Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[OH:12].[C:13]([CH2:15][C:16](O)=[O:17])#[N:14].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:13]([CH2:15][C:16]([O:12][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([F:9])=[C:5]([F:10])[C:4]=1[F:11])=[O:17])#[N:14]
Reactant: N#CCC(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#CCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a solution of 2,3,4,5,6-pentafluorophenol (1.08 g, 5.88 mmol) and 2-cyanoacetic acid (0.50 g, 5.9 mmol) in DCM (20 mL) was added DCC (1.21 g, 5.88 mmol). After stirring for about 4 h at ambient temperature, the reaction was concentrated under reduced pressure and then purified over silica gel (20 g) using DCM as the eluent to afford perfluorophenyl 2-cyanoacetate as a white solid (1.39 g, 94%): 1H NMR (400 MHz, CDCl3) δ 3.85 (s, 2H).
Reaction SMILES: O[C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(N(S(F)(F)[F:19])CC)C>ClCCl.O>[F:19][C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1ccc(C#N)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(F)c1ccc(C#N)cc1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 4-(2-hydroxypropan-2-yl)benzonitrile (1.00 g, 6.20 mmol; obtained from 4-(propan-2-yl)benzonitrile according to literature procedure: Synth. Comm. 2006, 36, 2145-2155) in dichloromethane (20 mL) was added diethylamino sulfur trifluoride (DAST; 1.20 g, 7.44 mmol) at a temperature of 0° C. The reaction mixture was allowed to stirr at rt for 2 h, whereupon it was diluted with water and extracted with dichloromethane. The organic extract was washed with water, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 95:5) to afford the title compound (675 mg, 67%): 1H NMR (400 MHz, CDCl3) δ 7.57 (d, 2H), 7.48 (d, 2H), 1.72 (s, 3H), 1.68 (s, 3H); ES-MS m/z 163, HPLC RT (Method F) 2.12 min.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[C:16]([CH2:19][NH:20][C@H:21]([C:25]([OH:27])=[O:26])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][C:5]1=2)#[N:2].[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]>ClCCl.C(N(C(C)C)CC)(C)C>[C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[C:16]([CH2:19][N:20]([C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])[C@H:21]([C:25]([OH:27])=[O:26])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][C:5]1=2)#[N:2]
Reactant: CC(C)[C@H](NCc1ccc2c(c1)CCc1ccccc1N2CC#N)C(=O)O
Reactant: CCCCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC(=O)N(Cc1ccc2c(c1)CCc1ccccc1N2CC#N)[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
Compound 40-b (1.2 g) was dissolved in a mixture of 30 ml of dichloromethane and 0.6 ml of diisopropylethylamine, and 0.4 ml of valeryl chloride was added to the solution under ice cooling, followed by stirring at room temperature for 5 hours. Then, ice was added thereto, and the mixture was stirred for some time. The mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (5/1)] to give 1.4 g (96%) of the product as a yellow oily substance.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:9])(=O)[CH3:7].CC(C1C=[CH:17][C:16]([F:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=O.C(OO)(=O)C>O>[F:19][C:16]1[CH:17]=[CH:7][C:6]([OH:9])=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: CC(=O)OO
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(O)ccc1F
Yield: 20 %

Procedure:
Concentrated sulfuric acid (200 mL) and acetic acid (120) mL are mixed at 0° C. To this solution is added 15 g (0.082 mol) of 4-fluoro-3-nitroacetophenone with stirring. To the cold reaction mixture is added 36 mL of 36% peracetic acid. The reaction mixture is then stirred at room temperature for 4 hours. Water (500 mL) is added to the mixture, and the crude product is extracted into diethyl ether. The combined ether fractions are washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified using column chromatography on silica gel, eluting with 3% methanol/chloroform, giving 3.2 g of Compound 23 (20% yield). mp: 86-87° C. 1H-NMR (CDCl3) 7.56 (dd, 1H); 7.29 (t, 1H), 7.12 (m, 1H); 5.36 (s, 1H). 19F-NMR (d6 -DMSO) 147.60 (s). Anal. calc. for C6H4FNO3 : C, 45.87; H, 2.57; N, 8.92. Found: C, 45.80; H. 2.51; N, 8.69.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][N:21]=3)=[O:19])[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[NH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[N:33]1([CH2:32][CH2:31][CH2:30][NH:29][C:24](=[O:26])[C:23]2[CH:27]=[CH:28][C:20]([C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:7]4[C:6]([NH:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:13][CH2:14]3)=[O:19])=[N:21][CH:22]=2)[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: CC(C)CNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: NCCCn1ccnc1
Product: CC(C)CNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCCn3ccnc3)cn2)CC1
Yield: 66 %

