Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[C:14]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH2:26][CH2:27][CH2:28][CH3:29])=CC=1)([O-])=O.[N:31]1[CH:36]=[C:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=[N:33][CH:32]=1>O1CCCC1>[CH2:26]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([O:24][CH3:25])=[CH:23][C:14]=1/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][C:35]1[CH:36]=[N:31][CH:32]=[N:33][CH:34]=1)=[O:10])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)cc(OC)c2ccccc12
Reactant: NCCCCCCc1cncnc1
Solvent: C1CCOC1
Product: CCCCc1c(/C=C/C(=O)NCCCCCCc2cncnc2)cc(OC)c2ccccc12
Reaction time: 1.5 h
Yield: 68.5 %

Procedure:
As in Example 114, (E)-3-(1-butyl-4-methoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester (1.21 g) was reacted with 5-pyrimidinehexanamine (0.505 g) in tetrahydrofuran (20 mL) at room temperature overnight and then at 50° C. for 1.5 hour. The product was isolated in the usual manner then was purified by HPLC (ethyl acetate) and twice crystallized from ethyl acetate-hexane to provide 0.86 g of (E)-3-(1-butyl-4-methoxy-2-naphthalenyl)-N-[6-(5-pyrimidinyl)hexyl]-2-propenamide, mp 128°-129° C. Anal. Calcd for C28H35N3O2 : C, 75.47; H, 7.92; N, 9.43 Found: C, 75.52; H, 7.95; N, 9.40
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:12](O)([OH:14])[CH3:13]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]1[O:14][CH2:12][CH2:13][O:5]1
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: CC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Br)c(C2OCCO2)c1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of 2-bromo-5-methoxybenzaldehyde (5.0 g, 23.2 mmol) in toluene (300 mL) was added ethanediol (2.16 g, 34.2 mmol) and p-TsOH (20 mg), whereafter the mixture was refluxed for 12 hours. The resulting mixture was cooled to room temperature, washed with NaHCO3/aq, dried (Na2SO4), and concentrated to yield 5.918 g (98%) of the sub-title compound.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=Cc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1NCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of anthranilic acid (1.37 g, 1.0 mmol), 4-fluorobenzaldehyde (1.24 g, 1.0 mmol), and p-toluenesulfonic acid mohohydrate (0.025 g, 0.13 mmol) in 30 mL of anhydrous toluene was stirred at reflux for 1 h, then cooled to RT and NaBH4 (1.1 g) was added. The mixture was stirred at RT for 30 min, then quenched with MeOH. The volatiles were removed under reduced pressure and the residue was taken up in water. AcOH was added to bring pH to 4, and the mixture was extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, condensed, and the residue was purified by flash column chromatography to give the titled compound. MS (ES+): 246.0 (M+H)+. Calc'd for C14H12FNO2-245.09.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH2:23]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1ccc(N)cc1OC
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: COc1ccc(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)cc1OC

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol), 3,4-dimethoxyaniline (44 mg, 0.288 mmol) similar to Example 76 and isolated as a yellow solid (52 mg, 72%). 1H NMR (CDCl3): 9.74 (d, J=1.2 Hz, 1H), 8.78 (dd, J=1.2, 2.4 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 7.36 (s, 1H), 6.96–6.90 (m, 3H), 6.88 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:26])[N:13](CC3C=CC(OC)=CC=3)[C:12](=[O:23])[C:11]([CH3:25])([CH3:24])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:26])[NH:13][C:12](=[O:23])[C:11]([CH3:25])([CH3:24])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)C(C)(C)OC[C@@]2(C)c2cccc(Br)c2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC[C@@](C)(c2cccc(Br)c2)NC1=O
Temperature: 73 °C

Procedure:
A solution of (R)-5-(3-bromo-phenyl)-4-(4-methoxy-benzyl)-2,2,5-trimethyl-morpholin-3-one (487 mg, 1.2 mmol) and anisole (2.305 g, 21.3 mmol) in trifluoroacetic acid (6 ml) was treated dropwise with trifluoromethanesulfonic acid (1.19 ml). After complete addition, the violet reaction mixture was heated at 73° C. for 23 hours. The cooled reaction mixture was poured into a saturated solution of sodium hydrogen-carbonate which was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 66/34 as the eluent. The product containing fractions (550 mg, orange foam) were collected and engaged in the next step without further purification and characterization.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:10][C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17].C(OCC)C>N1C=CC=CC=1>[Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([NH:5][C:6](=[O:7])[NH:10][C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[O:4]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: NC(=O)c1ccsc1N
Solvent: c1ccncc1
Solvent: CCOCC
Product: NC(=O)c1ccsc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Yield: 99.2 %

