Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][C:15]=2[CH3:25])=[CH:10][CH:9]=1.C(O)C.Cl>O.O1CCOCC1>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][C:15]=2[CH3:25])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCO)cc2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Lithium hydroxide monohydrate (0.19 g) was added to a mixture of ethyl 4′-(2-hydroxyethoxy)-2-methylbiphenyl-4-carboxylate (0.136 g), ethanol (2 mL), 1,4-dioxane (2 mL) and water (1 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (2.3 mL). The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the residue. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethylacetate/n-hexane=2/1-4/1) to afford the title compound (0.066 g).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4](C(OC)=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>[OH-].[K+]>[C:19]([OH:21])(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2]
Reactant: COC(=O)C(CCCCCCCCCCCCCCC(=O)O)C(=O)OC
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CCCCCCCCCCCCCCCC(=O)O
Temperature: 140 °C
Reaction time: 2 h

Procedure:
2-Methoxycarbonyl-heptadecanedioic acid 1-methyl ester (4.63, 12.4 mmol g) was dissolved in 20% aqueous KOH (15 ml) by heating. The resulting solution was refluxed for 2.5 h. The cold reaction mixture was carefully concentrated. The residue was suspended in water (30 ml) on an ice bath and acidified with 10% aqueous HCI. The resulting slurry was refluxed for 2 h. After cooling the precipitate was isolated by filtration and dried over night in vacuo. The compound was decarboxylated by heating under stirring at 140° C. for 2 h. (the reaction should be followed, heating to 180° might be necessary). The crude product (4.0 g, 100%) was used without further purification. HPLC-MS: 323 (M+Na), R14.61. 1H-NMR (DMSO-d6): δ 1.22 (br s, 22H) 1.47 (m, 4H), 2.18 (t, 4H).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:11].Cl.Cl.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:31].[ClH:11].[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:23][CH2:22]2)=[CH:26][CH:27]=1
Reactant: O=C=NCc1ccccc1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)NCc1ccccc1
Yield: 154.1 %

Procedure:
The procedure described in Example 21 was followed, using benzyl isocyanate (1.33 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (250 ml) and triethylamine (4.3 ml; 31 mmole) to provide the title compound (3.65 g; 77% yield) as colorless crystals, m.p. 203°-206° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[OH:29][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH2:4][CH2:3][CH2:2][N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]4[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=4[C:12]=3[C:11]=2[CH:10]=1
Reactant: c1c[nH]cn1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCBr
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCn1ccnc1
Yield: 53 %

Procedure:
Bromide (204) (80 mg, 0.18 mmol) prepared as described in example 173 was reacted with imidazole according to the procedure described in example 179 to give amine (212) (41 mg, 53%) as a yellow powder, mp 309–311° C. 1H NMR δ [(CD3)2SO] 11.06 (s, 1H), 9.36 (s, 1H), 8.40 (d, J=2.3 Hz, 1H), 7.69 (s, 1H), 7.64 (m, 3H), 7.47 (m, 4H), 7.22 (s, 1H), 7.14 (dd, J=8.8, 2.3 Hz, 1H), 6.89 (s, 1H), 4.44 (t, J=7.4 Hz, 2H), 4.07 (t, J=7.3 Hz, 2H), 2.24 (m, 2H). Found: C, 70.31; H, 4.78; N, 12.43. C26H20N4O3.1/2H2O requires: C, 70.10; H, 4.75; N, 12.57.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18]CC)=[O:17])[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=[O:17])[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(Br)nc2c1c(CC)nn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nn(C(C)C)c2nc(Br)cc(C(=O)O)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of ethyl 6-bromo-3-ethyl-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.4 g, 1.176 mmol) in EtOH (7 mL), aqueous NaOH (0.062 g, 1.529 mmol in 1 mL water) was added and reaction mixture stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 2N HCl and 10% citric acid solution. Solid obtained was filtered and azeotrope it with toluene to give the desired compound (0.3 g, 81.7%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:15]2[CH:16]=[C:12]([N+:9]([O-:11])=[O:10])[N:13]=[CH:14]2)[CH:7]=1
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: Cc1ccnc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(-n2cnc([N+](=O)[O-])c2)c1
Temperature: 130 °C
Reaction time: 21 h
Yield: 34.2 %

