Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[NH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:35]([Cl:43])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOCC>[ClH:43].[C:35]([N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[C:18]([N:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][CH:8]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:14]2)=[N:19]1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Fc1ccc(C(CCCN2CCN(c3n[nH]c4cc(F)ccc34)CC2)c2ccc(F)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Product: Cl
Product: O=C(c1ccccc1)n1nc(N2CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2ccc(F)cc21
Temperature: 25 °C

Procedure:
A mixture of 3-{4[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl}-6-fluoro-1H-indazole (3.7 g, 0.008 mol) of Example 36 and benzoyl chloride (18.2 g, 0.129 mol) was warmed on a steam bath under N2 for 2 hours. The reaction was cooled to room temperature and the only residue was diluted with ether. The product was isolated by vacuum filtration and the filter cake was washed well with ether affording 4.2 g of a solid. The product was recrystallized twice from ethanol to provide 2.7 g (50%) of 1-benzoyl-3-{4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl-6-fluoro-1H-indazole hydrochloride, mp 236°-238° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.[N+:27]([O-])([O-:29])=[O:28].[K+]>OS(O)(=O)=O>[N+:27]([C:5]1[C:6]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)=[O:15])=[CH:7][C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:26])([CH3:1])[C:3]=2[CH:4]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1ccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1ccc(C(=O)c2cc3c(cc2[N+](=O)[O-])C(C)(C)CCC3(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Compound 43 (693 mg, 1.98 mmol) was dissolved in concentrated H2SO4 (5 ml) and the mixture was added with KNO3 (240 mg, 2.37 mmol) under ice cooling. After 1 hour, the reaction mixture was poured into ice water and extracted with dichloromethane. The organic phase was washed with saturated aqueous solution of sodium hydrogen carbonate, water and saturated brine, and then concentrated after dryness. The residue was recrystallized from ethyl acetate to give methyl 4-[3-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylcarbonyl]benzoate as colorless needles (Compound 44, 414 mg, 53%).
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=2)[O:4]1.C(O)[CH2:19][OH:20]>>[N+:12]([C:8]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([OH:4])=[C:10]([O:11][CH2:3][CH2:19][OH:20])[CH:9]=1)([O-:14])=[O:13]
Reactant: OCCO
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(O)c(OCCO)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
0.2 mol (13.2 g) of potassium hydroxide pellets (85%) is added to 100 ml of ethylene glycol which has been heated beforehand at 50° C. 0.1 mol (21.2 g) of 4,5-methylenedioxy-1,2-dinitrobenzene is added in a single portion to this solution. The heating is maintained for 2 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O>C(O)C.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cccc(N)c1
Reaction time: 24 h
Yield: 97246.3 %

