Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([N:30]=[C:31]=[O:32])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:33]([NH2:35])[CH3:34]>C1COCC1.CCOC(C)=O>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH:28]([NH:30][C:31]([NH:35][CH2:33][CH3:34])=[O:32])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N=C=O)C3)ccc2n1CC1CCC(F)(F)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)NC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
A solution of 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(3-isocyanatoazetidin-1-yl)sulfonyl]-1H-benzimidazole in THF (4.0 mL, 0.095 mmol) (see following step B for preparation) was added to a solution of ethylamine (100 uL, 2.0 M in THF, 0.2 mmol) in THF (2.0 mL). The reaction mixture was stirred for 4 h at room temperature, diluted with EtOAc (50 mL), washed with NaHCO3 (2×5 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc/MeOH (20:1) on silica gel to give 21 mg (44%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.02 (t, J=7.13 Hz, 3 H), 1.51-1.64 (m, 2 H), 1.66 (s, 9 H), 1.69-1.87 (m, 4 H), 2.01-2.15 (m, 2 H), 2.21-2.37 (m, 1 H), 3.04 (q, J=7.16 Hz, 2 H), 3.62 (dd, J=8.11, 6.74 Hz, 2 H), 3.99 (t, J=8.10 Hz, 2 H), 4.16-4.29 (m, 1 H), 4.54 (d, J=7.62 Hz, 2 H), 7.90 (dd, J=8.59, 1.56 Hz, 1 H), 8.03 (d, J=8.59 Hz, 1 H), 8.17 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=512.3; Anal. Calcd for C24H35F2N5O3S+1.40 TFA+0.50H2O (680.28): C, 47.32; H, 5.54; N, 10.29. Found: C, 47.36; H, 5.57; N, 10.32.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[B:31](OC)([O:34]C)[O:32]C.Cl>C1COCC1.O>[F:1][C:2]1[C:7]([B:31]([OH:34])[OH:32])=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:13]=2)[N:3]=1
Reactant: CCCCCCCCCc1ccc(-c2cccc(F)n2)cc1
Reactant: COB(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccc(-c2ccc(B(O)O)c(F)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.8 %

Procedure:
A solution of 100 mol of 2-fluoro-6-(4-nonylphenyl)pyridine in 500 ml of dry THF is added dropwise to a solution of 110 mmol of lithium diisopropylamide in 100 ml of dry tetrahydrofuran at −70° C. under a protective gas atmosphere. The mixture is stirred for an additional 4 h at this temperature. A solution of 200 mmol of trimethyl borate in 40 ml of dry tetrahydrofuran is then added dropwise at a temperature of less than −60° C. The reaction mixture is then slowly warmed up to room temperature, admixed with a solution of 60 ml of water and 20 ml of concentrated hydrochloric acid while cooling with ice, and stirred for another hour at room temperature. The reaction mixture is extracted with tert-butyl methyl ether, the combined organic extracts are washed with water and saturated sodium chloride solution and dried with sodium sulfate, and the solvents are removed under reduced pressure. The raw product is crystallized from n-heptane/acetone 4:1, giving 19.8 g (58%) of 2-fluoro-6-(4-nonylphenyl)pyridine-3-boronic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])[CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2].Cl.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>CCCCCC>[CH2:1]([O:3][C:4]([C@@H:6]([NH:10][C@H:11]([C:13]([Cl:18])=[O:15])[CH3:12])[CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Agent: Cl
Solvent: CCCCCC
Product: CCC[C@H](N[C@@H](C)C(=O)Cl)C(=O)OCC
Reaction time: 1.5 h
Yield: 115.6 %

Procedure:
To a slurry of N-[1-(S)-ethoxycarbonyl-1-butyl]-(S)-alanine (III, 1.5 g, 0.0069 moles) in n-hexane (10 ml) was purged dry hydrogen chloride gas at 25-30° C. under agitation. To this was added finely grounf phosphorous pentachloride (1.8 g, 0.0086 moles) in four lots, each after an interval of 10 mns. After the complete addition the reaction mixture was agitated for 1.5 hrs. The solid precipitated was filtered, washed with hexane to give 1.88 g of the title compound (I).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[O:26]=[C:19]([C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:18][CH:17]=1)[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1
Yield: 73.8 %

