Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:20][CH:21]1[C:38](=[O:39])[N:23]2[C:24]([C:31]([O:33]C(C)(C)C)=[O:32])=[C:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][S:27][C@H:22]12)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>[N+](C)([O-])=O>[NH2:20][C@H:21]1[C:38](=[O:39])[N:23]2[C:24]([C:31]([OH:33])=[O:32])=[C:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][S:27][C@H:22]12
Reactant: CC(C)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: CC(C)C1=C(C(=O)O)N2C(=O)[C@H](N)[C@H]2SC1
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
A mixture of 541 mg of tert.butyl 7-tritylamino-3-isopropyl-3-cepheme-4-carboxylate in 11 ml of nitromethane was cooled on an ice bath and a current of gaseous hydrochloric acid was passed therethrough for 15 minutes. The mixture was evaporated to dryness and the residue was taken up in ether. The ether solution was vacuum filtered and the residue was washed with ether and dried. The residue was taken up in 1 ml of water and the pH was adjusted to 4 by addition of pyridine. The mixture was vacuum filtered and the crystals were washed with water, with acetone and then with ether and dried to obtain 204 mg of dl cis 7-amino-3-isopropyl-3-cepheme-4-carboxylic acid in the form of colorless crystals melting towards 230°C with decomposition.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][N:29]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[CH:31]=[N:30]1>>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][N:29]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:2]3[C:3]4[C:10]5[CH2:11][CH2:12][NH:13][CH2:14][C:9]=5[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:35][CH:36]=2)[CH:31]=[N:30]1
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5sc6c(c45)CCNC6)ccc32)nc1

Procedure:
The title compound was synthesized in analogy to Example 12A from tert-butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (4.84 g, 14.5 mmol) and 1-(pyridin-2-ylmethyl)-1H-indazol-5-amine from Example 61A (3.50 g, 15.6 mmol) to yield 4.39 g (71%).
Reaction SMILES: C(O[NH:6][N:7]([C:12]1([CH2:22][CH:23]=[CH2:24])[CH2:21][C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1)C(NN)=O)(C)(C)C.Cl>CCOC(C)=O.O1CCOCC1>[CH2:22]([C:12]1([NH:7][NH2:6])[CH2:21][C:16]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1)[CH:23]=[CH2:24]
Reactant: C=CCC1(N(NOC(C)(C)C)C(=O)NN)CCOC2(CCCC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=CCC1(NN)CCOC2(CCCC2)C1
Temperature: 25 °C
Yield: 112.1 %

Procedure:
A solution of (tert-butoxy)-N′-[9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]carbohydrazide (0.33 g, 1.06 mmol) in 4 mL of EtOAc was added 4M HCl in dioxane at rt. The solution was stirred at rt until reaction completion, monitored by LC-MS (30 h). The solvent was then removed to give [9-(prop-2-en-1-yl)-6-oxaspiro[4.5]decan-9-yl]hydrazine (250 mg). LCMS m/z 211.1 (M+1) observed.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:41])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:9][C:8]1=[O:42])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)(Cl)Cl>[OH:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18](=[O:41])[C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:40])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)=[CH:23][CH:24]=2)[CH2:10][CH2:9][C:8]1=[O:42]
Reactant: CC(=O)OCCN1C(=O)CCN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccc(C)cc3)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CCO)c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
A mixture of 1-(2-acetoxyethyl)-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (450 mg) and potassium carbonate (117 mg) in methanol (15 ml) was stirred at ambient temperature for 3 hours. The mixture was diluted with chloroform and the solution was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 1-(2-hydroxyethyl)-5-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1,3,4,5-tetrahydro -1,5-benzodiazepin-2(2H)-one (430 mg).
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:31]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-2,4-difluoro-benzenesulfonamide (68 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (85 mg, 65%). MS (ISN) 517.0 [(M−H)−]; mp 255-257° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:22][C:23]([F:28])([F:27])[C@@H:24]1[CH2:26][O:25]1>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:9]2[CH2:10][N:11]([CH2:26][C@H:24]([OH:25])[C:23]([F:28])([F:27])[F:22])[CH2:12][CH2:13][O:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1cccc([C@@H]2CNCCO2)c1
Reactant: FC(F)(F)[C@@H]1CO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O[C@@H](CN1CCO[C@H](c2cccc(Cl)c2)C1)C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a solution of (R)-2-(3-chloro-phenyl)-morpholine hydrochloride (45 mg, 192 μmol) and triethylamine (134 μL, 961 μmole) in 4 mL of acetonitrile was added (S)-2-(trifluoromethyl)oxirane (43.1 mg, 384 μmol). The mixture was stirred at 50° C. for 3 h, followed by evaporation in vacuo to afford (S)-3-((R)-2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (59.5 mg), which was used directly for next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C@H:5]([C:7]([N:9]2[CH2:13][C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=3)[C@@:11]([C@H:24]([OH:26])[CH3:25])([CH3:23])[CH2:10]2)=[O:8])[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:39]1[CH2:42][N:41]([CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)(=O)=O.C(OCC)(=O)C>C(#N)C>[CH3:27][C:2]1([CH3:1])[O:6][C@H:5]([C:7]([N:9]2[CH2:13][C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:39]4[CH2:42][N:41]([CH:43]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)[CH2:40]4)[CH:15]=3)[C@@:11]([C@H:24]([OH:26])[CH3:25])([CH3:23])[CH2:10]2)=[O:8])[CH2:4][O:3]1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COc1ccc([C@@H]2CN(C(=O)[C@@H]3COC(C)(C)O3)C[C@@]2(C)[C@@H](C)O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc([C@@H]2CN(C(=O)[C@@H]3COC(C)(C)O3)C[C@@]2(C)[C@@H](C)O)cc1OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Yield: 18.9 %

