Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C@H:14]1[C:23](O)=[O:24].[CH3:26][C@:27]12[C@@H:35]([CH3:36])[C@H:31]([NH:32][CH2:33][CH2:34]1)[CH2:30][C:29]1[C:37]([OH:41])=[CH:38][CH:39]=[CH:40][C:28]2=1>ClCCl>[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C@H:14]1[C:23]([N:32]1[CH2:33][CH2:34][C@:27]2([CH3:26])[C@@H:35]([CH3:36])[C@H:31]1[CH2:30][C:40]1[CH:39]=[CH:38][C:37]([OH:41])=[CH:29][C:28]=12)=[O:24]
Reactant: C[C@H]1[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2
Reactant: O=C(O)[C@@H]1COc2ccccc2O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@H]1[C@H]2Cc3ccc(O)cc3[C@]1(C)CCN2C(=O)[C@@H]1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Carbonyldiimidazole (0.47 g) is added to a solution of (S)-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (0.63 g) in dichloromethane (6 mL). The resulting solution is stirred at room temperature for 1 h before (2R,6R,11R)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-ol is added. The solution is further stirred at room temperature overnight. Then, dichloromethane (30 mL) is added and the resulting solution is washed with water. After drying (Na2SO4), the solvent is evaporated to give the product as a white foam-like solid.
Reaction SMILES: [C:1]([CH:6]=[C:7]1[CH:11]2[CH2:12][CH2:13][CH:8]1[CH2:9][CH2:10]2)([O:3]CC)=[O:2].C(O)C.[H][H].[OH-].[K+]>[Pd].O>[CH:8]12[CH:7]([CH2:6][C:1]([OH:3])=[O:2])[CH:11]([CH2:10][CH2:9]1)[CH2:12][CH2:13]2
Reactant: [H][H]
Reactant: CCOC(=O)C=C1C2CCC1CC2
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC1C2CCC1CC2

