Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31]>>[CH2:29]([N:33]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[CH:11][C:6]=2[CH2:5][CH:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:3]1=[O:2])[CH:30]([CH3:32])[CH3:31]
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Cl)c1ccc(OC)cc1
Reactant: CC(C)CN
Product: COc1ccc(C2Cc3cnc(Nc4ccccc4)nc3N(CC(C)C)C2=O)cc1

Procedure:
A mixture of 3-(4-chloro-2-phenylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (40 mg, 0.1 mmol) (from Example 12a supra) and isobutylamine (2.0 mL) (Aldrich) was heated at reflux for 3 hours. The reaction mixture was concentrated in vacuo and purified by preparative thin layer chromatography to give 8-isobutyl-6-(4-methoxy-phenyl)-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidine-7-one; (Yield 4.6 mg, 11.4%); and 3-(2-phenylamino-4-isobutylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester. (Yield 18.2 mg, 41.9%).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[CH:20]=[CH2:21])[C:14](Cl)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:22][C:23]1[CH:34]=[CH:33][C:26]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[CH:25][CH:24]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[CH:20]=[CH2:21])[C:14]([O:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[CH:33][CH:34]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C=Cc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C=CCOC(=O)c1ccc(O)cc1
Product: C=CCOC(=O)c1ccc(OC(=O)c2ccc(C=C)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Yield: 70.3 %

Procedure:
In a manner analogous to Example 9(e) by reacting 1.35 g (4.5 mmoles) of 3-(1-adamantyl)-4-vinylbenzoyl chloride with 800 mg (4.5 mmoles) of allyl 4-hydroxybenzoate, 1.4 g (70% yield) of the expected ester in the form of a colorless oil are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:28]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:29]2[CH:28]=[C:27]([CH3:26])[O:31][N:30]=2)=[O:34])=[CH:25][CH:24]=1)#[N:18]
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: Cc1cc(NC(=O)Oc2ccccc2)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)on4)cc3)c2cc1C#N
Yield: 87.6 %

Procedure:
The 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) synthesized in Production Example 10 and phenyl N-(5-methylisoxazol-3-yl)carbamate (72 mg) were added to toluene (5 ml), and then diisopropylethylamine (0.50 ml) was added and the mixture was heated to reflux for 2 hours. After cooling, the precipitated crystals were filtered and washed with an ethyl acetate/toluene (1/1) mixed solvent to obtain the title compound (120 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10](=[C:13](OC)[CH3:14])[C:11]#[N:12])=[N:7][C:6]=2[CH:17]=1.O.[NH2:19][NH2:20]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[C:13]([CH3:14])=[N:20][NH:19][C:11]=3[NH2:12])=[N:7][C:6]=2[CH:17]=1
Reactant: NN
Reactant: COC(C)=C(C#N)c1nc2cc(F)ccc2s1
Solvent: CO
Solvent: O
Product: Cc1n[nH]c(N)c1-c1nc2cc(F)ccc2s1
Temperature: 25 °C

