 1.91 mmol) in DMF (4 mL) was added cyanuric chloride (0.267 mL, 1.91 mmol) at 0° C., and the mixture was stirred at 0° C. for 14 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane) to give 1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (430 mg, 1.77 mmol, 92%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:14](=[O:17])([OH:16])[O-].[Na+:18].[N:19]1[C:26](Cl)=[N:25][C:23](Cl)=[N:22][C:20]=1[Cl:21]>O.[OH-].[Na+].CC(C)=O>[Na+:18].[Na+:18].[Na+:18].[Na+:18].[Cl:21][C:20]1[N:19]=[C:26]([NH:1][C:2]2[CH:3]=[C:4]([C:11]([O-:13])=[O:12])[CH:5]=[C:6]([CH:10]=2)[C:7]([O-:9])=[O:8])[N:25]=[C:23]([NH:1][C:2]2[CH:10]=[C:6]([C:7]([O-:9])=[O:8])[CH:5]=[C:4]([CH:3]=2)[C:14]([O-:16])=[O:17])[N:22]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C([O-])c1cc(Nc2nc(Cl)nc(Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)n2)cc(C(=O)[O-])c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
To a stirred solution of 18.1 g of 5 -aminoisophthalic acid in 200 ml of water plus 38.2 ml of 5 N sodium hydroxide is added 9.2 g of sodium bicarbonate. The solution is cooled to 10° C. in an ice bath, then a solution of 9.2 g of cyanuric chloride in 50 ml of acetone is added. The mixture is stirred at room temperature for 10 minutes, then at 40°-45° C. for 31/2 hours. The solution is allowed to stand at room temperature for 16 hours and is filtered. The filtrate is concentrated to 150 ml and diluted with 300 ml of absolute ethanol to give a colorless precipitate. The product is collected by filtration, washed with 75% aqueous ethanol, ethanol and ether and dried by conventional means to give 25.9 g of crude product. An 8.9 g portion of this material is dissolved in 50 ml of water, allowed to stand at room temperature for 2 hours, then filtered through diatomaceous earth. The filter is washed with 10 ml of water. The filtrate is diluted with 100 ml of absolute ethanol to give a thick precipitate. The mixture is filtered and the product is washed with (1:2) aqueous ethanol, ethanol and ether. The material is dried by conventional means to yield 7.64 g of a colorless powder as the product of the example.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([N:3]1[C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:11][C:9]1[CH:10]=[CH:4][CH:5]=[CH:7][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2nc(SCc3ccccc3)n(Cc3ccccc3)c2c1
Yield: 166.9 %

Procedure:
To a flask were added 2.0 g 2-mercapto-5-methylbenzimidazole, 4.2 g potassium carbonate, 30 ml N,N-dimethylformamide and 3.9 g benzyl chloride. The reaction mixture was heated to 60 C for 16 hours, then cooled to 50 C and quenched with 60 ml water and cooled to 5 C. The solid was filtered and washed with water and then recrystallized by dissolving in 50 ml hot acetonitrile and adding 10 ml of water. After cooling to 5 C, the product was filtered, washed and dried resulting in 3.5 g white solid as a mixture of the 5-methyl and 6-methyl isomers.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([CH3:21])=[C:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1>C1COCC1>[CH:16]1([C:15]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([CH3:21])[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: CC(C)=C1C=CC=C1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: C1CCOC1
Product: CC(C)(c1cccc2c1Cc1ccccc1-2)C1C=CC=C1
Temperature: 25 °C
Yield: 68.6 %

Procedure:
To 200 ml of THF and 16.5 g of fluorene cooled to a temperature of -50° C. or lower in a 500-ml flask thoroughly purged with nitrogen was added 67 ml of a dil. methyllithium diethyl ether solution (1.4 M) dropwise over 30 minutes. The mixture was warmed gradually to room temperature and subjected to reaction for 3 hours. The reaction mixture was cooled back to a temperature of -50° C. or lower and 10 g of 6,6-dimethylfulvene was added dropwise over 30 minutes. After the addition was completed, the solution was warmed slowly to room temperature and subjected to reaction for 2 days. The reaction was terminated by the addition of 60 ml of H2O, and the ether layer was separated and dehydrated over anhydrous MgSO4. Drying ether by evaporation, gave 17.6 g of 2-cyclopentadienyl-2-fluorenylpropane as crude crystals.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24](O)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:29][C:30](=[O:40])[CH2:31][NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:40])[CH2:31][N:32]([C:24](=[O:25])[C@H:19]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:28]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)CC