Procedure:
A mixture containing 0.05 mole of 7-carbethoxymethylene-bicyclo[2.2.1]heptane and 5 g. of 5% palladium on carbon catalyst and 250 ml. of ethanol is stirred under hydrogen until no more hydrogen is absorbed (about 1.2 liters are absorbed). The catalyst is removed by filtration and a solution containing 0.1 mole of potassium hydroxide in 20 ml. of water is added to the filtrate. The solution is then refluxed until no more starting material is observed by thin-layer chromatographic monitoring. The solvent is then removed by evaporation under vacuum and the resulting residue dissolved in 200 ml. of water and extracted three times with ethyl ether. The remaining aqueous phase is acidified with dilute aqueous hydrochloric acid and then extracted three times with ethyl acetate. The combined organic extracts are washed with water, then dried with anhydrous magnesium sulfate and filtered. The filtrate is evaporated to dryness, under vacuum, affording bicyclo[2.2.1]hept-7-yl acetic acid.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1.[O:20]1[CH2:25][CH:24]=[C:23]([C:26]2[C:27](F)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1.O>CN1C(=O)CCC1>[O:20]1[CH:21]=[CH:22][CH:23]([C:26]2[C:27]([O:19][C@H:16]3[CH2:15][CH2:14][C@H:13]([NH:12][C:4]4[S:3][C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[N:5]=4)[CH2:18][CH2:17]3)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:24][CH2:25]1
Reactant: O[C@H]1CC[C@H](Nc2nc3ccccc3s2)CC1
Reactant: Fc1ncccc1C1=CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C1=CC(c2cccnc2O[C@H]2CC[C@H](Nc3nc4ccccc4s3)CC2)CCO1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.054 g, 1.3 mmol, 60% dispersion in mineral oil) was added to a mixture of trans-4-(benzo[d]thiazol-2-ylamino)cyclohexanol (0.17 g, 0.67 mmol) in NMP (1.5 mL) in a microwave tube. The tube was sealed and placed under an argon atmosphere. The mixture was stirred at RT for 45 min before 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridine, as prepared in preparation 1a, step 1, (0.10 g, 0.56 mmol) was added via syringe. The reaction mixture was warmed to 120° C. and stirred for 1 h. Water was added, and the aqueous mixture was extracted with EtOAc (2×). The organic extracts were combined, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified via silica gel chromatography to give both N-(trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclohexyl)benzo[c/]thiazol-2-amine and N-(trans-4-(3-(3,4-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine as white solids. [M+1] 408.1 each. IC50 (uM): 0.007281 (Example 3b) and 0.9154 (Example 3c).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18](O)=[O:19].Cl.C(N=C=NCCCN(C)C)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]([F:16])([F:17])[F:15])=[CH:11][CH:12]=2)[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])[CH2:46][CH2:45]1)=[O:19]
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Reactant: COc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3ccc(OC(F)(F)F)cc3)noc2N)CC1
Yield: 70.7 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (603 mg, 1.30 mmol, 71%) was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C@@H:15]([NH:22]C(OC(C)(C)C)=O)[CH2:16][C:17]2[N:18]=[N:19][NH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:30])[C@@H:15]([NH2:22])[CH2:16][C:17]2[N:18]=[N:19][NH:20][CH:21]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](Cc2c[nH]nn2)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2c[nH]nn2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 739 mg 4-[(S)-2-tert-Butoxycarbonylamino-3-(1H-[1,2,3]triazol-4-yl)-propionyl]-piperazine-1-carboxylic acid butyl ester in 8 ml dichloromethane were added 1.3 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 1.32 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25](Br)=[C:24]([CH3:29])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[S:35]1[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:38]4([OH:41])[CH2:39][CH2:40][S:35][CH2:36][CH2:37]4)=[C:24]([CH3:29])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCSCC1
Reactant: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ccc1C1(O)CCSCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[4-(4-Bromo-3-methyl-phenoxymethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (409 mg, 0.8884 mmol) in dry THF (5 mL) cooled to −78° C. is added n-BuLi (1.6 M in hexanes, 1.1 eq., 0.9772 mmol, 0.61 mL). The resulting mixture is stirred at −78° C. for 30 minutes and a solution of tetrahydro-thiopyran-4-one (1.1 eq., 0.9772 mmol, 114 mg) in dry THF (0.5 mL) is then added dropwise. After 30 minutes, the reaction mixture is quenched with saturated aqueous NH4Cl and warmed to room temperature. The reaction mixture is diluted with EtOAc and washed sequentially with H2O and saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is partially purified by silica gel chromatography (3:1 hexanes/EtOAc) to give crude 4-{4-[4-(4-Hydroxy-tetrahydro-thiopyran-4-yl)-3-methyl-phenoxymethyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.[F:17][C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[C:20]([F:28])[C:19]=1B1OC(C)(C)C(C)(C)O1.C(N(C(C)C)CC)(C)C>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:17][C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[C:20]([F:28])[C:19]=1[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1
Reactant: Clc1ncc2cnn(C3CCCCO3)c2n1
Reactant: COc1cc(OC)c(F)c(B2OC(C)(C)C(C)(C)O2)c1F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc(OC)c(F)c(-c2ncc3cnn(C4CCCCO4)c3n2)c1F
Temperature: 125 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
A mixture of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (477 mg, 2.00 mmol), 2-(2,6-difluoro-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (600. mg, 2.00 mmol), bis(tri-t-butylphosphine)palladium (150.0 mg, 0.300 mmol) and diisopropylethylamine (0.700 mL, 4.02 mmol) in 1,4-dioxane (20 mL) was degassed and recharged with nitrogen for three times. The mixture was stirred at 125° C. overnight. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%) to afford the desired product (0.30 g, 40%). LCMS (M+H)+=377.2.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5]S(O)(=O)=O.[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>CCOCC>[Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][Cl:16]
Reactant: O=S(=O)(O)COc1ccccc1Br
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: CCOCC
Product: ClCOc1ccccc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.3 %

Procedure:
A mixture of 29.0 g of (o-bromophenoxy)methane sulfonic acid, sodium salt and 50.0 g of PCl5 are thoroughly blended in a mortar. After about 10 minutes of continuous mixing, the mixture partly melts, a vigorous reaction occurs, and the whole turns to a liquid. The mixture is kept 15 minutes with occasional stirring, 700 ml of ether is added (a white solid separates) and the mixture is poured into 750 g of crushed ice. The ether solution is separated, washed, dried, and concentrated in vacuo to give about 21.0 g of a liquid residue. This is distilled under reduced pressure to give about 19.5 g of the colorless liquid product, b2.0 74°-75°, nD24.5 1.5799.
Reaction SMILES: [OH:1][C:2]1([CH2:16][CH2:17][N:18]([CH3:32])[CH2:19][CH2:20][CH2:21][C:22]2[NH:23][C:24]3[C:30]([OH:31])=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35]>>[C:33]([O:31][C:30]1[C:24]2[NH:23][C:22]([CH2:21][CH2:20][CH2:19][N:18]([CH3:32])[CH2:17][CH2:16][C@:2]3([O:1][C:2](=[O:1])[CH:3]([CH3:9])[CH3:4])[CH2:7][C@H:6]4[CH2:8][CH2:9][C@@H:3]3[CH:4]=[C:5]4[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[N:26][C:25]=2[CH:27]=[CH:28][CH:29]=1)(=[O:37])[CH:34]([CH3:36])[CH3:35]
Reactant: CN(CCCc1nc2cccc(O)c2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Oc1cccc2nc(CCCN(C)CC[C@]3(OC(=O)C(C)C)C[C@H]4CC[C@@H]3C=C4c3ccccc3)[nH]c12

