Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@H]1CO[C@@]2(O[C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@H:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H]2C)CC1.C[C:32]1[C@@H]2[C@]3(C)[C@@H](C[C@@H]2[O:34][C:33]=1CC[C@H](CO)C)[C@@H]1CC=C2C[C@@H](O)CC[C@]2(C)[C@H]1CC3>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[OH:25][CH:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[C:19](=[CH:18][CH2:17][C@@H:16]3[C@@H:15]2[CH2:14][CH2:13][C@@:12]2([CH3:27])[C@H:11]3[CH2:10][CH:8]=[C:7]2[C:33](=[O:34])[CH3:32])[CH2:24]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reactant: CC1=C(CC[C@@H](C)CO)O[C@H]2C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@@H]12
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC=C4CC(O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
In this method too tigogenin is converted by conventional method to pseudodiosgenin and finally pseudodiosgenin is oxidized with chromium trioxide in acetic acid to give 3-hydroxy-5-pregnen-16-en-20-one.
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([CH:7]=[CH:8][N+:9]([O-:11])=[O:10])CC1.NC1C=[C:15]2[C:19](=[CH:20][C:21]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH2:18][CH2:17][CH2:16]2.Cl.CC(C)=O>O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([C:21]1[CH:20]=[C:19]2[C:18]([CH2:17][CH2:16][CH2:15]2)=[CH:6][C:5]=1[NH:4][CH:7]=[CH:8][N+:9]([O-:11])=[O:10])=[O:30]
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1Cl)CCC2
Reactant: O=[N+]([O-])C=CN1CCOCC1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccccc1Cl)c1cc2c(cc1NC=C[N+](=O)[O-])CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
1-Morpholino-2-nitroethene (3.93 g) was added to a mixture of 5-amino-6-(2-chlorobenzoyl)indan (4.50 g), 6N HCl (15 ml) and acetone (45 ml) and the whole mixture was stirred at room temperature for one hour. To this reaction mixture was added water to give crystals of 6-(2-chlorobenzoyl)-5-(2-nitroethenylamino)indan (5.40 g, 95.2%). Recrystallization from ethanol gave yellow needles, mp. 225°-226° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[N:4].Cl.[C:6]([N:10]=[C:11]=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>O1CCCC1>[C:3]([CH2:2][NH:1][C:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])#[N:4]
Reactant: CC(C)(C)N=C=O
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)NCC#N

Procedure:
To a stirring mixture of 18.7 g (0.2 mole) aminoacetonitrile·HCl in 300 ml. dry tetrahydrofuran under a nitrogen atmosphere, there is added 20.4 g. (0.2 mole) t-butyl isocyanate (97%), followed by 28 ml. (0.2 mole) triethylamine. The resulting mixture is heated at reflux for five hours, cooled and the tetrahydrofuran removed at reduced pressure. The solid is recrystallized from ethyl acetate to give N-cyanomethyl-N'-(1,1-dimethylethyl)urea, m.p. 128°-32° (Anal. Calcd. for C7H13N3O: C: 54.17, H: 8.44, N: 27.07; Found: C: 53.84, H: 8.33, N: 26.86.
Reaction SMILES: [C:1]([CH:3]([CH:9]([CH3:11])[CH3:10])[C:4]([O:6]CC)=O)#[N:2].[CH2:12]([NH:14][C:15]([NH2:17])=[O:16])[CH3:13].C[O-].[Na+].Cl>CO.O>[CH2:12]([N:14]1[C:1]([NH2:2])=[C:3]([CH:9]([CH3:10])[CH3:11])[C:4](=[O:6])[NH:17][C:15]1=[O:16])[CH3:13]
Reactant: CCOC(=O)C(C#N)C(C)C
Reactant: CCNC(N)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1c(N)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 12.25 h
Yield: 70.8 %