Procedure:
N-(9-Fluorenylmethoxycarbonyl)-L-isoleucine (1.36 g) and N-(benzyl)glycine ethyl ester (770 mg) were reacted in the same manner as in Preparation Example 52 to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[O:20])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(O)CC.CC(O)C.C(OCC)C>[Cl:29][C:27]1[CH:28]=[C:23]([CH:24]=[C:25]([Cl:30])[CH:26]=1)[CH2:22][O:21][C:19](=[O:20])[NH:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:17][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)OCc3cc(Cl)cc(Cl)c3)ccc2C1
Agent: Cl
Solvent: CCOCC
Solvent: CCCO
Solvent: CC(C)O
Product: O=C(Nc1ccc2c(c1)CCNC2)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
Starting material 46 (170 mg, 0.4 mmol) was dissolved in 5 ml propanol. Then 1 ml HCl in 2-propanol (5-6 N) was added and the mixture was stirred over night at ambient temperature. The reaction mixture was then diluted with diethyl ether, concentrated in vacuo and stirred with diethyl ether, repeatedly decanting. Finally the solid residue was filtered off and dried in vacuo at 45° C. Thus the desired product 47 was isolated as brownish crystals (46 mg, 0.1 mmol, 35%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.[CH:28]([C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH3:44])[C:35]3[C:40]([S:41][C:42]=2[CH:43]=1)=[CH:39][CH:38]=[CH:37][CH:36]=3)=O>CCCCCC.[Zn]>[Br:2][C:1]([Br:5])=[CH:28][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH3:44])[C:35]3[C:40]([S:41][C:42]=2[CH:43]=1)=[CH:39][CH:38]=[CH:37][CH:36]=3
Reactant: BrC(Br)(Br)Br
Reactant: CN1c2ccccc2Sc2cc(C=O)ccc21
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CN1c2ccccc2Sc2cc(C=C(Br)Br)ccc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.4 %

Procedure:
In an atmosphere of argon, carbon tetrabromide (8.29 g, 25 mmol) and zinc powder (1.63 g, 25 mmol) were added in that order to a mixture of triphenylphosphine (6.56 g, 25 mmol) and dichloromethane (75 ml), and the mixture was stirred at room temperature for 23 hours. A dichloromethane (25 ml) solution of 3-formyl-10-methylphenothiazine (3.02 g, 12.5 mmol) was added and the mixture was again stirred for 7 hours. The reaction mixture was diluted with hexane and the insoluble matter was removed by filtration. The reaction product was extracted from the insoluble matter three times with hexane (about 60° C.), and the thus collected organic layers were combined and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:dichloromethane:hexane=10:10:80) to give the title compound (3.15 g, 7.93 mmol, 63%) as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=2[CH3:39])=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:33][C:32]=2[CH3:39])=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (53 mg, 41%).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[OH:21].O.[C:24](O)(C(F)(F)F)=[O:25]>>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([CH:24]=[O:25])[CH:17]=[C:16]([CH3:20])[C:15]=1[OH:21]
Reactant: COC(=O)c1cccc(C)c1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: COC(=O)c1cc(C=O)cc(C)c1O
Temperature: 78 °C
Yield: 86 %