Procedure:
A suspension of 2-(5-fluorobenzothiazol-2-yl)-3-methoxybut-2-enenitrile (330 mg, 1.3 mmol) and hydrazine hydrate (70 μL) in methanol (40 mL) was heated to reflux overnight. The solution was then cooled to room temperature and the resulting solid was isolated by filtration. The crude material was recrystallized from ethanol to yield 260 mg (78%, 10% for five steps) of the title compound. MS (m/z, ES+): 249.0 (M+1,100%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[C:27]4[O:26][CH2:25][CH2:24][O:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]2=[O:28])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:50][C:51]1[CH:55]=[CH:54][N:53]([CH2:56][C:57]([CH3:60])([OH:59])[CH3:58])[N:52]=1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[C:27]4[O:26][CH2:25][CH2:24][O:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]2=[O:28])[C:9]([NH:50][C:51]2[CH:55]=[CH:54][N:53]([CH2:56][C:57]([OH:59])([CH3:58])[CH3:60])[N:52]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc3c2OCCO3)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3cccc4c3OCCO4)=CC2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
A solution of (S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (200 mg, 0.52 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (81 mg, 0.52 mmol) and 1-hydroxybenzotriazole (75 mg, 0.54 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 88 mg, 0.57 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (117 mg, 43%) as a white solid: LR-ES-MS m/z calculated for C28H36N4O6 [M]+ 524, observed [M+H]+ 525; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.74-1.33 (m, 6H) 1.04 (s, 3H) 1.06 (s, 3H) 1.49-1.89 (m, 7H) 3.89 (s, 2H) 4.11 (d, J=18.4 Hz, 1H) 4.28 (s, 4H) 4.52 (d, J=18.4 Hz, 1H) 4.68 (s, 1H) 4.84 (s, 1H) 4.89 (dd, J=10.6, 4.8 Hz, 1H) 6.44 (d, J=2.1 Hz, 1H) 6.72-6.95 (m, 3H) 7.53 (d, J=2.1 Hz, 1H) 10.77 (s, 1H).
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]3[NH:16][C:17]([CH2:20][CH3:21])=[CH:18][N:19]=3)=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].CO.Cl>O>[CH:1]1([C:5]2[C:14]([C:15]3[NH:16][C:17]([CH2:20][CH3:21])=[CH:18][N:19]=3)=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1cnc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1cnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A mixture of methyl 4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate (compound 245.2, 200 mg, 0.600 mmol, 1.00 equiv, 90%) and sodium hydroxide (107 mg, 2.68 mmol, 4.00 equiv) in a solvent mixture of methanol and water (4/2 mL) was stirred for 3 h at 60° C. After cooling to ambient temperature, the pH was adjusted to 3-4 with hydrogen chloride (aq., 6 M). The resulting mixture was concentrated in vacuo to yield 150 mg of a white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH:25]=[CH2:26])[CH3:23])=[CH:11][CH:10]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([N:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:7][CH3:6])=[CH:10][CH:11]=1)[CH:25]=[CH2:26]
Reactant: C=CCN(C)CCCCCCOc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(C)CCCCCCOc1ccc(NC)cc1
Temperature: 25 °C

Procedure:
A solution of 30.3 g (80.5 mmol) of {4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid tert-butyl ester in 160 ml CH2Cl2 was treated at −20° C. with 180 ml TFA and warmed up to room temperature during 5 h. The reaction mixture was evaporated, treated with aqueous saturated NaHCO3 solution/Et2O (3×), dried (Na2SO4) and evaporated to yield {4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-amine, MS: 277 (MH+).
Reaction SMILES: [C:1]([OH:9])(=O)/[C:2](=[C:4](\[CH:6]=O)/[Cl:5])/[Cl:3].S(O)(O)(=O)=O.[NH2:15][NH2:16].C([O-])(=O)C.[Na+]>O>[Cl:3][C:2]1[C:1](=[O:9])[NH:15][N:16]=[CH:6][C:4]=1[Cl:5]
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Reactant: NN
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ncc(Cl)c1Cl
Yield: 78.8 %

Procedure:
A stirred solution of 3.9 grams of mucochloric acid in water is warmed to 8°-100° C., and a mixture of 3.1 grams of hydrazine sulfate and 3.0 grams of sodium acetate is added. A solid is collected by filtration and recrystallized from water to yield 3.0 grams of 4,5-dichloro-3-pyridazone; m.p. 199°-200° C. The reaction is repeated several times.
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@H:7]([C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[C:32]1(C)C=CC=C[C:33]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC.C=C>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@H:7]([C:14]1[CH:19]=[C:18]([CH:32]=[CH2:33])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(CC[C@@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: C=Cc1ccc(OCc2ccccc2)c([C@@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (prepared as described in WO 94/11337, Example 1) (8 g, 12.7 mmol), Pd(OAc)2 (28 mg, 0.12 mmol), tri-o-tolyl-phosphine (74 mg, 0.14 mmol) and tributylamine (5.9 mL, 24.5 mmol) in dimethylacetamide (50 mL) was heated to 60° C. under nitrogen atmosphere. Ethene (g) was then added to 8 bars pressure. After stirring overnight the reaction mixture was allowed to cool to room temperature. Nitrogen was flushed through the reaction vessel, and toluene and water were added. The aqueous layer was extracted with toluene and the combined organic layers were dried (MgSO4) and concentrated. The residue was treated with sodium hydroxide (1 M) and extracted with diethyl ether and toluene. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica (gradient ethyl acetate-methanol 90:10 up to 0.06% NH3 in ethyl acetate-methanol 90:10) Yield 1 g (18%); 1H NMR (CDCl3) δ0.94 (d, 12H), 2.20 (br, 2H), 2.37 (br, 2H), 3.0 (br, 2H), 4.38 (t, 1H), 5.0 (s, 2H), 5.11 (d, 1H), 5.61 (d, 1H), 6.60-6.70 (m, 1H), 6.80 (d, 1H), 7.12-7.19 (m, 12H).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:14]([S:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1)([CH3:16])[CH3:15].[OH-].[K+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:26][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][S:17][CH:14]([CH3:16])[CH3:15])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)SCCOc1ccc(CO)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)SCCOc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
In 15 ml of N,N-dimethylformamide were dissolved 1.2 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone and 1.2 g of p-(2-isopropylthioethoxy)benzyl alcohol, and then 0.31 g of powdery potassium hydroxide was added thereto. The resulting mixture was stirred overnight at room temperature, poured into water, extracted with diethyl ether, washed with water, dried over anhydrous sodium sulfate and then freed of the diethyl ether by distillation under reduced pressure. The resulting solid was recrystallized from n-hexane to obtain 1.2 g of the aimed compound, m.p. 82.0°~84.5° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:15]1([CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCCCCCCCCCCCCBr
Reactant: O=C(O)CCCc1ccccc1
Product: O=C(CCCc1ccccc1)OCCCCCCCCCCCCBr
Yield: 85 %

