Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:14]=1)[NH:11][C:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:9]2)=[O:5])C.O.[OH-].[Na+]>CO>[CH:16]1([NH:15][C:13]2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]3[C:12]=2[NH:11][C:10]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:9]3)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cc(NC2CCCC2)c2[nH]c(-c3ccccc3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(NC2CCCC2)c2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7-(Cyclopentyl)amino-2-phenyl-1H-indole-5-carboxylic acid ethyl ester (5 g, 14.3 mmol) prepared in Example 28 was added to a solvent mixture of MeOH (20 mL) and water (20 mL). NaOH (1.3 g, 33.8 mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, MeOH was removed under reduced pressure, and 1N HCl was added to the residue. The resulting mixture was extracted with EtOAc, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was recrystallized from EtOAc and n-Hex to give the title compound.
Reaction SMILES: [Li]CCCC.[CH2:6]([N:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>C1COCC1>[CH2:20]([N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@@H:14]([C:27](=[O:30])[CH2:28][CH3:29])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: CCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C(=O)CC)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
In a round bottomed flask, at −78° C., under argon atmosphere, a solution of DIPA (0.3 mL, 2.12 mmol) in dry THF (10 ml) was treated with n-BuLi (2.5 M in n-hexane, 0.776 mL, 1.94 mmol). After 30 min a solution of ethyl 2-(dibenzylamino)-acetate (0.5 g, 1.77 mmol) in dry THF (10 ml) was added dropwise via a cannula. After 15 min, propanoyl chloride (0.46 mL, 5.29 mmol) was added dropwise at −78° C. and the mixture stirred for 10 min at rt. The reaction was then quenched with H2O, and Et2O was subsequently added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (98:2) gave a pure compound (0.6 g), as a mixture of two tautomers (ketone:enol=ca. 85:15), as a colorless oil. MS (ESI) m/z: 340 [M−H]+; (ESI) m/z: 338 [M−H]−. 1H NMR (DMSO-d6) δ 0.90 (t, J=7.24 Hz, 3H), 1.23 (t, J=7.07 Hz, 3H), 2.53-2.61 (m, 1H), 2.69 (dq, J=7.23, 18.13 Hz, 1H), 3.72-3.88 (m, 4H), 4.12-4.22 (m, 3H), 7.11-7.47 (m, 10H) (reported data refer to the major ketone tautomer).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12]O)[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CN1CCCc2ccc(CO)cc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(Cc2ccc3c(c2)N(C)CCC3)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred, cooled (0° C.) solution of (1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)methanol (200 mg, 0.733 mmol), ethyl 1H-pyrazole-4-carboxylate (103 mg, 0.733 mmol) and triphenylphosphine (289 mg, 1.100 mmol) in THF (10 ml) was added dropwise a 40% solution of DEAD in toluene (0.435 ml, 1.1 mmol). The reaction mixture was stirred for 2 h at 0° C., then over night at 20° C. Saturated aqueous NaHCO3 was added and the mixture was extracted with AcOEt. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound. The crude product was purified by preparative HPLC (Waters SunFire Prep C18 OBD 5 μm 30*100, Flow 40 mL/min, ACN: 2 min at 5%, then to 100% within 17.5 min, RT 10.00 min) to give the title compound. HPLC (Method H) Rt=2.919 min; MS (Method A) [M+H]+=300.0
Reaction SMILES: [CH:1]1=[CH:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10]1.[CH:11]1C=CC=C[CH:12]=1>[W](Cl)(Cl)(Cl)(Cl)(Cl)Cl>[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:12][CH:11]=1
Reactant: C1=CCCCCC=CCC1
Reactant: c1ccccc1
Agent: Cl[W](Cl)(Cl)(Cl)(Cl)Cl
Agent: C1=C\CCCC/C=C/CC/1
Product: C1=CCCCCCCCCCC1

Procedure:
Using the mode of operation set forth in Example 1--except for Experiment 31, wherein 15 ml. of monomer was employed--30 ml. (158 mmol.) of cyclododecene (mixture of isomers with 70.3% trans- and 29.7% cis-cyclododecene) was polymerized with a catalyst of varying amounts of cis,trans-1,5-cyclodecadiene and 1.5 ml. of a 0.1-molar solution of tungsten hexachloride in benzene. The results of Comparative Experiment B, as well as Experiments 31-38, are indicated in Table V.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16].Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([N:13]2[CH2:14][CH2:15][N:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:12]2=[O:16])[CH:19]=[N:20][CH:21]=1
Reactant: COc1cncc(Br)c1
Reactant: O=C1NCCN1c1ccc2ccccc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cncc(N2CCN(c3ccc4ccccc4c3)C2=O)c1
Yield: 28.3 %