Procedure:
Prepared according to procedure P1.4 in Example 1A using rac-(1R*,2R*,4R*)-2-(3-{[2-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl]-methyl-amino}-propyl)-3H-benzoimidazol-4-ol and 5 eq. of isobutyryl chloride.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([C:31]3[CH:41]=[CH:40][C:34]4[O:35][C:36]([F:39])([F:38])[O:37][C:33]=4[CH:32]=3)[CH:23]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+]>>[C:44]([CH2:43][CH2:42][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([C:31]3[CH:41]=[CH:40][C:34]4[O:35][C:36]([F:39])([F:38])[O:37][C:33]=4[CH:32]=3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])([OH:46])=[O:45]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc4c(c3)OC(F)(F)O4)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OC(F)(F)O3)c1
Yield: 71.3 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-{6-[3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-5-ethoxy-phenoxy)-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (395 mg, 0.58 mmol) and 1.0 N aqueous sodium hydroxide (5.8 mL) to afford 4-(2-(2-carboxy-ethyl)-3-{6-[3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-5-ethoxy-phenoxy]-hexyl}-phenoxy)-butyric acid (260 mg, 72%) as a light yellow solid: ES(+)-HRMS m/e calcd for C34H38F2O9 (M+Na)+ 651.2376. found 651.2381.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]([F:32])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: CC1(C)OB(c2ccc(C(F)(F)c3ccccc3)cc2)OC1(C)C
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(C(F)(F)c2ccccc2)cc1

Procedure:
Pd(dppf)Cl2 (19.4 mg) was added to a mixture of 1-bromo-4-(difluoro(phenyl)methyl)benzene (376 mg), potassium acetate (391 mg) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (506 mg) in DME (10 mL) and DMSO (0.5 mL). The mixture was stirred at 80° C. under nitrogen overnight. Activated-carbon powder was added and the mixture was stirred for 5 min. The insoluble material was removed by filtration. The filtrate was concentrated in vacuo to give a brown oil of 2-(4-(difluoro(phenyl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Tetrakis(triphenylphosphine)palladium(0) (38.4 mg) was added to a suspension of 3-bromopyridin-2-amine (192 mg), the prepared 2-(4-(difluoro(phenyl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and sodium carbonate decahydrate (634 mg) in DME (10 mL) and water (2 mL) and the mixture was stirred at 80° C. under nitrogen for 3 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (291 mg) as a colorless oil.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[C:1]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-(4-fluorophenyl)piperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=O)=[CH:5]2.[CH2:14]([O:16][C:17]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:18])[CH3:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([CH:12]=[CH:19][C:17]([O:16][CH2:14][CH3:15])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cc2cc(Cl)c(Cl)cc2[nH]1
Yield: 60.1 %