Procedure:
By the same procedure as described in the example 81, synthesis was carried out starting with 6-[1-[3-(isobutylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 1-(3-aminopropyl)imidazole. And then, the product was recrystallized with isopropanol to give a desired compound.
Reaction SMILES: [CH2:1]=[C:2]([C:7](OS(F)(=O)=O)([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[I-:15].[Na+].COCCOCCOC>O>[F:4][C:3]([F:6])([F:5])[C:2]([C:7]([F:9])([F:8])[I:15])=[CH2:1]
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: C=C(C(F)(F)F)C(F)(F)I
Reaction time: 8 h
Yield: 55.2 %

Procedure:
CH2═C(CF3)CF2OSO2F (10 g, 0.04 mole) is added gradually to a mixture of dry sodium iodide (NaI) (7 g, 0.047 mole) and dry diglyme (20 ml) at 10° C. with stirring. The reaction mixture is kept overnight and then poured into water. The organic layer is separated, washed with aqueous sodium bicarbonate solution and then with water and then dried over MgSO4. Distillation gives a mixture (6 g, 54%) of 2-trifluoromethyl−3,3,-difluoro−3-iodopropene (CH2═C(CF3)CF2I) (10%) and 1,1-difluoro−2-trifluoromethyl−3-iodopropene (CF2═C(CF3)CH2I) (90%), as shown by GC-MS and 19F NMR. B.pt. 98–99° C. The difluoromethylene isomer CF2═C(CF3)CH2I predominates in this example. The experience with chloride as nucleophile (Example 17), indicates that reaction conditions, time in the case of Example 17, can be varied to control the ratio of methylene to difluoromethylene isomer. Simple experimentation should identify conditions at which iodide as nucleophile will yield higher amounts of methylene monomer.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1.Cl.CCOCC>C(O)(C)C>[ClH:19].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([Cl:22])=[CH:24][C:25]=3[F:30])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: N#Cc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCc1ccccc1
Yield: 80.5 %