Procedure:
Using the same reaction conditions as in Example 79, 1-naphthalen-2-yl-imidazolidin-2-one (I-79b: 112.7 mg, 0.5319 mmol) was reacted with 3-bromo-5-methoxy-pyridine (100 mg, 0.5319 mmol), 1,4-dioxane (5 mL), copper iodide (10.13 mg, 0.05319 mmol), trans-1,2-diamino cyclohexane (18.27 mg, 0.1595 mmol) and potassium carbonate (147.07 mg, 1.0638 mmol) to afford the crude product. Purification by column chromatography on silica gel (30% EtOAc in hexane) afforded 48 mg of the product (30.3% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][CH:5]([C:8]2[S:26][C:11]3[N:12]=[C:13]([CH3:25])[N:14]=[C:15]([CH2:16][N:17]4[CH2:22][CH2:21][NH:20][CH2:19][C:18]4([CH3:24])[CH3:23])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[C:28](O)(=[O:31])[CH2:29][OH:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN1C(=O)CCC1>[CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][CH:5]([C:8]2[S:26][C:11]3[N:12]=[C:13]([CH3:25])[N:14]=[C:15]([CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:29](=[O:30])[CH2:28][OH:31])[CH2:19][C:18]4([CH3:23])[CH3:24])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1nc(CN2CCNCC2(C)C)c2cc(C3CCC(C)(C)CC3)sc2n1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(CN2CCN(C(=O)CO)CC2(C)C)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
To a mixture of 6-(4,4-dimethylcyclohexyl)-4-[(2,2-dimethylpiperazin-1-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (222 mg), glycolic acid (52 mg), and NMP (3.2 mL) were added HATU (306 mg) and DIPEA (492 μL), followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous NH4Cl solution, followed by extraction with EtOAc. The organic layer was washed sequentially with water and brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column to obtain 1-(4-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-3,3-dimethylpiperazin-1-yl)-2-hydroxyethanone (102 mg).
Reaction SMILES: [CH3:1][N:2]1CCCC1=O.Br[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:25])[N:16]2[CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)=[N:11][CH:10]=1.[Cu](C#N)C#N>C(OCC)(=O)C>[C:1]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:25])[N:16]2[CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)=[N:11][CH:10]=1)#[N:2]
Reactant: CN1CCCC1=O
Reactant: O=c1ccc2ncc(Br)cc2n1CC1OCCO1
Agent: N#C[Cu]C#N
Solvent: CCOC(C)=O
Product: N#Cc1cnc2ccc(=O)n(CC3OCCO3)c2c1
Temperature: 25 °C

Procedure:
To 10 mL of 1-methyl-2-pyrrolidinone, 358 mg of 7-bromo-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one and 183 mg of copper cyanide were suspended, and the suspension was heated under reflux for 70 minutes. The reaction mixture was cooled to room temperature, ethyl acetate was then added thereto, the mixture was washed sequentially with water and a saturated saline water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60 made by KANTO CHEMICAL CO., INC., and an eluent of ethyl acetate:hexane 1:1 to obtain 145 mg of 7-cyano-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[N:10]([CH3:30])[CH:11]=[C:12]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[N:15]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CCN(C(C)C)C(C)C>[CH3:30][N:10]1[CH:11]=[C:12]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[N:15]=2)[N:13]=[C:9]1[CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)[CH:7]=1
Reactant: CN1CCNCC1
Reactant: Cn1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nc1Cc1ccnc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(Cc3nc(-c4nc(-c5ccc(OC(F)(F)F)cc5)no4)cn3C)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 12.8 %