Procedure:
To a suspension of (1R)-1-[(3S,4S)-1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]carbonyl}-4-(4-methoxy-3-hydroxyphenyl)-3-methylpyrrolidin-3-yl]ethanol (2.0 g) and potassium carbonate (1.46 g) in acetonitrile (30 mL) is added 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (2.51 g). The mixture is heated at 80° C. overnight. Cool the reaction mixture and pour into ethyl acetate (100 mL), wash with water (40 mL) and brine (40 mL), dry over sodium sulfate, filter and evaporate the filtrate to dryness. Purify the resulting residue (silica gel, 60% ethyl acetate/hexanes to ethyl acetate) to provide 0.6 g of the title compound. MS (ES+)=601 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:6][C:7]=1[CH2:8][S:9][C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([CH3:23])[CH:11]=1.[CH3:34][C:35]1[O:39][N:38]=[C:37]([C:40]2[CH:41]=[C:42](O)[CH:43]=[CH:44][CH:45]=2)[N:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH3:23][C:12]1[CH:11]=[C:10]([S:9][CH2:8][C:7]2[S:6][C:5]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=3)=[N:4][C:3]=2[CH2:2][O:1][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:37]3[N:36]=[C:35]([CH3:34])[O:39][N:38]=3)[CH:41]=2)[CH:22]=[CH:21][C:13]=1[O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Cc1nc(-c2cccc(O)c2)no1
Reactant: CCOC(=O)COc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)cc1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COc2cccc(-c3noc(C)n3)c2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a stirred solution of ethyl [4-({[4-(hydroxymethyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetate (40mg, 0.08mmoles, 1eq) in dry toluene (2ml) was added 3-(5-methyl-1,2,4-oxadiazol-3-yl)phenol (15mg, 0.088mmoles, 1.1eq) followed by triphenylphosphine (25mg, 0.096mmoles, 1.2eq) as a solid. Diisopropylazodicarboxylate (0.017ml, 0.088mmoles, 1.1eq) was then added dropwise and the reaction was stirred for 2hours at room temperature. The reaction was then partitioned between EtOAc and H2O. After the separation of the phases the organic phase washed with 0.1N NaOH, brine, dried over Na2SO4, filtered, concentrated in vacuo and purified via flash chromatography (10% EtOAc/Hexanes to 35% EtOAc/Hexanes) to yield 40mg (76%) of product.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)[CH:8]=[N:7][C:6]=2[N:5]([CH3:20])[C:3]1=[O:4].C(OC(=O)C)(=[O:23])C.C([O-])(=O)C.[K+]>C(O)(=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:23])[CH:8]=[N:7][C:6]=2[N:5]([CH3:20])[C:3]1=[O:4]
Reactant: Cn1c(=O)c2c(ncn2CCCCCCBr)n(C)c1=O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cn1c(=O)c2c(ncn2CCCCCCO)n(C)c1=O
Yield: 90 %