Procedure:
In a manner similar to that described in Example 3, 3-phenyl-propionyl chloride (0.057 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.060 g of 4-oxo-4-[4-(3-phenyl-propionylamino)-phenyl]-butyric acid as an off-white solid; MS-(AP+) MH+326.
Reaction SMILES: C([N:5]1[C:13]2[CH:12]=[CH:11][NH:10][C:9](=[O:14])[C:8]=2[C:7]([C:15]2[CH:16]=[C:17]([C:20]([NH2:22])=[O:21])[S:18][CH:19]=2)=[N:6]1)(C)(C)C>FC(F)(F)C(O)=O.O>[O:14]=[C:9]1[C:8]2[C:7]([C:15]3[CH:16]=[C:17]([C:20]([NH2:22])=[O:21])[S:18][CH:19]=3)=[N:6][NH:5][C:13]=2[CH:12]=[CH:11][NH:10]1
Reactant: CC(C)(C)n1nc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(-c2n[nH]c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
4-(1-tert-Butyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (475 mg) obtained in Example 129 was dissolved in a mixed solvent of trifluoroacetic acid (60 mL)/water (6 mL), and the mixture was heated with reflux at 24 hr. The reaction mixture was allowed to be cooled to room temperature, and concentrated under reduced pressure. The residue was extracted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was crystallized from DMF-ethyl acetate, and dried in vacuum to give the title compound (240 mg).
Reaction SMILES: CSC.B.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH2:13][C:14](O)=[O:15]>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH2:13][CH2:14][OH:15]
Reactant: O=C(O)Cc1c(F)cccc1F
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of borane dimethyl sulfide complex (2M in THF, 26 mL) was added cautiously to a solution of 2-(2,6-difluorophenyl)acetic acid (3 g) in THF (50 mL) at 0° C. The reaction was then allowed to warm to RT and stirred for 3 h. The reaction was cooled in an ice bath and cautiously quenched with methanol (10 mL). The solvent was evaporated and the residue purified by silica gel chromatography eluting with 9:1 to 4:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 2.2 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:21]([CH3:23])[CH3:22])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH:21]([CH3:23])[CH3:22])[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(C(=O)OCc1ccccc1)c1ccc(N)cc1
Reaction time: 0.33 h

Procedure:
Iron powder, 55 g, was added in portions to a stirred mixture of 94.6 g of 2-(4-nitrophenyl)-3-methylbutanoic acid, benzyl ester, 400 ml of acetic acid, and 100 ml of water, while the temperature was kept at 90°-95° by occasional application of an ice bath. After an additional 20 minutes at 90°-95°, the hot mixture was filtered, and the filtrate was diluted with water, precipitating an oil. The oil was extracted into butyl chloride, and the butyl chloride solution washed with water (3 times) and saturated sodium bicarbonate solution, dried (MgSO4) and evaporated to 85.7 g of orange oil, 2-(4-aminophenyl)-3-methylbutanoic acid, benzyl ester. Mass spectral analysis shows the expected molecular ion, m/e 283, of the product.
Reaction SMILES: Cl.[Cl:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH:6]=NOC.C=O.CC(C)=[O:20]>O.CCCCCC>[Cl:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH:6]=[O:20]
Reactant: CC(C)=O
Reactant: CON=CCCC(Cl)c1ccccc1
Agent: C=O
Agent: Cl
Solvent: O
Solvent: CCCCCC
Product: O=CCCC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.1 mL of 2 mol/L hydrochloric acid was added to a mixture of 82 mg of (4-chloro-4-phenylbutylidene)(methoxy)amine, 0.32 mL of a 36% formalin aqueous solution and 4 mL of acetone, and the obtained mixture was then stirred at room temperature for 0.5 hours. Thereafter, hexane and water were added to the reaction mixture, and the water layer was then removed. The solvent was distilled away under reduced pressure, so as to obtain 61 mg of 4-chloro-4-phenylbutanal in the form of a colorless oily product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[H][H]>[Pd].CO.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1