Procedure:
A solution of 5-(2-((2-chloropyridin-4-yl)methyl)-1-methyl-1H-imidazol-4-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (60 mg, 0.138 mmol) and 1-methylpiperazine (2 mL) in DIPEA (2 mL) was stirred at 150° C. for 5 h. After cooled to RT, the mixture was quenched by water (5 mL), and extracted with EtOAc (2×10 mL). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried (Na2SO4), filtered, and concentrated to afford the crude product, which was purified with prep-HPLC (Mobile phase:A=0.01% formic acid/water, B=acetonitrile; Gradient: B=36%-95% in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to give 5-(1-methyl-2-((2-(4-methylpiperazin-1-yl)pyridin-4-yl)methyl)-1H-imidazol-4-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (8.8 mg, 12.8%). MS (ES+) C24H24F3N7O2 requires: 499, found: 500 [M+H]+; 1H-NMR (500 MHz, CDCl3) δ ppm 8.20 (d, J=7.5 Hz, 2H), 8.14 (d, J=5.0 Hz, 1H), 7.63 (t, 1H), 7.32 (d, J=4 Hz, 2H), 6.58 (d, J=5 Hz, 1H), 6.47 (s, 1H), 4.53 (s, 2H), 3.79-3.74 (m, 2H), 3.63-3.58 (m, 2H), 3.56 (s, 3H), 3.29-3.25 (m, 2H), 2.92-2.87 (m, 2H), 2.79 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]([CH3:31])[CH:16]2[CH2:30][CH:19]3[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:15]([CH3:31])[CH:16]2[CH2:30][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of tert-butyl 5-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(methyl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (217.4 mg, 0.48 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then the resulting mixture was extracted with DCM (200 mL×3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a beige solid (100.3 mg, 59.4%).
Reaction SMILES: [F-].[K+].[C:3]([C:5]([C:27]#[N:28])=[C:6]1[C:10]([C:11]#[N:12])=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][CH:14]=2)[C:8]([CH3:26])([CH3:25])[O:7]1)#[N:4].O>C1COCC1.CO>[C:11]([C:10]1[C:6](=[C:5]([C:3]#[N:4])[C:27]#[N:28])[O:7][C:8]([CH3:26])([CH3:25])[C:9]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)#[N:12]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(C#C[Si](C)(C)C)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#Cc1ccc(C2=C(C#N)C(=C(C#N)C#N)OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(RS01039) Potassium fluoride (260 mg, 4.5 mmol) was added to a solution of 2-dicyanomethylene-3-cyano-5,5-dimethyl-4-(4′-trimethylsilylethynylphenyl)-2,5-dihydrofuran (500 mg, 1.4 mmol) in degassed THF/methanol (1.5:1, 40 mL). The reaction mixture was stirred for 24 h at room temperature, poured into water, stirred for 1 hr, kept in the refrigerator overnight, filtered and air-dried. The product was recrystallized from dichloromethane/1-propanol. Yield: 330 mg. (90%). mp: 225° C. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 3.36 (s, 1H), 1.81 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 176.24, 174.31, 133.32, 128.00, 126.93, 110.98, 110.06, 109.97, 102.50, 99.08, 82.29, 81.71, 26.13. IR (neat, cm−1 2965, 2226, 1623, 1614, 1534.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH2:18][CH:11]2[CH2:12][C:13](=[O:19])[CH2:14]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH:20](OCC)=[O:21].[O-]CC.[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:11]3[CH2:18][CH2:17][CH2:16][CH:15]2[C:14](=[CH:20][OH:21])[C:13](=[O:19])[CH2:12]3)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)s1
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)s1
Temperature: 60 °C

Procedure:
To a stirring mixture of 9-(5-chloro-thiophene-2-sulfonyl)-9-aza-bicyclo[3.3.1]nonan-3-one (160 mg, 0.50 mmol) in THF/ethanol (3 mL, 1/1, v/v) was added ethyl formate (500 mg, 6.76 mmol) followed by sodium ethoxide (0.56 mL of 21% solution in ethanol). The resulting mixture was heated to 60° C. for 30 minutes after which the solution was cooled to room temperature and quenched by the addition of a saturated aqueous NH4Cl solution (10 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to yield 9-(5-chloro-thiophene-2-sulfonyl)-2-hydroxymethylene-9-aza-bicyclo[3.3.1]nonan-3-one as a white solid. This crude product was directly taken to the next reaction without any further purification. Retention time (min)=1.985 min, Method [1], MS (ESI) 348.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CCN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Solvent: CCCCO
Product: CCN1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)CC1