Procedure:
A mixture of methyl 3-nitrobenzoate (18.1 g, 0.10 mmol) in ethanol/tetrahydrofuran (THF) (9:1), and 1.8 g of 10% Pd/C was hydrogenated at atmospheric pressure and ambient temperature for 24 hr. The reaction mixture was filtered through Celite (Celite is a registered trademark of the Johns-Manville Product Corporation for diatomaceous earth) and washed with ethanol. The solvent was removed in vacuo to give the title compound as a pale yellow solid (14.7 g; 97% yield) that was used without further purification in the next reaction. 1H-NMR (200 MHz; CDCl3) δ 7.43 (d, 1H, J=7.6 Hz), 7.35 (t, 1H, J=2.3 Hz), 7.25 (d, 1H, J=2.3 Hz), 7.19 (d, 1H, J=7.7 Hz), 3.89 (s, 3H), 3.7 ppm (bs, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:46][N:47]([CH2:54][C@H:55]1[CH2:60][CH2:59][C@H:58]([NH2:61])[CH2:57][CH2:56]1)[CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([NH:61][C@H:58]4[CH2:57][CH2:56][C@H:55]([CH2:54][N:47]([CH3:46])[CH:48]5[CH2:53][CH2:52][O:51][CH2:50][CH2:49]5)[CH2:60][CH2:59]4)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N[C@H]2CC[C@H](CN(C)C4CCOCC4)CC2)CCC3)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (200 mg) and 1-hydroxybenzotriazole (146 mg) in acetonitrile (10 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (207 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (323 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (326 mg) and triethylamine (0.2 ml) in acetonitrile (15 ml), and the resulting mixture was stirred for 10 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent and the residue was then subjected to purification using column chromatography (ethanol/ethyl acetate 1:1) and to recrystallization (ethyl acetate/hexane) to obtain trans-2-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (compound 64) (253 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12](=[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)[CH2:13]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH4+:33].[OH-]>>[CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12](=[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:33])=[O:23])=[CH:20][CH:19]=1)[CH2:13]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Agent: [OH-]
Product: NC(=O)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1.5 g (0.0034 mole) sample of 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzoyl chloride was cooled in an ice bath. 30 mL of NH4OH was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for 2 h. The solid was filtered off and dried. The product was passed through a Biotage Flash 40 L (silica gel, 9:1; CH2Cl2:MeOH). Conversion to the HCl salt and recrystallization from EtOH/Et2O gave 0.45 g of 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzamide; mp. 210-212° C. MS m/z (MH+) 423. 1H NMR (DMSO-d6) δ 7.95 (s, 1H); 7.9 (d, 2H); 7.4-7.2 (ar, 12H); 4.05 (bs, 1H); 3.6 (q, 2H); 2.9 (d, 2H); 2.4-2.1 (m, 5H); 1.8 (m, 3H); 1.1 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[CH2:12]([O:14][CH:15]([O:24][CH3:25])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH3:13].S([O-])([O-])(=O)=O.[Mg+2].Cl[CH2:33]Cl>>[CH2:12]([O:14][CH:15]([O:24][CH2:25][CH3:33])[C:16]1[CH:23]=[CH:22][C:19](/[CH:20]=[N:1]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][O:5][C:6]3=[O:11])=[CH:18][CH:17]=1)[CH3:13]
Reactant: ClCCl
Reactant: Nc1cccc2c1COC2=O
Reactant: CCOC(OC)c1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CCOC(OCC)c1ccc(/C=N/c2cccc3c2COC3=O)cc1

Procedure:
4-Aminoisobenzofuran-1(3H)-one (600 mg, 4 mmol), 4-(ethoxy(methoxy)methyl)benzaldehyde (1.6 g, 8 mmol) and 1 g of magnesium sulfate were added into 40 mL of dichloromethane and stirred under reflux overnight, then the mixture was evaporated under reduced pressure and the residue was dried in vacuum to give 600 mg of crude product (E)-4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one which without further purification was used in next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][CH:3]=1.O.NN.ClCCl>CO>[NH2:13][CH2:12][CH2:11][CH2:10][N:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N(CCCN1C(=O)c2ccccc2C1=O)Cc1ccc(F)cc1
Agent: NN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCN)Cc1ccc(F)cc1
Yield: 83.3 %