Procedure:
A suspension of 2-fluoro-4-methylpyridine (1.11 g), 4-nitroimidazole (1.24 g) and potassium carbonate (1.65 g) in N,N-dimethylformamide (10 ml) was stirred at 130° C. for 21 hours. After cooling, the mixture was poured into water and stirred for 30 minutes. The precipitate was collected by filtration and dried to give 1-(4-methylpyridin-2-yl)-4-nitroimidazole (698 mg).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][O:27]5)[CH:20]=4)[C:15]3=[O:31])=[CH:10][C:9]=2[O:32][CH3:33])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[CH3:33][O:32][C:9]1[CH:10]=[C:11]([N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][O:27]4)[CH:20]=3)[C:15]2=[O:31])[CH:12]=[CH:13][C:8]=1[N:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH:37]2[CH2:38][CH2:39][O:34][CH2:35][CH2:36]2)[CH2:3][CH2:2]1
Reactant: O=C1CCOCC1
Reactant: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCNCC1
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCN(C2CCOCC2)CC1

Procedure:
Reaction of 2-(4-[1,4]Diazepan-1-yl-3-methoxy-phenyl)-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-2H-isoquinolin-1-one with Tetrahydro-pyran-4-one by method J resulted in the desired product with the molecular weight 533.67 (C31H39N3O5); MS (ESI): 534 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[C:4]([Cl:11])[CH:3]=1.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:9])=[C:4]([Cl:11])[CH:3]=1
Reactant: Oc1ccccc1
Reactant: CC(O)c1ccc(Br)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccccc1)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1-(4-bromo-2-chlorophenyl)ethanol (1.32 g, 5.6 mmol), phenol (525 mg, 5.6 mmol) and triphenylphosphine (2198 mg, 8.4 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 0.5 hour. Diisopropyl azodicarboxylate (1695 mg, 8.4 mmol) was dropwise to the reaction mixture and was stirred at room temperature for 12 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=5:1) to give 4-bromo-2-chloro-1-(1-phenoxyethyl)benzene as a colorless oil (882 mg 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]=[C:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.Cl.[BH4-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)=[N:10][NH:9][CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: CC1Cc2cc(Cl)ccc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
1.5 g (4.78 mmoles) of the benzodiazepine derivative prepared in Step C are suspended in 60 ml of methanol, and to the suspension obtained, 4.64 g (57.3 mmoles) of concentrated hydrochloric acid are added, then, under cold water cooling, 2.07 g (54.8 mmoles) of sodium borohydride are added in portions. The suspension is stirred at 25° C. for 1 hour, then solid sodium carbonate is added to adjust the pH of the mixture to a value of about 8. The mixture is diluted with 60 ml of water, the product separated is filtered, washed 4 times using 5 ml of 50% aqueous methanol each time, and dried to obtain 1.47 g (97.4%) of the title compound. M.p.: 152°-154° C.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[CH3:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=1)=[O:32].[Cl-].[NH4+]>O1CCCC1>[CH3:3][C:2]([CH3:4])=[CH:39][C:36]1[CH:37]=[CH:38][C:33]([C:31]([O:30][CH3:29])=[O:32])=[CH:34][CH:35]=1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=C(C)C)cc1
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
To a suspension of isopropyltriphenylphosphonium iodide (9.5 g) in tetrahydrofuran (90 mL) was added n-butyllithium (1.5 mol/L hexane solution, 15 mL) at 0° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added a solution of methyl terephthalaldehydate (3.3 g) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: hexane/ethylacetate=3/1) and then by column chromatography on silica gel (eluent: dichloromethane/ethyl acetate=10/1)to give methyl 4-(2-methylprop-1-en-1-yl)benzoate (3.4 g). To a suspension of lithium aluminum hydride (0.68 g) in diethyl ether (120 mL) was added a solution of methyl 4-(2-methylprop-1-en-1-yl)benzoate (3.4 g) in diethyl ether (30 mL) at 0° C., and the mixture was heated under reflux for 50 minutes. After the reaction mixture was cooled to 0° C., water (0.69 mL), 15% aqueous sodium hydroxide solution (0.69 mL) and water (2 mL) were added, and the mixture was stirred at room temperature for 30 minutes. Insoluble materials were removed by filtrate, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1-2/1) to give 4-(2-methylprop-1-en-1-yl)benzyl alcohol (2.8 g).