Procedure:
A flask was charged with ethyl 2-cyano-3-methylbutanoate (3b, 20.72 g, 133.5 mmol), ethyl urea (3a, 12.35 g, 140.2 mmol) and MeOH (97.2 mL). To the slurry at room temperature was added sodium methoxide in methanol (25% w/w soln, 36.8 mL), mild exotherm detected. The heterogeneous reaction mixture was then heated to reflux. The reaction was refluxed for 4-12 h. Upon reaction completion, as determined by TLC analysis, the reaction mixture was concentrated and solvent exchanged to acetonitrile (ACN) through 3×50 mL co-evaporations leaving a basic 1-2 vol. solution in ACN. To the reaction mixture was added 1-2 vol. of water followed by a pH adjustment with 2N HCl (aq.). As the pH approached 10, white to off-with solids began forming and, as the pH was further reduced to 3 to 4, (by pH paper) white slurry resulted. This slurry was aged for 0.5 to 24 h and then filtered. The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE. The white to off-white solids were then dried in a vacuum oven at 40 to 50° C. giving 18.63 g (60%) of 1-ethyl-5-isopropyl-6-amino uracil 2 (HCl salt).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=[O:13])[CH2:5][C:6]2=[O:12].[N+:14]([O-])([OH:16])=[O:15]>CCOCC>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]2[C:7]=1[C:6](=[O:12])[CH:5]([N+:14]([O-:16])=[O:15])[C:4]2=[O:13]
Reactant: Cc1ccc(C)c2c1C(=O)CC2=O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Product: Cc1ccc(C)c2c1C(=O)C([N+](=O)[O-])C2=O

Procedure:
4,7-Dimethyl indane-1,3-dione (0.52 g; 0.003 mole) in dry ether (5 ml) was nitrated with fuming nitric acid (1.0 ml) as described in Example 12 to give 4,7-dimethyl-2-nitro-indane-1,3-dione, m.p. (water, hydrochloric acid) 108°-110° C, (Found: C, 60.07; H, 4.20; N, 6.29; C11H9NO4 requires: C, 60.28; H, 4.14; N, 6.39%).
Reaction SMILES: C([O:8][C:9](=[O:27])[C@H:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[O:17]1[CH2:18][CH2:19][N:14]([C:12]([NH:11][C@H:10]([C:9]([OH:27])=[O:8])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:13])[CH2:15][CH2:16]1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Yield: 94.4 %

Procedure:
A solution of N-morpholinocarbonyl-L-phenylalanine benzyl ester (1.43 g) in methanol (20 ml) was hydrogenated over 10% palladium on carbon (150 mg) at 3 atmospheric pressure of hydrogen for 1 hour. The solution was filtered and concentrated in vacuo to give N-morpholinocarbonyl-L-phenylalanine (1.02 g) as an amorphous powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:10]=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>CO.[OH-].[Na+]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:17][CH2:16]2)[CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1cc(COC2CCCCO2)cc(N2CCNCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCN(c2cc(COC3CCCCO3)ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 1-(4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)piperazine (8.5 g, 30.6 mmol) in MeOH (30 mL), NaOH (2 M, 31 mL) was slowly added at RT, followed by the addition of benzyl chloroformate (6.4 g, 37 mmol) in portions at 0° C. The mixture was stirred at RT overnight. The solution was concentrated and diluted with H2O (500 mL), extracted with EtOAc (3×200 mL). The combined organic layers were washed with H2O (100 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by silica gel column chromatography (Petroleum ether:EtOAc=1:1) to afford benzyl 4-(4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)piperazine-1-carboxylate as a yellow oil (7.3 g, 58%). MS (ES+) C23H29N3O4 requires: 411, found: 412[M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])(=[O:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([CH2:11][Br:20])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1c(C)cccc1Oc1ccccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CC(=O)Oc1c(CBr)cccc1Oc1ccccc1Cl
Yield: 102.5 %