Procedure:
A mixture of 120 mg (0.26 mmol) of tert-butyl 3-(4-(5-(3-cyano-4-isopropyloxyphenyl)-1,2,4-thiadiazol-3-yl)-3-methylphenyl)-2-propenoate (from Step C) and 41 mg of palladium on activated carbon (10% w/w; 0.025 mmol) in 15 mL of methanol/EtOAc (1/1) was hydrogenated under atmospheric pressure of hydrogen for 2 h. The heterogeneous mixture was filtered through a disposable frit to remove palladium and the filtrate was concentrated. The crude product was found to be pure by ESI-MS and 1H NMR analyses and used in subsequent step without purification: 1H NMR (500 MHZ, CDCl3) δ 1.46 (s, 9H), 1.49 (d, J=6.5, 6H), 2.61 (t, J=7.5, 2H), 2.65 (s, 3H), 2.97 (t, J=7.5, 2H), 4.79 (sep, J=6.5, 1H), 7.11 (d, J=9.0, 1H), 7.18 (d, J=9.0, 1H), 7.23 (s, 1H), 7.69 (d, J=8.0, 1H), 8.18 (d, J=2.0, 1H), 8.24 (dd, J=8.0, 2.0, 1H).
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7](/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1.O1CCCC1>O>[CH:10](/[CH:7]1[CH2:6][CH2:5][CH:4]([CH:3]=[O:2])[CH2:9][CH2:8]1)=[CH:11]\[CH2:12][CH2:13][CH3:14]
Reactant: CCC/C=C/C1CCC(=COC)CC1
Solvent: O
Solvent: C1CCOC1
Product: CCC/C=C/C1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
2.75 g of 1-(methoxymethylene)-4-(trans-1-pentenyl)cyclohexane [crude product from paragraph (a)] were heated to reflux for 30 minutes with 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) and then stirred at room temperature overnight. The mixture was subsequently treated with 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The extracts were washed with dilute sodium hydrogen carbonate solution and water and the aqueous phases were back-extracted with diethyl ether. The organic phases were dried over magnesium sulphate and evaporated. Low-pressure chromatography of the resulting, yellowish liquid (2.5 g) on silica gel with petroleum ether and ethyl acetate/petroleum ether (vol. 3:97) gave 1.65 g (76%) of 4-(trans-1-pentenyl)cyclohexanecarboxaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([OH:39])[CH2:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=3)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:30]2[S:34][C:33]([C:35]3([OH:39])[CH2:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:18][CH:19]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3ccc(C(=O)O)cc3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc3[nH]2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(5-chloro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid (Example 16B) (450 mg, 0.776 mmol) in methanol (7.8 mL) and 2N sodium hydroxide solution (2.7 mL, 5.43 mmol) was heated by microwave irradiation (Biotage, Initiator) in a sealed vessel to 105° C. for 7 minutes. The reaction was cooled to room temperature and concentrated to dryness. The residue was suspended in water, and the pH adjusted to ˜2 with 10% aqueous HCl solution. The solid was filtered and air-dried to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.69 (bs, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.09 (d, J=8.4 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H), 7.19 (s, 1H), 6.68 (s, 1H), 2.70-2.58 (m, 2H), 2.47-2.35 (m, 1H), 2.15-1.82 (m, 2H); MS ESI(+) m/z 425.9 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[O:10][C:9](=[O:14])[C:8]=2[CH:15]=1.[CH3:16]I>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH3:16])[C:11](=[O:13])[O:10][C:9](=[O:14])[C:8]=2[CH:15]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
As illustrated in the scheme above, NaH (2.43 g of a 60% dispersion, 60.8 mmol) was added to a solution of 6-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (10.0 g, 50.6 mmol) dissolved in DMF (200 mL). The resulting mixture was stirred at room temperature for 30 min., and then methyl iodide (6.3 mL, 101 mmol) was added dropwise. After the reaction had stirred at room temperature overnight, it was concentrated in vacuo. Water and brine were added to the residue, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with 3:1 hexanes:EtOAc. The solvent was removed by filtration, and the resulting solid was washed with additional 3:1 hexanes:EtOAc, followed by 100% hexanes. The product was dried briefly under vacuum to produce the title compound as a pale yellow solid. (8.59 g, 80%). 1H-NMR (DMSO-d6): δ 7.96 (d, J=2.6 Hz, 1H), 7.89 (dd, J=2.6 Hz, J=9.0 Hz, 1H), 7.48 (d, J=9.0 Hz, 1H), 3.45 (s, 3H). MS (ESI) (M+H)+=212.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.Cl.[CH3:20][O:21][C:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23]>>[CH3:20][O:21][C:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: COC(=O)[C@H]1CC[C@H](Nc2ncc(C#Cc3ccccc3)cn2)CC1

Procedure:
The title compound, MS: m/e=336.4 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and trans-4-amino-cyclohexylcarboxylic acid methyl ester hydrochloride.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1([CH:18]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:20][C:19](=[O:21])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:22][CH:23]=[CH:24][C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CC=Cc1ccc(C)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C=CCC(C(=O)C=Cc2ccc(Cl)cc2)c2ccccc2)cc1