Reaction SMILES: [C:1]([CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[NH:13][C:12]=1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=[O:8])([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[NH:13][C:12]=1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=[O:8])([OH:3])=[O:2]
Reactant: COC(=O)CCC(=O)NCc1cc(-c2cccs2)[nH]c1-c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC(=O)NCc1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
A mixture of compound XXVI (200 mg, 0.53 mmol), 0.6N aqueous sodium hydroxide (1.34 ml, 0.80 mmol) and 4 ml of methyl alcohol was stirred at room temperature for 16 hours. The reaction mixture was poured onto 15 ml of ice water and was washed with diethyl ether. The aqueous layer was acidified with 1N aqueous hydrochloric acid to pH 4.0, then saturated with sodium chloride. The saturated solution then was extracted four times with 5 ml portions of ethyl acetate. The combined organic extracts were washed with the 5 ml portions of water, dried over anhydrous magnesium sulfate, then filtered. Evaporation of solvent in vacuo gave a crude acid that was then purified on 20 g of silica gel. Elution with ethyl acetate:acetic acid, 95:5, provided 121 mg (63%) of acid (XXVII), having Rf :0.28 (ethyl acetate:acetic acid, 95:5).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[C:13]([NH:23][S:24]([C:27]2([CH2:30][CH:31]=[O:32])[CH2:29][CH2:28]2)(=[O:26])=[O:25])=[C:14]2[O:22][CH2:21][CH2:20][N:15]2[C:16](=[O:19])[C:17]=1[CH3:18]>C1COCC1.CO.C(Cl)Cl>[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[C:13]([NH:23][S:24]([C:27]2([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28]2)(=[O:26])=[O:25])=[C:14]2[O:22][CH2:21][CH2:20][N:15]2[C:16](=[O:19])[C:17]=1[CH3:18]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CC=O)CC2)c2n(c1=O)CCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CCO)CC2)c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
Sodium borohydride (0.1 g, 2.6 mmol) was added to a stirred solution of 1-(2-Oxo-ethyl)-cyclopropanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-8-yl]-amide (0.12 g, 0.21 mmol) in THF (5 mL) and MeOH (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mixture was concentrated under reduced pressure and partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over Na2SO4, filtered and the filtrate was concentrated. Purification by column chromatography on silica gel (2-4% MeOH in DCM) afforded 70 mg of the product (58% yield).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[C:7](O)=[O:8])(=[O:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[C:7]([Cl:30])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)SCC(Cc1ccc(-c2ccccc2)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 3-acetylthio-2-(4-phenylbenzyl)propionic acid (3.39 g, 10.8 mmole) in toluene (25 ml) add 1% DMF in toluene (2 drops) and thionyl chloride (1.2 ml, 1.65 g, 13.8 mmoles) and stir the resulting solution at room temperature for 18 hours. Concentrate the reaction mixture in vacuo, dissolve the residue in toluene (100 ml) and concentrate the solution in vacuo to give the title compound, a light brown oil (3.37 g).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[N:14]3[N:15]=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:17]=[C:18]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:31][NH2:32]>C(O)CCC>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([C:10]3[N:14]4[N:15]=[C:16]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:17]=[C:18]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]4=[N:12][CH:11]=3)=[CH:7][CH:6]=2)[NH:32][N:31]=1
Reactant: CC(C)CNc1cc(-c2ccccc2)nn2c(-c3ccc(C#N)c(F)c3)cnc12
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CC(C)CNc1cc(-c2ccccc2)nn2c(-c3ccc4c(N)n[nH]c4c3)cnc12
Temperature: 120 °C
Yield: 53 %