Procedure:
From 12-bromo-1-dodecanol and 4-phenylbutyric acid. Yield: 85% (oil).
Reaction SMILES: [CH2:1]([S:8]([N:11]([CH2:35][C:36]([F:39])([F:38])[F:37])[C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:27][Si](CC)(CC)CC)([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH2:14][CH2:13]1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl>C1COCC1.CCOCC>[F:39][C:36]([F:37])([F:38])[CH2:35][N:11]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:27])([C:19]([F:22])([F:20])[F:21])[C:23]([F:24])([F:25])[F:26])[CH2:14][CH2:13]1)[S:8]([CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:10])=[O:9]
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](N(CC(F)(F)F)S(=O)(=O)Cc2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=S(=O)(C(Cc1ccccc1)c1ccccc1)N(CC(F)(F)F)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Reaction time: 0.5 h

Procedure:
A solution of 50 mg (0.08 mmol) of trans benzyl-N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-sulfonamide (example 30.1) in 0.5 mL of THF was cooled to −78° C. and treated with 0.11 mL of a 1M solution lithium bis(trimethylsilyl)amide in THF. The mixture was allowed to reach ca −5° C. within 30 min and treated with 0.11 mL (0.1 mmol) of benzylbromide. The mixture was stirred overnight and distributed between diluted aqueous solution of HCl and Et2O. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. The residue was redissolved in MeOH and treated with 0.5 mL of a 2M solution of NaOMe in MeOH. Distribution of this solution between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases over Na2SO4, evaporation and column chromatography on silica gel with heptane/EtOAc 4:1 gave 50 mg (76%) of (rac) trans 1,2-diphenyl-ethanesulfonic acid (2,2,2-trifluoro-ethyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide as a colorless foam, MS: 590 (M−H)−.
Reaction SMILES: C([C:3](CC)([C:7]([C:9]([O-:11])=[O:10])=O)[C:4]([O-])=[O:5])C.[Na+].[Na+].C(O)(=O)C.[CH:20]([NH2:22])=[NH:21].[OH-].[Na+].C>O>[OH:5][C:4]1[N:22]=[CH:20][N:21]=[C:7]([C:9]([OH:11])=[O:10])[CH:3]=1
Reactant: N=CN
Reactant: CCC(CC)(C(=O)[O-])C(=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
63.5 g (0.3 mol) sodium diethyloxalacetate and 30.2 g (0.3 mol) formamidine acetate were added to 24.1 g (0.6 mol) NaOH in 3.6 L water. The mixture was stirred overnight at RT. Then activated charcoal was added and the mixture was refluxed for 1 h. It was filtered off while hot and after cooling acidified with a hydrochloric acid solution. The solution was concentrated to dryness by rotary evaporation. The residue contained the desired product and was used in the next step without any further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl[CH2:21][CH:22]([CH3:30])[CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH:22]([CH3:30])[CH2:21][O:1][C:2]2[C:11]3[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:13])[C:3]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:26]1
Reactant: O=c1oc2c(O)cccc2c(O)c1-c1ccccc1
Reactant: CC(CCl)CN1CCOCC1
Product: CC(COc1c(-c2ccccc2)c(=O)oc2c(O)cccc12)CN1CCOCC1
Yield: 60.7 %

Procedure:
Prepared according to the method of Example 30 by alkylation of 4,8-dihydroxy-3-phenyl-coumarin by 1-chloro-2-methyl-3-morpholino-propane. After recrystallisation from isopropanol, a white solid is obtained with the melting point of 136° C. Yield 60.7%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16]C)=[O:14].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[C:21]([C:38]([F:41])([F:40])[F:39])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(O)(C)(C)C>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH2:26][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=4)[N:5]=[CH:4][C:3]=3[C:13]([O:15][CH3:16])=[O:14])=[CH:20][C:21]=2[C:38]([F:40])([F:41])[F:39])[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2C(F)(F)F)CC1
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.1 %