Procedure:
A mixture of 2-chlorophenyl 2-acetoxy-3-methylphenyl ether (17 g), N-bromosuccinimide (13 g) and 2,2'-azobisisobutyronitrile (1.7 g) in benzene (150 ml) was refluxed under heating for 3 hours. After cooling, the precipitate was filtered off. The filtrate was washed with water, aqueous sodium thiosulfate and water successively, dried over magnesium sulfate and then evaporated to give oily 2-chlorophenyl 2-acetoxy-3-bromomethylphenyl ether (22.4 g).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[C:49]1([C:55]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([CH3:59])[C:56](O)=[O:57])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[O:57]=[C:56]([C:16]1[C:17]([CH:30]([CH3:31])[CH3:32])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)[C:55]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH3:59]
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)C(C)(c2ccccc2)c2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2,2-diphenylpropionic acid, mp 140°-145° C.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:18]3[CH:35]=[CH:34][C:21]([C:22]([NH:24][CH2:25][CH:26]([OH:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:23])=[CH:20][CH:19]=3)[CH2:15][C:16]#[CH:17])[CH:8]=2)[N:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37].N1C=CC=CC=1>CN(C=O)C>[C:36]([O:33][CH:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:25][NH:24][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([N:14]([CH2:13][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[NH:11][C:10]3=[O:12])[CH2:15][C:16]#[CH:17])=[CH:35][CH:34]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCC(O)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCC(OC(C)=O)c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
p-[N-(2-Methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-(2-hydroxy-2-phenylethyl)benzamide (0.105 g) was dissolved in DMF (3 ml) and acetic anhydride (34 mg) and pyridine (37 mg) were added in turn. The mixture was stirred at 20° C. for 24 hours. The mixture was evaporated and the residue was triturated with water (5 ml). The solid was filtered off, washed with water and dried in air to give N-(2-acetoxy-2-phenylethyl)-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide (0.095 g; containing 1 equivalent of water), m.p. 203°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(OC)cc3)CC2)ccc1Cl
Yield: 60 %

Procedure:
The title compound (24 mg, 60%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 4-methoxybenzoyl chloride. MS: 403.4(MH+).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>ClC(Cl)C.O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH:19]([C:20]([CH:19]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(C(c1ccccc1)c1ccc(O)cc1O)C(c1ccccc1)c1ccc(O)cc1O
Reaction time: 1 h
Yield: 82 %

Procedure:
120 kg (1.09 kmole) of resorcinol were suspended in 660 l of dichlorethane and 150 kg (1.12 kmole) of anhydrous aluminum chloride were added to the suspension while the temperature raised from 15° C. to 25° C. The complex obtained dissolved in the reaction medium. 171 kg (1.10 kmole) of phenyl-acetyl chloride were added over a period of one hour while the temperature raised to 35°-40° C. The mixture was stirred for one hour thereafter it was admixed with diluted hydrogen chloride (the mixture of 300 l of hydrogen chloride and 600 l of water), and it was treated as described in the preceding Examples. The solvent was removed by distillation, the residue was recrytallized from toluene, the product obtained was centrifuged and dried at 45°-50° C. 205-210 kg of 2,4-dihydroxy-phenyl-benzyl-ketone were obtained, yield 82-84.5%. Calculated amount: 248.5 kg. The physical data are identical with the data given in Example 1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.[CH2:24]([CH2:26][NH2:27])[OH:25].O>CN(C=O)C>[OH:25][CH2:24][CH2:26][NH:27][C:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:23]
Reactant: NCCO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCO)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.64 mmol) in DMF (8 mL) was added 1,1-carbonyl-diimidazole (135 mg, 0.83 mmol) and the mixture was stirred for 4 h at room temperature. Ethanolamine (0.27 mL, 4.50 mmol) was added and stirring was continued for 1 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate (90 mL). The combined organic layers were washed with water (60 mL) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 30:70) afforded the title compound (215 mg, 94%) as a white foam. MS: m/e=355.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)(=[O:17])=[O:16])[CH2:9][CH2:10][NH:11][C:12](=[O:14])[O-])=[C:4]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH:3]=1.[CH3:37][NH2:38]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][CH2:10][NH:11][C:12]([NH:38][CH3:37])=[O:14])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)(=[O:17])=[O:16])=[C:4]([CH2:28][C:29]2[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=2[F:35])[CH:3]=1
Reactant: CN
Reactant: COc1ccc(S(=O)(=O)N(CCNC(=O)[O-])c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNC(=O)NCCN(c1ccc(Cl)cc1Cc1c(F)cccc1F)S(=O)(=O)c1ccc(OC)c(OC)c1