Procedure:
To a solution of HMTA (1,3,5,7-Tetraaza-tricyclo[3.3.1.13,7]decane, 8.43 g, 60.2 mmol) in TFA (100 mL) is added 2-hydroxy-3-methyl-benzoic acid methyl ester (5 g, 30.1 mmol) and the reaction is refluxed (78° C.) overnight. The reaction is cooled to 50° C. and water (400 mL) is added with stirring. The mixture is stirred at 50° C. for 2 h then cooled to RT and extracted with EtOAc (2×200 mL). The combined organic layers are washed with brine (75 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 silica gel, gradient elution: 0-50% EtOAc in heptane) to give product (281) as off-white solid (5.05 g, 86%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:23][C@H:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:25][C:26](O)=[O:27])(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:26](=[O:27])[CH2:25][C@H:24]([O:23][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCC
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Solvent: ClCCCl
Solvent: CI
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1)OC(=O)CCCCCC
Yield: 90.9 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-heptanoyloxytetradecanoic acid (780 mg, 2.2 mmol) in the presence of EDC MeI (745 mg, 2.5 mmol) in CH2Cl2 to afford 0.97 g (91%) of N-[(R)-3-heptanoyloxytetradecanoyl]-L-serine benzyl ester: mp 46-48° C.; 1H NMR (CDCl3) δ 0.88 (t, 6 H, J=6.9 Hz), 1.1-1.7 (m, 28 H), 2.30 (t, 2 H, J=7.7 Hz), 2.50 (d, 2 H, J=5.8 Hz), 2.62 (t, 1 H, J=6.0 Hz), 3.97 (m, 2 H), 4.65 (m, 1 H), 5.19 (m, 3 H), 6.61 (d, 1 H, J=6.9 Hz), 7.35 (br s, 5 H).
Reaction SMILES: ClC1C=CC(C2(O)CCN(CCC=C3C4C(=NC=CC=4)OC4C=CC=C(OCC(OCC)=O)C=4C3)CC2)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2([OH:83])[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH:55]=[C:56]3[C:66]4[C:61](=[N:62][CH:63]=[CH:64][CH:65]=4)[O:60][C:59]4[CH:67]=[CH:68][CH:69]=[C:70]([O:71][C:72]5[CH:77]=[CH:76][C:75]([C:78]([O:80]CC)=[O:79])=[CH:74][CH:73]=5)[C:58]=4[CH2:57]3)[CH2:49][CH2:48]2)=[CH:43][CH:42]=1>>[C:78]([C:75]1[CH:74]=[CH:73][C:72]([O:71][C:70]2[C:58]3[CH2:57][C:56](=[CH:55][CH2:54][CH2:53][N:50]4[CH2:51][CH2:52][C:47]([C:44]5[CH:43]=[CH:42][C:41]([Cl:40])=[CH:46][CH:45]=5)([OH:83])[CH2:48][CH2:49]4)[C:66]4[C:61]([O:60][C:59]=3[CH:67]=[CH:68][CH:69]=2)=[N:62][CH:63]=[CH:64][CH:65]=4)=[CH:77][CH:76]=1)([OH:80])=[O:79]
Reactant: CCOC(=O)c1ccc(Oc2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2cccnc2O3)cc1
Agent: CCOC(=O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: O=C(O)c1ccc(Oc2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2cccnc2O3)cc1

Procedure:
The titled compound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of step 1.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9](O)=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>ClCCl>[C:9]([Cl:16])(=[O:10])/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[CH:2][CH:1]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)/C=C/c1ccc(O)cc1

Procedure:
To a solution of coumaric acid (36.3 g) in dichloromethane (1.03 L) were added oxalyl chloride (45.2 mL) and N,N-dimethylformamide (0.6 mL). After foaming calmed down, the mixture was heated to reflux for 3 hours. The reaction mixture was concentrated to give the title compound. The obtained compound was used for the next reaction without being purified.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5](I)=[C:4]([CH3:10])[N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:32]>C1(C)C=CC=CC=1.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>[Cl:32][C:6]1[C:5]([C:12]#[C:11][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)=[C:4]([CH3:10])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1nc(C)c(I)c(=O)[nH]1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(C#Cc2ccc(C(F)(F)F)cc2)c(Cl)n1
Temperature: 25 °C

Procedure:
2,6-Dimethyl-5-iodo-4(3H)-pyrimidinone and 4-ethynyl-α,α,α-trifluorotoluene were reacted in toluene in the presence of dichlorobis(triphenylphosphine)palladium, cuprous iodide, and triethylamine while stirring under room temperature to heating to obtain a compound. The compound was mixed with POCl3 and reacted while heating under reflux to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:28][CH2:27][NH:26][CH2:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C(O)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]2[CH2:28][CH2:27][N:26]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:25]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C2CCNC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)C2)cc1
Temperature: 70 °C
Yield: 56.3 %

Procedure:
A solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (50 mg, 0.22 mmol) in ethanol (1 mL) was added to 3-(4-methoxyphenyl)pyrrolidine hydrochloride (71 mg, 0.33 mmol). The reaction mixture was treated with DIPEA (86 mg, 0.66 mmol) and the mixture was heated at 70° C. for 16 hours. The reaction mixture was evaporated to leave an involatile residue that was purified by preparative reverse phase chromatography to give 6-[3-(4-methoxyphenyl)pyrrolidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (45 mg, 55%).
Reaction SMILES: C1C(C(OO)=[O:8])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:29]([CH:36]=[CH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH2:38]([CH:37]=[CH:36][CH2:29][C:30]12[O:8][CH:31]1[CH:32]=[CH:33][CH:34]=[CH:35]2)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C(=CCc1ccccc1)Cc1ccccc1
Reactant: O=C(OO)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C1=CC2OC2(CC=CCc2ccccc2)C=C1
Reaction time: 72 h