Procedure:
3.4 g of 1,3-dimethyl-7-(6-bromohexyl)-xanthine are boiled overnight under reflux in 50 ml of glacial acetic acid to which 1 ml of acetic anhydride and 5 g of potassium acetate have been added. After evaporated of the solvent by distillation in vacuo the residue is dissolved in 50 ml of 5% sulfuric acid on the addition of 20 ml methanol. The solution is boiled under reflux for 1 hour. The mixture is extracted with chloroform. The chloroform phase is washed until it is neutral and concentrated in vacuo. 1,3-dimethyl-7-(6-hydroxyhexyl)-xanthine having a melting point of 80° C. is obtained in a yield of more than 90%.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][O:16][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CO)cn2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Oc2ccc([N+](=O)[O-])cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
[6-(4-nitrophenoxy)pyridin-3-yl]methanol (6.1 g, 24.8 mmol) was dissolved in dichloromethane (150 mL), and to the resulting solution was added triethylamine (4.15 mL, 29.8 mmol) under ice cooling. To the resulting solution was added dropwise methanesulfonic acid chloride (2.11 mL, 27.3 mmol), and then stirred under a nitrogen atmosphere for 30 minutes at 0° C. The reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. To the residue was added a mixed solvent (50 mL) of n-hexane ethyl acetate=1:1. The precipitated crystals were removed by suction filtration, to thereby yield 7.9 g of the title compound.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]([CH2:15][CH:16]1[CH2:18][O:17]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].S(=O)(=O)(O)[OH:20].[Cl-].[Na+]>O1CCCC1>[OH:17][CH2:18][C@H:16]1[O:20][C@@H:2]([CH2:3][OH:1])[CH2:4][N:5]([S:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:15]1
Reactant: O=S(=O)(O)O
Reactant: O=S(=O)(c1ccccc1)N(CC1CO1)CC1CO1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1C[C@@H](CO)O[C@@H](CO)C1
Reaction time: 72 h
Yield: 25 %

Procedure:
Tetrahydrofuran (60 mL) was added to chirally-enriched N,N-bis(2-oxiranylmethyl)benzenesulfonamide (from step (i) above; 14.8 g, 55 mmol), followed by dilute sulfuric acid (15 mL of 1 M), and the mixture stirred for 3 days. Solid sodium chloride (11 g) was added and the mixture stirred for 1 hour. The organic phase was separated and concentrated under reduced pressure to give crude product (22.4 g). The material was purified by column chromatography over silica, eluting with dichloromethane:ethanol (19:1), to give the title compound (4 g, 25%) and an impure fraction that was a 2:1 mixture of cis- and trans- isomers (8 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1.[P:38]([O:45]CC)([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41]>CCOCC.ClCCCl>[CH2:40]([O:39][P:38]([CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)([O:42][CH2:43][CH3:44])=[O:45])[CH3:41]
Reactant: COC(=O)c1ccc(C)cc1
Reactant: CCOP(OCC)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: ClCCCl
Product: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of methyl 4-methylbenzoate (2.01 g, 13.3 mmol) and 1,2-dichloroethane (100 mL) was added benzoyl peroxide (catalytic amount) and NBS (2.84 g, 16.0 mmol). The resulting mixture was heated to reflux while being stirred under nitrogen. After three hours, another catalytic amount of benzoyl peroxide was added and the mixture was refluxed for an additional three hours. The reaction mixture was allowed to cool to RT, followed by the addition of Et2O (20 mL) and filtration of a solid which precipitated out of solution. The filtrate was washed with water (2×) and brine (2×), dried over MgSO4, filtered and the solvent was removed under reduced pressure to give a light yellow clear oil. Triethyl phosphite (2.28 mL, 13.3 mmol) was added to the oil and the reaction was stirred under nitrogen at 160° C. for three hours. Excess triethyl phosphite was distilled off and the product was purified by column chromatography (EtOAc) to give a transparent light yellow oil (2.28 g, 7.97 mmol, 60%). Characterization data matches literature. E. N. Durantini, Synthetic Communications, 29:4201-4222 (1999).
Reaction SMILES: [CH2:1]([C:7]1[S:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[CH:13]=2)=[N:10][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(O)CCC>[CH2:1]([C:7]1[S:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:18]=3)[CH:13]=2)=[N:10][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCI
Reactant: CCCCCCc1nnc(-c2ccc3cc(O)ccc3c2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCOc1ccc2cc(-c3nnc(CCCCCC)s3)ccc2c1
Yield: 35.5 %