Procedure:
Trichloroacetyl isocyanate (10 g, 53 mmol) was added dropwise to the solution of 2-amino-thiophene-3-carboxylic acid amide (3.8 g, 26.5 mmol) in pyridine (110 mL) at 0° C. The resulting reaction mixture was stirred at 0° C. The temperature of the reaction mixture was raised to room temperature over a 3 h period until LC-MS showed no remaining starting material. Diethyl ether (100 mL) was added to the reaction mixture and the resulting precipitate was filtered and dried under vacuum to give the above titled compound as a light grey solid (8.7 g, 26.3 mmol, 99% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17](=[O:19])[NH2:18])[CH:12]=1)[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]>CO.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17](=[O:19])[NH2:18])[CH2:12]1)[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1ccnc(C(N)=O)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H](NC(=O)OC(C)(C)C)C1CCNC(C(N)=O)C1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of [(S)-1-(2-carbamoyl-pyridin-4-yl)-propyl]-carbamic acid tert-butyl ester (1 g, 3.58 mmol) in MeOH (16.6 mL) and glacial acetic acid (3.3 mL) was added to a flask containing 10% palladium on carbon (0.38 g, 0.36 mmol) under nitrogen. The reaction was stirred at 60° C. under hydrogen at 400 psi using a Biotage Endeavour Argonaut instrument. After 20 hours, the reaction was filtered and concentrated. The crude material was diluted with EtOAc (100 mL), washed with saturated sodium carbonate solution (20 mL), brine, dried over sodium sulfate, filtered and concentrated to afford [(S)-1-(2-carbamoyl-piperidin-4-yl)-propyl]carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:18])=[CH:13][CH:12]=1)[CH2:6][C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO>[C:3]([CH2:4][N:5]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:18])=[CH:15][CH:16]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:30])=[O:2]
Reactant: CCCCCCCCCCNC(=O)c1ccc(N(CC(=O)OC)CC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCNC(=O)c1ccc(N(CC(=O)O)CC(=O)O)cc1
Yield: 92.9 %

Procedure:
A solution of 1.88 g (4.47 mmol) of N-[4-[(decylamino)carbonyl]phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester and 17.9 ml (17.9 mmol) of 1N NaOH in 125 ml of methanol was kept atroom temperature for 18 hours. The solvent was removed, water was added to the residue and the pH was adjusted to 2 with 6N HCl. The precipitate was filtered and recrystallized from methanol-water to give 1.63 g (93% yield,mp 155°-157°) of N-(carboxymethyl)-N-[4-[(decylamino)carbonyl]phenyl]glycine.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([C:30]([O:32]C)=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:18]([CH2:34][CH2:35][CH3:36])[CH:17]=2)[C:13](=[O:37])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:38])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([C:30]([OH:32])=[O:31])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:18]([CH2:34][CH2:35][CH3:36])[CH:17]=2)[C:13](=[O:37])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:38])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)c(CCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(OC(C(=O)O)c2ccccc2)c(CCC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 10 %

Procedure:
To a solution the product of Example 3, Step A (11 mg; 0.22 mmol) in MeOH (2 mL) was added NaOH (1.5 eq, 2.0N) and a few drops of water. After stirring for 20 hours at room temperature, the reaction mixture was concentrated in vacuo, dissolved in water/THF, treated with HCl (5 eq) for 30 minutes at room temperature, concentrated in vacuo, and chromatographed on a Sephadex LH-20 column eluting with MeOH to afford 11 mg (99%) of the title compound.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])=[O:14].[OH-].[Na+]>CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:12]/[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[O:23][CH3:24])=[O:14])=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1ccc(C(C)=O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)/C=C/c2ccc3c(c2)OCO3)c(OC)c1
Reaction time: 2 h