Procedure:
To a solution of N-[5-(p-fluorophenyl)-4-(tert-butoxycarbonyl)-4-azapentyl]phthalimide (2.1 g, 5.1 mmol) in methanol (20 ml) was added hydrazine monohydrate (0.4 ml) and the mixture was heated under reflux for 3 hours. After cooling, to the reaction mixture was added dichloromethane (50 ml) and then washed with aqueous ammonia (50 ml×2). The organic layer was dried over anhydrous potassium carbonate and the solvent was distilled off under reduced pressure to give 1.2 g of the title compound as a colorless oily substance. Yield=85%.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:10]2[C:9]([CH3:20])([CH3:19])[CH2:8][CH2:7][C:6]([CH3:22])([CH3:21])[C:5]=2[CH:4]=1.[C:23]1([P:29]([C:36]2C=CC=CC=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:42]1(C)[CH:47]=[CH:46]C=[CH:44][CH:43]=1>>[Br-:1].[CH2:2]([C:3]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[P+:29]([CH3:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:11][C:10]2[C:9]([CH3:20])([CH3:19])[CH2:8][CH2:7][C:6]([CH3:22])([CH3:21])[C:5]=2[CH:4]=1)[CH2:44][CH2:43][CH2:42][CH2:47][CH3:46]
Reactant: Cc1ccccc1
Reactant: CCCCCCc1cc2c(cc1CBr)C(C)(C)CCC2(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCc1cc2c(cc1-c1ccccc1[P+](C)(c1ccccc1)c1ccccc1)C(C)(C)CCC2(C)C
Product: [Br-]
Temperature: 115 °C

Procedure:
A solution of 2.58 g of 2-bromomethyl-3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (from Example 6) and 1.94 g of triphenylphosphine in 50 ml of toluene was heated to reflux (oil bath at 115° C.) for 3 hours. The mixture was cooled to −5° C. for 1 hour and the white solid was filtered off. Concentration in vacuo of the filtrate gave a pale yellow residue, which was crystallized from toluene. The combined white solids were dried, giving 4.0 g of the title product. 1H NMR (CDCL3): 7.78 (m, 3H), 7.50-7.75 (m, 12 H), 6.95 (s, 1H), 6.90 (s, 1H), 5.14 (d, J=15 Hz, 2H), 1.76 (t, J=7.8 Hz, 2 H), 1.50-1.70 (m, 4 H), 1.22 (s, 6 H), 1.30-1.05 (m, 8 H), 0.85 (t, J=6.8 Hz, 3 H), 0.81 (s, 6 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C@H:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22].Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:17])[N:10]([CH2:22][CH:21]=[CH2:20])[C@H:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: C=CCC[C@@H](C)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC[C@@H](C)N(CC=C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
((R)-1-Methyl-pent-4-enyl)-carbamic acid benzyl ester (790 mg, 3.39 mmol) was dissolved in DMF (8 ml) and was cooled to 0 degrees C. Sodium hydride (60% dispersion, 271 mg, 6.78 mmol) was added and the reaction was stirred for 15 minutes. Allyl bromide (1.23 g, 0.88 ml, 10.17 mmol) was added and the reaction mixture was stirred for 3 h at 0 degrees C. H2O (10 ml) was added, then 2N HCl was added dropwise adjusting the pH to 1. The reaction mixture was extracted with Et2Q (2×50 ml). The combined organics were washed with aq. 2N HCl, then aq. NaHCO3, then brine. The combined organics were dried with MgSO4, filtered, concentrated in vacuo, then chromatographed on silica gel (5% EtOAc/hexanes) to yield the title compound as a colorless oil (883 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]1=2.O.C(OCC)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:10](=[O:15])[C:11]3[CH2:19][CH2:18][CH2:17][CH2:16][C:12]=3[C:13]2=[O:14])=[C:4]([F:9])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(Cl)cc1F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A solution of 4-chloro-2-fluoroaniline (19.0 g, 130.6 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (19.85 g, 130.6 mmol) in acetic acid is refluxed for 2 hours, treated with additional 4-chloro-2-fluoroaniline (3.0 g), refluxed for 90 minutes, stirred at room temperature overnight and poured into water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extract is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a purple oil. Flash column chromatography of the oil using silica gel and 15 to 20% ethyl acetate in hexanes solutions gives the title product as an off-white solid (25.3 g, 69% yield, mp 81-82° C.) which is identified by 1H, 13C and 19F NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:27]=[N:26][CH:25]=[C:24]([F:28])[C:21]=1[CH:22]=[O:23].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:27]=[N:26][CH:25]=[C:24]([F:28])[C:21]=2[CH:22]=[O:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=Cc1c(F)cncc1Br
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cncc(F)c2C=O)cc1Cl
Temperature: 100 °C
Yield: 18 %