Procedure:
In a 50 ml-round-bottomed flask, 0.60 g (1.92 mM) of 2-hexyl-5-(6-hydroxynaphthalene-2-yl)-1,3,4-thiadiazole prepared in Step ii) of Example 24, 0.18 g (2.73 mM) of potassium hydroxide and 15 ml of butanol were placed and dissolved under heating. To the mixture, 0.53 g (2.50 mM) of hexyl iodide was added at about 100° C. under stirring, followed by refluxing for 6 hours under stirring. After the reaction, butanol was distilled off under reduced pressure, and water and ethyl acetate were added to the residue, followed by stirring. The resultant organic layer was washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent to obtain a solid. The solid was purified by silica gel column chromatography (eluent: benzene) and recrystallized from a mixture solvent (ethyl acetate-ethanol) to obtain 0.27 g of 2-hexyl-5-(6-hexyloxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 35.5 %). ##STR141##
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:24])[CH2:16][N:17]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:24])[CH2:16][N:17]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]3)[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1)=[O:30]
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ncc(Cl)cc3N)CC2)n1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ncc(Cl)cc3NC(=O)c3cccc(Cl)c3)CC2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-[4-(3-amino-5-chloro-pyridin-2-yl)-piperazin-1-yl]-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone (0.040 g, 0.11 mmol) in methylene chloride (2 mL) is added 3-chlorobenzoyl chloride (0.020 mL, 0.160 mmol) followed by of N,N-diisopropylethylamine (0.045 mL, 0.25 mmol). The mixture is stirred at room temperature for 3 days. The mixture is concentrated under a stream of nitrogen and the residue is purified by preparative reverse phase HPLC to provide, after removal of the eluent under reduced pressure, 0.030 g of 3-chloro-N-(5-chloro-2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-pyridin-3-yl)-benzamide as a white solid in 53% yield. MS; MH+=487.7
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:16][CH2:15][CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: NCCO
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: CCO
Product: OCCNCc1ccc(C(F)(F)F)cc1
Yield: 96 %

Procedure:
Following the method of Preparation 8, step a, 4-trifluoromethylbenzyl bromide (664 mg, 2.78 mmol) was heated with ethanolamine (1.02 g, 16.7 mmol) in ethanol (3 mL) at 75° C. overnight. The product was isolated to give the title intermediate as a yellowish oil (585 mg). (m/z): [M+H]+ calcd for C10H12F3NO 220.10; found 220.3. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.59 (d, J=7.8 Hz, 2H), 7.45 (d, J=7.8 Hz, 2H), 3.88 (s, 2H), 3.66-3.70 (m, 2H), 2.80-2.83 (m, 2H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.[CH2:26]=O>C(O)=O>[CH3:26][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CN1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (25 g, 61 mmol) in 140 mL of formic acid (96%) was added 50 g of formaldehyde (37%). The solution was stirred at 75° C. for 48 h and was cooled to room temperature. The excess formic acid was removed under reduced pressure and the residue was dissolved in 100 mL of water. The solution was added to concentrated NH4OH/H2O and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (1×250 mL) and was dried over Na2SO4. The solution was filtered and concentrated to leave a white solid. The solid was triturated with ether and was filtered to afford the title compound: MS (M+H): 353 (base peak).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.[C:28](O)(=[O:48])/[CH:29]=[CH:30]\[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=[CH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl.O>[C:28]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][C:12](=[O:13])[CH2:14][C:15](=[O:16])[CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([OH:23])=[C:24]([O:25][CH3:26])[CH:27]=2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:48])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=[CH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Reactant: CCCCCCCCCC=CC=CC=CC=C/C=C\C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)Oc1ccc(C=CC(=O)CC(=O)C=Cc2ccc(O)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
To a solution of curcumin (300 mg, 0.81 mmol), cis-eicosapentaenoic acid (250 mg, 0.83 mmol) and catalytic amount of 4-(dimethylamino)pyridine in dichloromethane (10 mL) was added a solution of N,N′-dicyclohexylcarbodiimide (252 mg, 1.2 mmol) in dichloromethane (5 mL) for 5 min at ice cold temperature. The mixture was stirred at rt for 16 h and diluted with water. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (3×100 mL). The combined dichloromethane layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10) mixture as an eluent to give the product as an oil (235 mg, 44%). IR (neat) νmax 3013, 2961, 2929, 1762, 1630, 1593, 1268, 1123, 1032, 970 cm−1; 1H NMR (CDCl3) δ 7.61 (1H, d, J=16.0 Hz, H-1), 7.60 (1H, d, J=15.6 Hz, H-7), 7.03-7.16 (5H, m, H-2′, 2″, 5′, 6′, 6″), 6.93 (1H, d, J=8.4 Hz, H-5″), 6.55 (1H, d, J=16 Hz, H-2), 6.49 (1H, d, J=16 Hz, H-6), 5.89 (1H, br s, Ar—OH), 5.83 (1H, s, H-4), 5.38-5.39 (10H, m, H-5′″, 6′″, 8′″, 9′″, 11′″, 12′″, 14′″, 15′″, 17′″, 18′″), 3.95 (3H, s, Ar—OCH3), 3.87 (3H, s, Ar—OCH3), 2.84-2.86 (8H, m, H-7′″, 10′″, 13′″, 16′″), 2.58-2.66 (2H, m, H-2′″), 2.22-2.23 (2H, m, H-19′″), 2.05-2.09 (2H, m, H-4′″), 1.82-187 (2H, m, H-3′″), 0.97 (3H, t, J=7.4 Hz, H-20′″); LCMS (ESI, negative ion mode): m/z 651 (M-H)−.