Procedure:
To a stirred solution of piperonal (1 g, 6.7 mmol) and 2,4-dimethoxyacetophenone (1.21 g, 6.7 mmol) in methanol (30 ml) was added 20 equivalents of aqueous sodium hydroxide (˜11 ml, 50% w/v) and the mixture stirred for 2 h. The resultant solid was collected by filtration and then recrystallised from methanol as pale yellow crystals (0.86 g, 41%): mp 137° C.; 1H NMR δ (CDCl3) 3.9 (3H, s, OCH3), 3.92 (3H, s, OCH3), 6.01 (2H, s, CH2O), 6.50 (2H, dd, ArH), 6.80 (1H, d, ArH), 7.00 (2H, m, ArH), 7.25 (1H, d, J=15.7 Hz, ArH), 7.59 (1H, d, J=15.7 Hz, ArH), 7.70 (1H, d, ArH); 13C NMR δ 101.45, 122.35, 129.93, 148.23, 149.37, 160.29, 164.05, 190.34; Infra red νMAX (KBr)/cm−1 1659.6 (C═O); MS (rel intensity) m/z 313 ([M+H]+, 37%); Anal. Calcd (CO18H16O5): C, 69.23; H, 5.13. Found C, 68.97; H, 5.26.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[I:6][C:7]1[CH:8]=[N:9][N:10]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:13]2)[CH:11]=1.CCN(C(C)C)C(C)C.Cl>C1COCC1>[Cl:1][CH2:2][C:3]([N:18]([CH2:19][CH2:20][OH:21])[CH:15]1[CH2:14][CH2:13][CH:12]([N:10]2[CH:11]=[C:7]([I:6])[CH:8]=[N:9]2)[CH2:17][CH2:16]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: OCCNC1CCC(n2cc(I)cn2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCl)N(CCO)C1CCC(n2cc(I)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Chloro-acetyl chloride (0.25 mL; 3.14 mmol; 1.1 eq.) was added dropwise over 2 min to a solution of 2-[4-(4-Iodo-pyrazol-1-yl)-cyclohexylamino]-ethanol (intermediate 25; 1.0 g; 2.89 mmol; 1.0 eq.) and DIEA (2.00 ml; 11.45 mmol; 3.96 eq.) in THF (80.00 mL) at −30° C. The reaction solution was allowed to warm slowly to RT and stirred for 16 h. It was then poured into a 1 N HCl solution and extracted with DCM. Combined organic phases were washed with saturated NaHCO3 solution, dried over magnesium sulfate, filtrated and concentrated to give 2-Chloro-N-(2-hydroxy-ethyl)-N-[4-(4-iodo-pyrazol-1-yl)-cyclohexyl]-acetamide as a brown oil. This oil was redissolved in THF (30 mL; 370 mmol; 128 eq.) and sodium tert-butoxide (2M solution in THF; 30 mL; 60.0 mmol; 21 eq.) was added in one portion. The reaction solution was heated at 40° C. for 1 h then cooled to RT and poured into 1 N HCl solution. It was extracted with DCM (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was triturated sequentially with EtOAc and Et2O, filtered and dried to give the title compound as a yellow solid (275 mg; 21%). 1H NMR (300 MHz, DMSO) δ 7.98 (s, 1H), 7.50 (s, 1H), 4.40-4.25 (m, 1H), 4.25-4.10 (m, 1H), 4.03 (s, 2H), 3.87-3.75 (m, 2H), 3.32-3.23 (m, 2H), 2.14-1.99 (m, 2H), 1.93-1.60 (m, 6H). MS (ESI+): 376.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)#[CH:19]>CCCCCCC.CCOC(C)=O>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]#[C:19][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(C#Cc2cccnc2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid pyridin-3-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (83 mg, 80%); 1H NMR δ (CDCl3): 8.76-8.74 (m, 1H), 8.50-8.53 (m, 1H), 7.76-7.73 (m, 1H), 7.49-8.46 (m, 2H), 7.24-7.20 (m, 1H), 6.88-6.85 (m, 2H), 3.78 (s, 3H); LCMS m/z: 209.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[I:11]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[C:10]([I:11])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1cc2ccccn2n1
Solvent: CC#N
Product: Clc1nn2ccccc2c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-pyrazolo[1,5-a]pyridine (0.500 g, 3.28 mmol) in acetonitrile (16.4 mL) was added N-iodosuccinimide (0.885 g, 3.93 mmol). The resulting mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The resulting residue was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-15% ethyl acetate in hexanes) provided the title compound. LCMS m/z 278.72 [M+H]+, 280.64 [M+2+H]+, 1H NMR (500 MHz, CDCl3) 8.35 (d, J=6.8 Hz, 1 H), 7.38 (d, J=9.0 Hz, 1H), 7.24 (d, J=8.6 Hz, 1 H), 6.84-6.81 (m, 1 H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH2:15][CH3:16])=[C:6]1[CH3:17])[CH:2]=[CH:3][CH3:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:24][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH2:15][CH3:16])=[C:6]1[CH3:17])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(CC)c2cnnc(Cl)c21
Reactant: OCc1ccc(F)cc1
Product: CC=CCn1c(C)c(CC)c2cnnc(OCc3ccc(F)cc3)c21
Yield: 63.1 %