Procedure:
To the solution of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (264 mg, 1.00 mmol), 3-bromo-5-fluoroisonicotinaldehyde (204 mg, 1.00 mmol) and PdCl2(PPh3)2 (56 mg, 0.08 mmol) in DMF (3 mL) was added 2M Na2CO3 solution (1.50 ml, 3.00 mmol) under nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and saturated NH4Cl solution. After extraction and separation, the combined extracts were concentrated and purified by SNAP10 g (10% MeOH/DCM 0-15% gradient) to give 2-chloro-4-(5-fluoro-4-formylpyridin-3-yl)benzonitrile (47 mg, 18%) as a white solid; ESI-MS m/z: 293 [M+MeOH+1]+, Retention time 1.15 min. 1H-NMR (CDCl3, 400 MHz) δ 7.33 (dd, J=8.0, 1.6 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 8.49 (s, 1H), 8.78 (d, J=1.2 Hz, 1H), 10.27 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Br:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Br:37])[C:29]=1[C:30](=O)[C:31]([O:33]CC)=O.CC(O)=O>COCCO.CCOC(C)=O>[Br:37][C:28]1[CH:27]=[N:26][CH:25]=[C:24]([Br:23])[C:29]=1[C:30]1[C:31](=[O:33])[N:21]([CH3:22])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=O)C(=O)c1c(Br)cncc1Br
Reactant: CNc1nc(Nc2ccc(N3CCOCC3)cc2)ncc1N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: COCCO
Product: Cn1c(=O)c(-c2c(Br)cncc2Br)nc2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Yield: 26.2 %

Procedure:
A mixture of 0–30 g (1 mmol) of 5-amino-4-(methylamino)-2-[[4-(morpholin-4-yl)phenyl]amino]pyrimidine, 0.67 g (2 mmol) of ethyl 2-(3,5-dibromopyridin-4-yl)-2-oxoacetate (from preparation 17), and 0.5 mL of HOAc in 15 mL of 2-methoxyethanol is heated under reflux for 18 hours. Workup in EtOAc, followed by chromatography on silica, eluting with CH2Cl2/EtOAc (4:1), gives 0.15 g (26%) of the title compound (Compound 19): mp (EtOH) 204–206° C.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC(C)([O-])C.[K+].[Si:34]([O:41][CH2:42][C@@H:43]1[C@@H:50]2[C@@H:46]([O:47][CH:48](O)[CH2:49]2)[CH2:45][C@H:44]1[O:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>O1CCCC1>[Si:34]([O:41][CH2:42][C@H:43]1[C@H:44]([O:52][CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][O:54]2)[CH2:45][C@H:46]([OH:47])[C@@H:50]1[CH2:49]/[CH:48]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 184.6 %