Procedure:
Ethyl 4,6-dichloro-1,5-naphthyridine-3-carboxylate (0.5 g, 1.84 mmol) and tert-butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (0.766 g, 2.22 mmol) were dissolved in a mixture of dichloromethane (5 mL) and tert-butanol (5 mL), to the system added potassium carbonate (0.612 g, 4.43 mmol). The reaction mixture was stirred at room temperature for 24 h, suction filtrated, the solid was washed with 30 mL of dichloromethane, and the resulting wash solution and the filtrate were combined, concentrated under reduced pressure, and the resulting residue was recrystallized from diethyl ether to give 0.73 g of a pale yellow solid.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([O:16][CH2:17][CH2:18][OH:19])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].O>C1C=CC=CC=1>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:19][CH2:18][CH2:17][O:16][CH:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCCOC1c2ccccc2C=Cc2ccccc21
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3C=Cc3ccccc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
Under a nitrogen atmosphere, 2-(5H-dibenzo[a,d]cyclohepten-5-yloxy)-ethanol (400 mg, 1.6 mmol), tributylphosphine (480 mg, 2.4 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (380 mg, 1.6 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (480 mg, 2.4 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 2 h. The mixture was added water and the product extracted with ethyl acetate. The combined organic phases was dried (MgSO4), and concentrated in vacuo. The residue was purified chromatography eluting with ethyl acetate/hexane (1:9) to give 350 mg (47%) of the title compound: MS 472 (M+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.F[C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19].[CH2:26]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH3:27]>O>[CH2:26]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][C:13]2[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([CH:22]=2)[C:18]([O:20][CH3:21])=[O:19])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH3:27]
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CCS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(C(=O)OC)c2)cc1
Temperature: 80 °C
Yield: 100.3 %

Procedure:
11 g of potassium carbonate was added to a dimethylformamide (150 ml) solution of 10.7 g of methyl 5-fluoro-2-nitrobenzoate and 11.1 g of 4-(ethylsulfonyl)phenol obtained from Reference Example 2, and stirred under heat at 80° C. for 90 minutes. The reaction liquid was restored to room temperature, then 300 ml of water was added to it, and the formed solid was taken out through filtration. This was dried under reduced pressure to obtain 19.7 g of the entitled compound as a creamy white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.Cl[N:12]1C(=O)[CH2:15][CH2:14][C:13]1=O.C(N)C#C.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH:15]=[C:14]([CH2:13][NH2:12])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: C#CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NCc1cc(-c2ccc(Cl)cc2)no1
Yield: 110.2 %

Procedure:
1.56 g (10 mmol) of p-chlorobenzaldoxime was dissolved in 40 ml of dried dichloromethane in a erlenmeyer flask equipped with a magnetic stirrer, and 1.7 g (12 mmol) of N-chlorosuccinimide was added slowly. The reaction mixture was stirred until completely dissolved. The system was heated slightly for 20 min. Then, 0.56 g (10 mmol) of propargyl amine was introduced and 1.2 g (12 mmol) of triethylamine was added dropwise, which caused the emission of white smog. The reaction mixture was heated under reflux for 2 h, and then purified by column chromatography on silica gel using petroleum ether (b.p. 60-90° C.)—ethyl acetate (v:v=4:1) as eluant, to obtain 2.3 g of the product as yellow solid. The yield was 62%.
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=O)[C:19]3=[O:26])(=[O:15])=[O:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:28][C:29]1([C:34]#[N:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:1]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:13]([C:16]2[CH:24]=[CH:23][C:22]3[N:21]4[CH2:28][C:29]5([CH2:33][CH2:32][CH2:31][CH2:30]5)[CH2:34][N:35]=[C:20]4[C:19](=[O:26])[C:18]=3[CH:17]=2)(=[O:14])=[O:15])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3CN3CCOCC3)cc2C1=O
Reactant: N#CC1(CCl)CCCC1
Product: O=C1C2=NCC3(CCCC3)CN2c2ccc(S(=O)(=O)N3CCC[C@H]3CN3CCOCC3)cc21

Procedure:
The title compound was prepared as a orange solid from 5-{[(2S)-2-(morpholin-4-ylmethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2,3-dione and 1-chloromethyl-cyclopentanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 471 [M−H]. m.p.: 162.9-163.6° C.