Procedure:
The title compound (cis/trans=22/78) was prepared as a white powder in 63.1% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-3-ethyl-2-methylpyrrolo[2,3-d]pyridazine (cis/trans=26/74) and 4-fluorobenzyl alcohol.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH:19]=[CH2:20]>C(O)(C)(C)C.CO>[C:8]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:20][CH2:19][C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])#[N:9]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CO
Product: CC(C)(C)OC(=O)CCC(C#N)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A suspension of diphenylacetonitrile (38.6 g, 200 mmol) in tert-butanol (200 ml) was warmed to 60° C. for 30 minutes. The resulting solution was cooled to 50° C. and a solution of potassium hydroxide (0.6 g, 10.69 mmol) in methanol (2 mL) was added. tert-Butyl acrylate (30 mL, 200 mmol) was then added dropwise and the mixture was stirred at 50° C. for 2 hours and at room temperature for 18 hours. Further potassium hydroxide (0.6 g, 10.69 mmol) was added and the mixture was re-warmed to 50° C. for 3 hours. The reaction mixture was then concentrated in vacuo and the residue was diluted with diethyl ether (300 mL), washed with water (200 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid in 90% yield, 57.95 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([CH3:15])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([N:28]3[CH2:29][CH2:30][N:31]([CH:13]([CH3:15])[CH2:12][C:8]4[C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=5[O:10][CH:9]=4)[CH2:32][CH2:33]3)[CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2
Reactant: COc1cccc2c(CC(C)=O)coc12
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(N2CCN(C(C)Cc3coc4c(OC)cccc34)CC2)c2ncccc2c1

Procedure:
6-methoxy-8-{4-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl)piperazin-1-yl]quinoline was prepared by generally following the procedure outlined in example 35, step 2, starting from the 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-methoxy-8-piperazino quinoline (243.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown semi-solid. Yield: 75 mg (17%); (M+H): 432.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[S:58][CH:59]=[CH:60][CH:61]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[S:58][CH:59]=[CH:60][CH:61]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C=Nc1cccs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccs1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 20 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-isocyanatothiophene as the starting materials in 20% yield. LCMS for C29H31ClN7O2S (M+H)+: m/z=576.0.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[NH2:10])=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)N(N)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 64 h

Procedure:
A quantity (25.0 g.; 0.14 mole) of (4-chlorophenyl)-hydrazine hydrochloride was suspended in 150 ml. of pyridine. The suspension was cooled to 0° C. and 16.9 g. (0.14 mole) of pivaloyl chloride was added with stirring. The reaction mixture was set aside at about 25° C. for 64 hrs. when 300 ml. of water was added. The precipitate that formed was collected on a filter and washed repeatedly with water, 1 N hydrochloric acid, and finally with water. The filter cake was dried under reduced pressure and 60° C. to remove water. After two recrystallizations from benzene and technical hexane there was thus obtained 24.1 g. of pivalic acid (4-chlorophenyl)hydrazide having a melting point of 137° to 138° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[C:19]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>C(Cl)Cl>[Cl:13][C:14]1[C:19]([S:20]([NH:23][C:24]([NH:1][C:2]2[N:11]=[C:10]([CH3:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[O:25])(=[O:21])=[O:22])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=C=NS(=O)(=O)c1cccnc1Cl
Reactant: Cc1nc(N)nc2ccccc12
Solvent: ClCCl
Product: Cc1nc(NC(=O)NS(=O)(=O)c2cccnc2Cl)nc2ccccc12

Procedure:
To a dry, stirred solution of 8.0 g of 2-amino-4-methylquinazoline in 200 ml of methylene chloride at ambient temperature and pressure is added 13 g of 2-chloropyridin-3-sulfonylisocyanate. The resulting mixture is stirred at reflux for 2 hours and then concentrated at reduced pressure. The residue is triturated with 1-chlorobutane and filtered to yield the desired solid product.