Procedure:
A suspension of 7-benzyloxy-4-chloro-6-cyanoquinoline (2 g, 6.8mmol), 4-chloro-2-fluoroaniline (1.1 g, 7.5 mmol) in isopropanol (50 ml) containing 1M ethereal hydrogen chloride (8 ml) was heated at reflux for 2 hours. After cooling to ambient temperature ether was added. The precipitate was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum to give 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-cyanoquinoline hydrochloride (2.41 g, 81%).
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C@H:25]([OH:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:30]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH2:71]([O:73][C:74](=[O:84])[C@H:75]([CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[NH2:76])[CH3:72]>ClCCl.C(N(CC)CC)C>[CH2:1]([N:8]([CH2:24][C@H:25]([OH:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:30]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:76][C@H:75]([C:74]([O:73][CH2:71][CH3:72])=[O:84])[CH2:77][C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)=[O:20])=[CH:22][CH:23]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)ccc1OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
A solution of 0.3 g (0.45 mmol) of trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoic acid (preparation 3), of 0.78 g (0.91 mmol) of 1-hydroxybenzotriazole, of 0.175 g (0.91 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, of 0.19 ml of triethylamine and of 0.165 g (0.91 mmol) of L-phenylalanine ethyl ester hydrochloride in 5 ml of dichloromethane is stirred for 24 h. The solvents are evaporated under reduced pressure. Dichloromethane and water are added and the organic phase is washed three times with water. The organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The product is obtained in the form of a white solid (0.350 g, 92%) after purification on silica gel (eluent: dichloromethane/methanol 100/00 to 90/10 gradient in 35 min). [M+H+]=835
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(C#N)cc3)CC2)CC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl 4,4′-bipiperidine-1-carboxylate (181 mg; 0.674 mmol) in DMF (3 mL) was treated with 4-fluorobenzonitrile (98 mg; 0.809 mmol) and cesium carbonate (264 mg; 0.809 mmol). The mixture was stirred at 70° C. for 18 hr. The mixture was partitioned between isopropyl acetate (25 mL) and pH7 phosphate buffer (10 mL). The organic was washed twice more with pH7 phosphate buffer (2×10 mL). The organic was dried over magnesium sulfate, filtered and evaporated to a solid. The crude product was chromatographed over silica gel (PTLC; 2:1 hex/MTBE). The major band was recovered affording the title compound. LRMS calc: 369.2. obs: 370.1 (M+H), 270.1 (M-BOC+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[N:26]1[CH2:29][CH:28]([C:30]([OH:32])=O)[CH2:27]1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.Cl.[F:56][C:57]([F:61])([F:60])[CH2:58][NH2:59]>CN(C=O)C>[F:56][C:57]([F:61])([F:60])[CH2:58][NH:59][C:30]([CH:28]1[CH2:29][N:26]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH2:12][C:11]([C:17]4[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=4)([C:13]([F:15])([F:16])[F:14])[O:10][N:9]=3)=[CH:7][C:2]=2[Cl:1])[CH2:27]1)=[O:32]
Reactant: NCC(F)(F)F
Reactant: O=C(O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.9 %

Procedure:
To a stirred solution of 1-{2-chloro-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-azetidine-3-carboxylic acid (Preparation 14, 0.1 g, 0.190 mmol) in dry DMF (3 mL) was added EDCl.HCl (0.055 g, 0.280 mmol), DIPEA (0.049 g, 0.380 mmol) and 2,2,2-trifluoro-ethylamine hydrochloride (0.026 g, 0.190 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (50 mL), white solid was precipitated out, and solid was filtered, dried. Solid was purified by preparative TLC to afford off white solid (0.045 g, 41%). 1H-NMR (400 MHz, CDCl3) δ: 3.38-3.42 (m, 1H), 3.60 (d, 1H, J=17.08 Hz), 3.93-4.03 (m, 3H), 4.26-4.36 (m, 4H), 5.95 (t, 1H), 6.49 (d, 1H, J=8.52 Hz), 7.42 (dd, 1H, J1=8.56 Hz, J2=1.88 Hz), 7.47 (d, 1H, J=1.84 Hz), 7.62 (s, 2H); LC-MS (m/z): [M−H] 605.40.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:26]([O-])([OH:28])=[O:27]>>[C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10](=[O:14])[NH:11]2)=[CH:7][C:6]=1[N+:26]([O-:28])=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2CC(C)C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(CC(C)C)C(=O)N2
Reaction time: 0.5 h

Procedure:
A solution of 4.2 g. (0.017 mol) 6-acetamido-3-(2-methylpropyl)-indolin-2-one in 50 ml. acetic anhydride is mixed, while cooling, with 0.8 ml. (0.019 mol) fuming nitric acid and then stirred for about 30 minutes. Subsequently, the reaction mixture is carefully poured on to ice and the crystals obtained are filtered off with suction, washed with water and dried. Yield: 3.2 g. (66% of theory); m.p. 192°-197° C.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([CH3:13])[CH:11]([OH:14])[CH2:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:26](Cl)(=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:26]([O:14][CH:11]1[CH2:10][CH:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]1[CH3:13])(=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CC1C(O)CC(c2ccccc2)NC1c1ccccc1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Li]CCCC
Product: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)NC(c2ccccc2)C1C
Yield: 65.3 %