Procedure:
To 0.42 g of phenyl(2-{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl)sulfonyl]amino}ethylcarbamate in 1.2 ml of dimethyl sulfoxide is added, at room temperature, 0.053 ml of an aqueous solution of methylamine, and the mixture is left at room temperature for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel to give 0.326 g of the expected product.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][N:8]([C:10](=[O:22])[CH:11]([NH:14]C(OC(C)(C)C)=O)[CH2:12][CH3:13])[CH:7]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=3)[NH:26][C:25]=2[C:34]2[NH:35][C:36]3[C:41]([C:42]=2[CH2:43][CH:44]2[N:48]([C:49](=[O:61])[CH:50]([NH:53]C(OC(C)(C)C)=O)[CH2:51][CH3:52])[CH2:47][CH:46]([O:62][C:63](=[O:65])[CH3:64])[CH2:45]2)=[CH:40][CH:39]=[C:38]([F:66])[CH:37]=3)[CH2:6]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:4][CH:5]1[CH2:9][N:8]([C:10](=[O:22])[CH:11]([NH2:14])[CH2:12][CH3:13])[CH:7]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=3)[NH:26][C:25]=2[C:34]2[NH:35][C:36]3[C:41]([C:42]=2[CH2:43][CH:44]2[N:48]([C:49](=[O:61])[CH:50]([NH2:53])[CH2:51][CH3:52])[CH2:47][CH:46]([O:62][C:63](=[O:65])[CH3:64])[CH2:45]2)=[CH:40][CH:39]=[C:38]([F:66])[CH:37]=3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)N1CC(OC(C)=O)CC1Cc1c(-c2[nH]c3cc(F)ccc3c2CC2CC(OC(C)=O)CN2C(=O)C(CC)NC(=O)OC(C)(C)C)[nH]c2cc(F)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)C(=O)N1CC(OC(C)=O)CC1Cc1c(-c2[nH]c3cc(F)ccc3c2CC2CC(OC(C)=O)CN2C(=O)C(N)CC)[nH]c2cc(F)ccc12
Temperature: 0 °C

Procedure:
A solution containing 11 (27.5 g, 30 mmol) in DCM (200 mL) was cooled to 0° C. TFA (50 mL) was added and the reaction was monitored by LC/MS analysis until complete conversion of 11 to 12 (ca. 3 h). The solvent was removed in vacuo and the dark, green-colored residue was dissolved in EtOAc (ca. 1 L). The EtOAc solution was carefully poured into a saturated aqueous NaHCO3/ice/water mixture to neutralize the residual TFA. The organic phase was separated and washed twice with saturated aqueous NaHCO3 then once with brine. The combined aqueous washes were back-extracted with EtOAc (2×100 mL) and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford 22 g of crude 12 as an off-white solid. 1H NMR (300 MHz, CDCl3+d4-MeOH), mixture of rotomers: δ11.62 (br s, 2H), 7.48-7.62 (m, 4H), 6.89 (ddd, J=2.4, 9.3, 9.3 Hz, 2H), 5.48 (dd, J=4.5, 4.8 Hz, 2H), 4.52 (dd, J=9.3, 9.3 Hz, 2H), 4.06 (dd, J=4.8, 12.3 Hz, 2H), 3.78 (d, J=12.3 Hz, 2H), 3.54-3.70 (m, 4H), 3.30-3.40 (m, 2H), 2.33 (s, 6H), 2.02-2.16 (m, 2H), 1.70-1.96 (m, 4H), 1.09 (t, J=7.2 Hz, 6H) ppm; 13C NMR (75 MHz, CDCl3+d4-MeOH): 6173.5, 170.9, 161.8, 158.6, 137.2, 137.1, 128.2, 128.1, 125.6, 118.7, 118.6, 108.6, 108.3, 108.0, 98.6, 98.1, 74.6, 60.1, 53.5, 33.5, 28.0, 21.4, 9.7 ppm. Mass spectrum (ESI), m/z 721.4 [(M)+; calcd for C38H46F2N6O6: 720.8].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC#N>[O:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]1=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 53 %