Procedure:
A sodium hydroxide solution (8 ml., 20%) is added to a solution of p-chlorobenzaldehyde (20.4 g., 0.14 mole) and crude 3-phenyl-6-(p-methylphenyl)-5-hexen-2-one (Step A, above) in ethanol (350 ml.) with stirring. The off-white solid that separates on continued stirring is filtered, washed with cold ethanol and air-dried, yield 44 g., m.p. 114°-118°C. Recrystallization from ethanol gives material with m.p. 134°-136.5°C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[Cl:33])[O:19][CH:20]([C:22]1[S:26][C:25]([N:27]=[C:28]=[O:29])=[N:24][N:23]=1)[CH3:21]>CCCCCC>[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[Cl:33])[O:19][CH:20]([C:22]1[S:26][C:25]([NH:27][C:28](=[O:29])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:24][N:23]=1)[CH3:21]
Reactant: CC(Oc1ccc(Cl)c(Cl)c1)c1nnc(N=C=O)s1
Reactant: CNCC(OC)OC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccc(Cl)c(Cl)c2)s1)OC
Yield: 68.1 %

Procedure:
3.3 grams (0.028 mole) of methylaminoacetaldehyde dimethylacetal was slowly added to a 50 milliliter benzene solution containing 9.0 grams (0.028 mole) of the 5-[1-(3,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was heated to reflux and hexane was added, crystals formed on cooling. The crystals were filtered off, and dried in a vacuum oven at 80° C. to give 8.3 grams of fluffy white crystals at 3-[5-[1-(3,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-1-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea. (Melting point 124°-127° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([CH:19]([OH:22])[CH:20]=[CH2:21])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([C:19](=[O:22])[CH:20]=[CH2:21])[CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC(O)c1cc(OCCCNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C=CC(=O)c1cc(OCCCNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Yield: 62.6 %

Procedure:
1-(5′-(3″-t-butoxycarbonylaminopropyloxy)-2′-nitrophenyl)-2-propen-1-ol (9.66 g) is dissolved in chloroform (300 ml) and thereto is added activated manganese dioxide (7.2 g), and the mixture is heated with reflux. After completion of the reaction, inorganic materials are filtered off with celite, and the filtrate is concentrated, and thereto is added ethyl acetate. The organic layer is separated, washed with an aqueous saturated saline solution, dried over sodium sulfate. After distilling off the solvent, the residue is purified with a silica gel column chromatography to give 1-[5′-(3″-t-butoxycarbonylaminopropyloxy)-2′-nitrophenyl]-2-propen-1-one (6.01 g) as yellow color crystal. m.p.: 65-71° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]4[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][C:10]1[N:9]2[CH:13]=[C:14]([CH:16]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]3)[N:15]=[C:8]2[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[N:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cn3ccnc(N4CCOCC4)c3n2)C1
Reactant: O=C1CCC(=O)N1Br
Product: CC(C)(C)OC(=O)N1CC(c2cn3c(Br)cnc(N4CCOCC4)c3n2)C1

Procedure:
Compound 29a was brominated with NBS using the methods described in Example 1, Step E to obtain compound 29b. Mass Spectrum (LCMS, ESI pos.): Calcd. for C18H24BrN5O3: 438.1 (M+H). found: 438.2.
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:4]2=[C:3]([C:10]#[N:11])[CH:2]=1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:9]2[CH2:8][CH2:7][CH2:6][N:5]3[N:1]=[CH:2][C:3]([C:10]#[N:11])=[C:4]23)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#Cc1cnn2c1NCCC2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: N#Cc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CCC2
Temperature: 65 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
To a solution of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (6.9 g) in pyridine (70 ml) was added triphenylmethyl chloride (15.6 g), and the mixture was stirred at 65° C. for 4 hours. After evaporation of the solvent in vacuo, the residue was dissolved in chloroform, and the solution was washed with 10% aqueous citric acid solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give 4-triphenylmethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (16.2 g) as a solid.
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=[C:3]([C:12]([O:14]CC)=[O:13])[N:2]=1.Cl>C(O)C.[OH-].[Na+].CCOCC>[CH2:10]([O:9][C:7]([C:6]1[N:1]=[N:2][C:3]([C:12]([OH:14])=[O:13])=[CH:4][CH:5]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1ccc(C(=O)O)nn1
Reaction time: 2 h

Procedure:
To the diethyl 3,6-pyridazinedicarboxylate (5.0 g, 22.3 mmol) in 150 ml ethyl alcohol, 24.5 ml 1N NaOH was added. The mixture was stirred for 2 hours. The resulting salt was collected by filtration then was dissolved in minimum amount of water. The aqueous solution obtained was then acidified with 2N HCl in ether until the PH=2 and extracted with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. Removal of the solvent afforded 4.1 g of light yellowish oil. 1HNMR (400 MHz, CD3OD) δ 8.42 (s, 2H), 4.52 (q, 2H), 1.42 (t, 3H) ppm.