Procedure:
To perbenzoic acid in chloroform prepared from 15 g of benzoylperoxide was added 6.0 g of o-benzylallylbenzene and the mixture was allowed to stand at 5° C for 3 days. The mixture was washed with 2% sodium hydroxide solution, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain the residue, which was chromatographed over a silica gel, and as eluted with benzene/n-hexane (1/1), there was obtained 1.5 g of o-benzylallylbenzene oxide as an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=S)[NH:11][NH2:12])=[C:4]([CH3:14])[CH:3]=1.Cl[CH:16]([C:22]([CH3:24])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:22]([CH3:24])[NH:12][N:11]=2)=[C:4]([CH3:14])[CH:3]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Cc1cc(Br)cc(C)c1NC(=S)NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2c(C)cc(Br)cc2C)n[nH]c1C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
A mixture of 14.6 g (0.06 mole) of 4-(4-bromo-2,6-dimethylphenyl)-3-thiosemicarbazide and 9.93 g (0.06 mole) of ethyl 2-chloroacetoacetate in 60 mL of absolute ethanol was stirred under nitrogen atmosphere for 2 hr, treated with 30 mL of 2N ethanolic hydrogen chloride and heated at reflux until the reaction mixture cleared (3 hr). The reaction mixture was filtered hot then concentrated in vacuo to give an orange solid which, when triturated with warm benzene/ligroin (50:50) and filtered gave 10.8 g of slightly orange crystalline product. The filtrate upon standing for ~16 hr gave an additional 4.4 g of yellow crystals which became white when washed with warm acetone. The 2 fractions were combined and recrystallized from benzene/ligroin to give 10.35 g of fine white crystalline rods, mp 171°-199° C. (with degassing). An NMR analysis showed the solid to be a salt with some solvent present; mass spectra confirmed the presence of hydrogen chloride. After drying at 82° C. under high vacuum, there was left 9.56 g, mp 168°-196° C. A broad melting point range suggested that it may be a mixture of free base and salt; therefore, it was dissolved in methanol/water along with other reaction mixture material, made basic with 3N sodium hydroxide and extracted with 5×60 mL of methylene chloride. The extracts were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo to give a dark yellow solid. Recrystallization from benzene/ligroin then from benzene gave 10.7 g of white granular power, mp 184°-185° C.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:9]O>C(#N)C>[C:1]1([O:7][CH3:8])[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:9].[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: OO
Solvent: CC#N
Product: COc1ccc(O)cc1
Product: COc1ccccc1O
Temperature: 65 °C
Reaction time: 8 h

Procedure:
In to a 150 ml round-bottomed double-necked flask containing anisole (0.05 mol, 5.4 g), 50% aq. hydrogen peroxide (0.25 mol, 17.0 g) in acetonitrile (50 ml) was added vanadyl tetraphenoxyphthalocyanine (2.5 mol %, 1.18 g). The reaction was continued with vigorous stirring at 65° C. for 8 h. The reaction mixture was then filtered through a Buckner funnel, passed through a short column of silica gel to remove the catalyst and concentrated under reduced pressure. The resulting residue was analyzed by high resolution GCMSD, EI, quadrapole mass analyzer, EM detector. The conversion of anisole was determined on the basis of the weight of the residue left after evaporation and yields of guaiacol and 4-methoxyphenol were determined by GC. Conversion of anisole was 18%. The yield of the mixture of guaiacol and 4-methoxyphenol was 17.5%.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].[CH:16]([CH2:27]S([O-])(=O)=O)=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C.O>CS(C)=O>[CH2:25]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:27]
Reactant: CCCCCCCCCC=CCS(=O)(=O)[O-]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 46.1 %

Procedure:
This example illustrates a synthesis of 1-(10,11-Oxidoundecanyl)-3,7-dimethylxanthine (inventive compound no. 1594). Sodium hydride (95%) (1.26 g, 50 mmol) was added to a solution of theobromine (7.2 g, 40 mmol) in dimethylsulfoxide (300 mL). After 20 minutes of stirring, undecenylmesylate (7.95 g, 30 mmol) was added and stirred for 12 hours at room temperature. The reaction was warmed to 70-80° C. and stirred for 4 hours. The reaction mixture was then poured into a separatory funnel containing 1 L of water and extracted with dichloromethane (5×200 mL). The organic extracts are combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel (eluant: 20% hexane/dichloromethane) to yield 4.6 g (46.3% yield) 1-(10-Undecenyl)-3,7-dimethylxanthine (inventive compound no. 2501).