Procedure:
A suspension of (4-carboxy butyl) triphenyl phosphonium bromide (289.3 g, 652.6 mmol) in tetrahydrofuran (1000 ml) was cooled on ice. To the suspension, potassium t-butoxide (146.3 g, 1304 mmol) was added and the mixture was warmed to room temperature. A solution of (3aR,4S,5R,6aS)-4-(t-butyldimethylsilyloxymethyl)-5-(2-tetrahydropyranyl-oxy)hexahydrocyclopenta[b]furan-2-ol (23) (97.2 g, 261 mmol) in tetrahydrofuran (500 ml) was added, and the resulting solution was stirred for approximately 1.5 hours. Ice water (800 ml) was added to the reaction and the mixture was concentrated under reduced pressure. Then, ice-cooled 1N-hydrochloric acid (600 ml) and ethyl acetate (800 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (400 ml). The organic layers were combined, and washed with saturated aqueous sodium chloride (800 ml). After drying with anhydrous magnesium sulfate, the solution was concentrated under reduced pressure, diethyl ether (1400 ml) was added to the residue and the mixture was stirred for 30 minutes. The resulting mixture was filtered, and the deposited white solid was eliminated. The filtrate was concentrated under reduced pressure to give crude (Z)-7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenoic acid (24) (220 g) as white solid. The entire amount was used in the following step without purification.
Reaction SMILES: O.O.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[O:29]=[C:30]([N:44]1[CH2:49][CH2:48][N:47]2[C:50]([C:53]([F:56])([F:55])[F:54])=[N:51][N:52]=[C:46]2[CH2:45]1)[CH2:31][CH:32]([NH2:43])[CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42]>CC(O)C>[O:29]=[C:30]([N:44]1[CH2:49][CH2:48][N:47]2[C:50]([C:53]([F:56])([F:55])[F:54])=[N:51][N:52]=[C:46]2[CH2:45]1)[CH2:31][C@@H:32]([NH2:43])[CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: O
Solvent: CC(C)O
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 42.5 °C
Reaction time: 1 h

Procedure:
In a 50 mL three neck flask IPA (5 mL), water (2 mL) and Dibenzoyl-L-tartaric acid monohydrate (1.84 g) were taken. It was heated to 40-45° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2.0 g, % purity-94%) dissolved in IPA (5 mL) was added into reaction mixture at 60-65° C. It was stirred for 1 h at 60-65° C. It was gradually cooled to room temperature. Then it was further cooled to 0-5° C. and stirred for 1 h. The salt was filtered and washed with cold IPA. An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt of mixture of (2R) and (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-1.1 g, % Y-28.7%, Purity by HPLC-99.1%, % Chiral purity by HPLC of R-isomer 74%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1.C1C=NC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.Cl.Cl.[NH2:38][CH:39]1[CH2:47][CH2:46][C:42]2[NH:43][CH:44]=[N:45][C:41]=2[CH2:40]1.C(N(CC)CC)C>CC(N(C)C)=O.Cl>[NH:43]1[C:42]2[CH2:46][CH2:47][CH:39]([NH:38][C:12](=[O:14])[CH:11]=[CH:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:16])[F:15])=[CH:9][CH:8]=3)[CH2:40][C:41]=2[N:45]=[CH:44]1
Reactant: O=C(O)C=Cc1ccc(OC(F)(F)F)cc1
Reactant: NC1CCc2[nH]cnc2C1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccc(OC(F)(F)F)cc1)NC1CCc2[nH]cnc2C1
Reaction time: 0.17 h

Procedure:
To a solution of 3-(4-trifluoromethoxyphenyl)acrylic acid (186 mg, 1.0 mmol) in DMA (5 ml), HOAt (136 mg, 1.0 mmol) and DIC (126 mg, 1.0 mmol) were added and the mixture was stirred for 10 min. A mixture prepared from 5-amino-4,5,6,7-tetrahydro-1H-benzimidazole, dihydrochloride (210 mg, 1.0 mmol), DMA (5 ml) and triethylamine (202 mg, 2 mmol) was added to the activated ester and the mixture was stirred for 16 hours at ambient temperature. The volatiles were evaporated and the residue was stirred with a mixture of H2O (40 ml), 1 N hydrochloric acid (20 ml) and diethyl ether (25 ml). The phases were separated and the aqueous phase was washed with diethyl ether (2×25 ml) and then made alkaline to pH 10-11 with 4 N sodium hydroxide. The alkaline mixture was extracted with ethyl acetate (3×50 ml) and the combined organic extracts were dried (magnesium sulphate). The solvent was evaporated in vacuo to give a residue that was dissolved in 1 N hydrochloric acid (50 ml) and the acidic mixture was evaporated to dryness. The residue was re-evaporated with acetone (2×15 ml), stirred with acetone for 1 hour and the solid was isolated by filtration and dried. This afforded 141 mg (36%) of the title compound.