Procedure:
The general procedure of Example 1 is repeated using 22.8 g (85.2 mmol) of 2,6-diphenyl-3-methyl-4-hydroxypiperidine, 34 mL (85 mmol) of n-butyllithium (2.5M in hexanes) and 18.6 g (85.2 mmol) of lauroyl chloride. 25.0 g (65% yield) of the title compound is isolated after purification by LC (silica gel, ethyl acetate/hexane): mp 56°-59° C.
Reaction SMILES: O=[C:2]1[N:21]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2=[N:6][C:7]([C:10]3[CH:11]=[N:12][N:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=34)=[CH:8][CH:9]=[C:4]2[NH:3]1.[C:28](OCC)(OCC)(OCC)C>CCO>[CH3:28][C:2]1[N:21]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2=[N:6][C:7]([C:10]3[CH:11]=[N:12][N:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=34)=[CH:8][CH:9]=[C:4]2[N:3]=1
Reactant: N#Cc1ccn2ncc(-c3ccc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Reactant: CCOC(C)(OCC)OCC
Solvent: CCO
Product: Cc1nc2ccc(-c3cnn4ccc(C#N)cc34)nc2n1C1CCOCC1
Temperature: 145 °C
Reaction time: 2.5 h
Yield: 15 %

Procedure:
To a solution of the compound obtained in example 2 section d (56.4 mg, 0,169 mmol) in EtOH (1.5 mL), PTSA monohydrate (3.21 mg, 0.017 mmol) and triethyl orthoacetate (547 mg, 3.37 mmol) were added. The reaction mixture was heated in a OEM Explorer microwave oven at 145° C. and 270 W for 2.5 hours. The crude residue was chromatographed on a silica gel flash system (ISCO Rf) using CH2Cl2/MeOH mixtures of increasing polarity a eluent to afford the desired product (15% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.N1C2C=CC=CC=2N=N1.[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:16]=1[CH:17]=[CH:18][CH2:19]O>ClCCl>[Cl:3][CH2:19]/[CH:18]=[CH:17]/[C:16]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:15]=1[F:14]
Reactant: O=S(Cl)Cl
Reactant: OCC=Cc1cc(F)ccc1F
Agent: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Product: Fc1ccc(F)c(/C=C/CCl)c1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A solution of 0.66 cm3 (9.07 mmol) of thionyl chloride and 1.08 g (9.07 mmol) of benzotriazole in 70 cm3 of dichloromethane are added at a temperature in the region of 20° C., under an argon atmosphere, to 1.25 g (7.34 mmol) of 2,5-difluorocinnamyl alcohol in solution in 130 cm3 of dichloromethane. After stirring for 10 minutes, the reaction mixture is filtered on No. 3 sintered glass and the solid residue rinsed with twice 20 cm3 of dichloromethane. The filtrate is washed with 3 times 75 cm3 of water. The organic phase is dried over anhydrous magnesium sulfate and filtered to give a solution of 2-[(1E)-3-chloro-1-propenyl]-1,4-difluorobenzene (7.34 mmol) which is immediately used as it is in the next step.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10]P(=O)(OCC)OCC)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][O:22][CH2:23][O:24][C:25]1[C:29]([CH:30]=O)=[CH:28][N:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]=1.O>O1CCCC1>[C:1]([C:5]1[S:6][CH:7]=[C:8](/[CH:10]=[CH:30]/[C:29]2[C:25]([O:24][CH2:23][O:22][CH3:21])=[N:26][N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1csc(C(C)(C)C)n1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(C(C)(C)C)n1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of diethyl [(2-tert-butyl-1,3-thiazol-4-yl)methyl]phosphonate (2.2 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.48 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.3 g) was added to the reaction mixture, and the mixture was heated under reflux for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (4:1, v/v) to give 2-tert-butyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as pale-yellow crystals (2.6 g, yield 71%). melting point: 112-113° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH:7]1[CH2:11][C:10]([CH3:12])=[CH:9][C:8]1=[O:13])[OH:6])[CH3:2].C.[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([OH:6])[CH:7]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8]1=[O:13])[CH3:2]
Reactant: CCOC(=O)C(O)C1CC(C)=CC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)C1CC(C)CC1=O