Procedure:
5,6-Dichloro-1H-indole-2-carboxaldehyde (35 g, 164 mmol) and (ethoxycarbonylmethylene)triphenylphosphorane (60 g, 176 mmol) were dissolved in toluene and refluxed for three hours. The solvent was evaporated under reduced pressure and the reaction mixture was purified by chromatography on silicagel (n-hexane/AcOEt, 8/2) obtaining pure title compound (28 g, 98.5 mmol, yield 60.1%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[CH:12]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[C:25]([O:39][CH3:40])=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:30]([C:28]1[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([O:39][CH3:40])=[C:24]([NH:23][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:13]([N:11]3[CH:12]=[C:8]([C:5]4[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[N:10]3)[CH:14]=2)[CH:29]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(Cl)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-(6-Chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid (470 mg; 1.49 mmol), N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (WO 02/083628) (488 mg; 1.79 mmol), and 0.87 mL (5.0 mmol) of DIPEA were combined in 15 ML DMF. Then 1.14 g (2.99 mmol) of HATU and 403 mg (2.99 mmol) of HOBt were added and the dark brown solution was stirred overnight at room temperature. The mixture was then partitioned between EtOAc and water. The layers were separated and the organic portion was washed with water (2×50 mL), brine (50 mL), dried (MgSO4), filtered, and concentrated. Chromatography provided 375 mg (0.66 mmol; 44%) of the title compound with 95% purity. ESI MS m/z 569 [C27H29ClN6O4S+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Br)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-bromophenyl acetic acid (7.5 g, 35.0 mmol) in DMF (60 mL) at rt were added Cs2CO3 (12.41 g, 38.15 mmol) and benzyl bromide (6.77 g, 39.6 mmol). The reaction mixture was stirred overnight at room temperature, and then at 100° C. for 1 h and cooled to rt. The solvent was removed under reduced pressure and poured into cold 1 N HCl (50 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was recrystallized from hexanes to afford (4-bromo-phenyl)acetic acid benzyl ester as a white solid. (10.65 g, 100%): 1H NMR (300 MHz, CDCl3): δ 7.42 (d, J=8.4 Hz, 2H), 7.25-7.34 m, 5H), 7.14 (d, J=8.4 Hz, 2H), 5.12 (s, 2H), 3.61 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:5); Rf=0.8.
Reaction SMILES: C([O:8][C@@H:9]([C:11]1[N:15]2[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:14]2=[N:13][N:12]=1)[CH3:10])C1C=CC=CC=1.CC#N.[Si](I)(C)(C)C>CCOC(C)=O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[C:14]3[N:15]([C:11]([C@H:9]([OH:8])[CH3:10])=[N:12][N:13]=3)[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:31]#[N:32])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc([C@@H](C)OCc3ccccc3)n21
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc([C@@H](C)O)n21
Temperature: 60 °C
Reaction time: 20 h
Yield: 43.5 %

Procedure:
To a round bottom flask was added (R)-4-(3-(1-(benzyloxy)ethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (40 mg, 0.061 mmol), CH3CN (2 ml) and TMSI (244 mg, 1.22 mmol). The reaction was stirred at 60° C. under argon for 20 hr. After this time, the solution was cooled to rt and diluted with EtOAc (50 ml). The resulting organic solution was extracted with water (20 ml), 10% NaHSO3 (20 ml) and saturated NaCl (20 ml). The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (8 g silica gel) eluting with a gradient of 20% to 80% EtOAc/Hex to give the product (R)-4-(8-(4-chlorophenyl)-3-(1-hydroxyethyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as a white solid (15 mg, 44% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].B(F)(F)F.CO.[C:18](=O)(O)[O-].[Na+]>CO>[CH3:18][O:6][C:5](=[O:7])[C:4]1[C:3](=[C:2]([F:1])[CH:10]=[CH:9][CH:8]=1)[OH:11]
Reactant: O=C(O)c1cccc(F)c1O
Reactant: O=C([O-])O
Agent: FB(F)F
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(F)c1O

Procedure:
A 15.6 g (0.10 mole) portion of 3-fluorosalicylic acid was dissolved in a 100 ml portion of absolute methanol. A 22 ml portion of borontrifluoride-methanol reagent (2 equivalents, 51% BF3) was added and the reaction allowed to reflux for about six hours. The reaction mixture was cooled and added carefully to a saturated solution of sodium bicarbonate. The resulting mixture was then extracted with ether, the ether layer dried over magnesium sulfate and evaporated in vacuo. The oil obtained was crystallized from methanol. The methyl-3-fluorosalicylate obtained had a melting point of 94°-5° C.
Reaction SMILES: C(C[O:4][C:5](=O)[CH:6]=[CH:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1)#N.CO.O.[NH2:21][NH2:22]>O>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=[C:8]1[CH:7]=[CH:6][C:5]([NH:21][NH2:22])=[O:4]
Reactant: N#CCOC(=O)C=Cc1cc2ccccc2o1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)C=Cc1cc2ccccc2o1
Yield: 90.1 %

Procedure:
187 g of the β-(2-benzofuryl)acrylic acid cyanomethyl ester were added to 2 liters of methanol, and to the mixture, with stirring, were added 76.8 g of hydrazine hydrate, and then the resulting mixture was refluxed by heating for 30 minutes. After the reaction, 2 liters of water were added to cool the reaction product, and the deposited crystals were filtered by a suction filter, then washed, and then recrystallized from methanol, thereby obtaining 150 g of β-(2-benzofuryl)acrylic acid hydrazide having a melting point between 173° C. and 174° C.