Procedure:
Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 93 μL of 1-ethylpiperazine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-ethylpiperazin-1-yl)nicotinamide. MS (Q1) 422.0 (M)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([Cl:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([Cl:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(=O)O)cc1Cl
Yield: 97.5 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (0.40 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 1 hr. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the precipitated crystals were collected by filtration to give 1-benzyl-3-[(3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (0.37 g, yield 97%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 191-192° C.
Reaction SMILES: [OH:1][CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:5](=[O:13])[C:4]2[S:14][CH2:15][CH2:16][S:17][C:3]1=2.[H-].[Na+].Cl[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22]>O1CCCC1>[CH3:29][N:26]1[CH2:27][CH2:28][N:23]([C:21]([O:13][CH:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:2](=[O:1])[C:3]3[S:17][CH2:16][CH2:15][S:14][C:4]2=3)=[O:22])[CH2:24][CH2:25]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccccn2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
A solution of 5-hydroxy-7-oxo-6-(pyrid-2-yl)-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (6.0 g.) in anhydrous tetrahydrofuran (60 cc.) is treated for 17 minutes at about 5°-10° C, with sodium hydride (0.64 g.), and a solution of 1-chlorocarbonyl-4-methylpiperazine (11.0 g.) in anhydrous tetrahydrofuran (80 cc.) is then added, at 5° C. The reaction mixture is stirred for 4 hours at 5° C. After evaporating the solvent under reduced pressure (20 mm.Hg), the residue is dissolved in diethyl ether (300 cc.). The diethyl ether solution is washed three times with N sodium hydroxide solution (total 450 cc.) and then three times with distilled water (total 300 cc.), treated with vegetable charcoal (0.1 g.), dried over anhydrous potassium carbonate, filtered and evaporated. The residue (7.6 g.; m.p. 145° C.) is dissolved in boiling ethanol (20 cc.). After being cooled for 2 hours at 2° C, the crystals which have appeared are filtered off, washed twice with ice-cold ethanol (total 12 cc.) and dried under reduced pressure (20 mm.Hg). 5-(4-Methylpiperazin-1-yl)carbonyloxy-7-oxo-6-(pyrid-2-yl)-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (3.9 g.), melting at 150° C, is thus obtained.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])(O)[C:5]1=[CH2:11])([CH3:3])=[CH2:2].C[O:13][C:14]([CH3:16])=[CH2:15]>P(=O)(O)(O)O>[C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])=[C:5]1[CH2:11][CH2:15][C:14](=[O:13])[CH3:16])([CH3:3])=[CH2:2]
Reactant: C=C(C)C1CCC(C)(O)C1=C
Reactant: C=C(C)OC
Agent: O=P(O)(O)O
Product: C=C(C)C1CCC(C)=C1CCC(C)=O
Yield: 60.4 %

Procedure:
15 drops of 85% phosphoric acid were added to a mixture, cooled in a laboratory autoclave, of 76 g of 3-isopropenyl-1-methyl-2-methylene-cyclopentan-1-ol and 120 g of isopropenyl methyl ether. After gassing with nitrogen, the autoclave was brought, in an oil bath of 180° C, to an internal temperature of 150° C and held at this temperature until a distinct drop in pressure occurred (about 50-75 minutes). The reaction mixture was quenched by intensive cooling, treated with solid potassium hydroxide and concentrated under reduced pressure on a rotary evaporator. By fractional distillation over solid potassium hydroxide there were obtained 58 g (60%) of 3-isopropenyl-1-methyl-2-(3-oxobutyl)-cyclopent-1-ene; boiling point 0.01 = 69°-72° C; ND20 = 1.4836. The compound has a woody, camphoraceous, ionone-like fragrance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].C(OC(CC1C2SC=CC=2C(O[CH2:40][CH2:41][C:42]2[N:43]=[C:44]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[O:55][CH2:56][CH3:57])[O:45][C:46]=2[CH3:47])=CC=1)C(O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:40][CH2:41][C:42]2[N:43]=[C:44]([C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=3[O:55][CH2:56][CH3:57])[O:45][C:46]=2[CH3:47])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOc1cc(F)ccc1-c1nc(CCOc2ccc(CC(OCC)C(=O)O)c3sccc23)c(C)o1
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(F)cc3OCC)oc2C)c2c1CCCC2)OCC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 108 b]) was reacted with 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (example 95) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid as colorless solid.