Procedure:
Step 2, Hydrogenation Process (Ethyl Ester): 99.1 g of crude alpha-hydroxy-(4-methyl-2-oxo-3-cyclopenten-1-yl)-acetic acid ethyl ester (as prepared in Example 1) in 882 ml of toluene was hydrogenated over 9.91 g of 10% by weight of palladium and 90% by weight of charcoal at room temperature and 25-50 psi. After hydrogen uptake had ceased, the catalyst and solvent were removed by filtration and evaporation to give 101 g of a viscous, amber-colored oil. This oil is distilled to provide the product alpha-hydroxy-4-methyl-2-oxo-cyclopentane acetic acid ethyl ester, bp 96°-111°/0.05 mmHg, for use in Example 5.
Reaction SMILES: [OH:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4](=[O:13])[C:3]=1[CH:14]=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CCOCC>[C:17]1([NH:16][CH:14]=[C:3]2[C:2](=[O:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][CH2:5][C:4]2=[O:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: O=CC1=C(O)c2ccccc2OCC1=O
Agent: Cl
Solvent: CCOCC
Product: O=C1COc2ccccc2C(=O)C1=CNc1ccccc1
Reaction time: 0.08 h
Yield: 58 %

Procedure:
A quantity of 10.0g (0.049 mole) of 2,3-dihydro-5-hydroxy-3-oxo-1-benzoxepin-4-carboxaldehyde was added to 15g of aniline. The temperature rose to 45° as most solid went into solution. The dark mixture was heated at 105°-110° for 10 minutes and cooled. Ether (500ml) and 300ml of cold 2N hydrochloric acid were added, and the mixture was stirred for 5 minutes. The entire mixture was filtered to remove the dark, suspended insolubles. The ether phase of the filtrate was washed well with water, dried (Na2SO4) and concentrated to give 8.0g (58%) of crude product; m.p. 94°-96°. Recrystallization from ethyl acetate gave pure, orange-tan crystals; m.p. 98°-100°.
Reaction SMILES: [CH3:1][C:2]1[C:17]([C:18]([OH:20])=O)=[C:5]2[CH:6]=[C:7]([CH3:16])[CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:4]2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[C:42]([O:46][C:47](=[O:56])[NH:48][C:49]([CH3:55])([CH2:52][CH2:53][CH3:54])[CH2:50][NH2:51])([CH3:45])([CH3:44])[CH3:43].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:42]([O:46][C:47](=[O:56])[NH:48][C:49]([CH3:55])([CH2:52][CH2:53][CH3:54])[CH2:50][NH:51][C:18]([C:17]1[C:2]([CH3:1])=[N:3][N:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])=[CH:8][C:7]([CH3:16])=[CH:6][C:5]=12)=[O:20])([CH3:45])([CH3:44])[CH3:43]
Reactant: Cc1cc(OCCC(C)C)n2nc(C)c(C(=O)O)c2c1
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCCC(C)C)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 45 mg (0.163 mmol) of 2,5-dimethyl-7-(3-methylbutoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 8A in 3 ml of tetrahydrofuran was admixed with 30 mg (0.177 mmol) of 1-hydroxybenzotriazole and 30 mg (0.177 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The resulting solution was stirred at room temperature for 15 min, and then 45.7 mg (0.212 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 152A were added, followed by 0.85 ml (0.212 mmol) of N,N-diisopropylethylamine. The mixture was stirred at room temperature for a further 18 h. The solvent was drawn off under reduced pressure and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was removed and washed with water and aqueous sodium chloride solution, dried with a phase separation cartridge and dried further under reduced pressure, which gave 80 mg (61% of theory, 54% pure) of the target compound.