Procedure:
To a solution of 46 mg (119 μmol) 2-fluoro-4-[8-(isobutylamino)-6-phenylimidazo[1,2-b]pyridazin-3-yl]benzonitrile which was prepared according to intermediate example 11a in 2.5 mL n-butanol were added 232 μL hydrazine hydrate and the mixture was heated at 120° C. overnight. The precipitate was filtered, washed with 2-propanol and dried to give 26.5 mg (53%) of the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.Cl[CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][O:32]C1=O.[OH-].[Na+].Cl>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:28][CH2:29][NH:30][CH2:34][CH2:33][OH:32])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: O=C1OCCN1CCCl
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCN(CCNCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.26 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrochloride and 46 mg (0.31 mmol) of 3-(2-chloroethyl)oxazolidin-2-one. The protecting group was cleaved off using a 1N sodium hydroxide solution. The product is in the form of the hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[CH3:24][C:25]1([CH3:35])[S:30][CH2:29][CH2:28][NH:27][C@H:26]1[C:31]([O:33][CH3:34])=[O:32].CN1CCOCC1>C(Cl)(Cl)Cl.C(OCC)(=O)C.CO>[CH3:34][O:33][C:31]([CH:26]1[C:25]([CH3:35])([CH3:24])[S:30][CH2:29][CH2:28][N:27]1[S:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])=[O:32]
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Reactant: COC(=O)[C@@H]1NCCSC1(C)C
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN1CCOCC1
Product: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of 0.5 g (2.6 mmol) of 4-hydroxybenzenesulfonyl chloride (J. Org. Chem. 1973, 38, 1047) in 5 mL of chloroform at room temperature was added 0.706 mL (2.86 mmol) of N,O-bis(trimethylsilyl)acetamide. The reaction mixture was stirred for 1 h and added a solution of 0.41 g (2.16 mmol) of methyl(3S)-2,2-dimethyl-3-thiomorpholinecarboxylate in 1 mL of chloroform in one portion, followed by 0.48 mL (4.37 mmol) of N-methylmorpholine. The resulting mixture was stirred for 18 h and 10 mL of methanol was added and the resulting mixture was heated to reflux for 1 h. The reaction was diluted with ethyl acetate, washed with water, 5% HCl and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether:hexanes (1:2) to provide 0.62 g (83%) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester as a pale yellow solid. Electrospray Mass Spec: 344.4 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]=O)=[CH:6][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:42](Br)([F:44])[F:43]>ClCCl>[C:1]([C:3]1[C:7]([CH:8]=[C:42]([F:44])[F:43])=[CH:6][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=O
Reactant: FC(F)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=C(F)F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-formylpyrazole (1.3 g), triphenylphosphine (5.1 g), dibromodifluoromethane (2 g) and dichloromethane (50 ml) were placed in a stainless steel bomb and heated and stirred at 70° C. for 3 hours. The reaction mixtiure was evaporated and the residue was purified by column chromatography on silica gel eluting with dichloromethane: hexane (9:1). Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 75-77° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(=NC1CCCCC1)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:26]([CH:29]([CH3:31])[CH3:30])C=O)=[CH:21][CH:20]=1.[O:39]1C[CH2:42][CH2:41][CH2:40]1>>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[C:26]([CH:29]([CH3:31])[CH3:30])[CH:42]=[CH:41][CH:40]=[O:39])=[CH:37][CH:36]=1
Reactant: C1CCOC1
Reactant: CC(C)C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Product: CC(C)C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide (9 mL of 1.8M solution, 15 mmol) was added to N-ethylidenecyclohexanamine (7.5 mL of 2M solution, 15 mmol) in tetrahydrofuran at -40° C. After stirring for 30 minutes and cooling to -70° C., 3,3-bis(4-fluorophenyl)-2-(1-methylethyl)propenal (1.43 g, 5.0 mmol) was added. The reaction was stirred -70° for 1.5 hrs. and quenched with 2N hydrochloric acid. The mixture was extracted with diethyl ether and the extracts concentrated in vacuo. The residue was stirred for 64 hours with a mixture of 50 mL of benzene, 35 mL acetic acid and 15 mL of water. The layers were separated and the aqueous layer extracted with diethyl ether. The combined organic solution was washed with saturated sodium bicarbonate solution, water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 1% ethyl acetate in hexane and the material obtained crystallized from hexane to give 0.55 g of the title compound as a yellow solid; m.p. =105°-107° C.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7](OC2CCC(=O)C=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[CH3:23][NH:24][C:25]1[CH2:29][CH2:28][C:27](=[O:30])[CH:26]=1.[H-].[Na+]>CS(C)=O>[OH:1][C@H:2]1[C@H:7]([N:24]([CH3:23])[C:25]2[CH2:29][CH2:28][C:27](=[O:30])[CH:26]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)CC2)[C@@H]1O
Reactant: CNC1=CC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C1=CC(=O)CC1)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
4.02 g of the epoxide of example 1 are reacted analogously to example 5 with 2.44 g N-methyl-3-amino-cyclopent-2-en-1-on and 660 mg of sodium hydride (80%) in dimethylsulfoxide. Usual working up yields crystalls of the title compound having a m.p. of 271°-74° C.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].C(=O)(O)O.[OH:14][CH2:15][CH:16]([CH2:18][OH:19])[OH:17].C(=O)([O-])[O-].[K+].[K+]>>[C:15]([O:3][C:2]1[C:1]([O:8][CH3:9])=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:14])[CH:16]([CH2:18][OH:19])[OH:17]
Reactant: OCC(O)CO
Reactant: COc1ccccc1O
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1OC(=O)C(O)CO
Temperature: 185 °C

Procedure:
Guaiacol (249 grams), glycerine carbonate (254 grams) and potassium carbonate (1 gram) were combined and heated to 185° C. over a 6 hour period to result in a guaiacol mono-glycerate product.