Procedure:
A mixture of N-(4-bromobutyl)phthalimide) (2.00 g, 7.09 mmol), phenol (0.67 g, 7.09) and K2CO3 (1.96 g, 14.18 mmoml) in dry MeCN (30 ml) was stirred at rt for 66 h. The reaction mixture was then warmed to 50° C. for 20 h before more phenol (0.33 mg, 3.54 mmol) was added and the resulting mixture was warmed at reflux. After 4 h EtOAc was added, the mixture was washed with brine, then 1N NaOH, and brine again before evaporated the organic phase to dryness to give the title compound (1.11 g, 53%) which was used without further purification. 1H NMR (500 MHz CDCl3): δ 7-90-7.83 (m, 2H), 7.76-7.70 (m, 2H), 7.28 (t, 2H), 6.93 (t, 1H), 6.89 (d, 2H), 4.01 (t, 2H), 3.79 (t, 2H), 1.96-1.82 (m, 4H); Mass Spectrum: M+H+ 296.
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=C[C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[CH:5][CH:4]=1)C.ClCC1C=CC(C)=C[N:28]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:1])=[CH:24][N:28]=2)[CH:10]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Product: COCOc1cc(SCc2ccc(C)cn2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 2-chloromethyl-5-methylpyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][C@H:4]([NH:18][C:19](=[O:29])[CH2:20][NH:21]C(=O)OC(C)(C)C)[B:5]1[O:9][C@@H:8]2[CH2:10][C@@H:11]3[CH2:14][C@H:13]([C@:7]2([CH3:17])[O:6]1)[C:12]3([CH3:16])[CH3:15].Cl>C(Cl)Cl.O1CCOCC1>[NH2:21][CH2:20][C:19]([NH:18][C@H:4]([B:5]1[O:9][C@@H:8]2[CH2:10][C@@H:11]3[CH2:14][C@H:13]([C@:7]2([CH3:17])[O:6]1)[C:12]3([CH3:15])[CH3:16])[CH2:3][CH:2]([CH3:30])[CH3:1])=[O:29]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)CN)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]carbamate (2.5 g, 5.9 mmol) in DCM (15 mL) was added 4M HCl in dioxane (5.9 mL). The reaction mixture was allowed to stir for 2 h and concentrated to give 2-amino-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}acetamide which was used in the next step without purification.
Reaction SMILES: [OH-].[K+].[CH:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\Br)/[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1>O.O.CC(C)=O>[CH:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(/C(Br)=C/c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(C#Cc1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
Potassium hydroxide (3.48 mmol), dissolved in water (0.87 M (4.0 ml)), is added over about 30 minutes to a refluxing solution of the alpha-bromochalcone (3.48 mmol) in 0.35 M of 1:1 water/acetone (5 ml each). After 20 minutes of further refluxing, the solution is cooled and diluted with water. The water is extracted with ether, which is dried with MgSO4 and evaporated. Chromatography on silica gel yielded 1,3-diphenylpropynone and its derivatives. VI. alpha-Tetralonylideneacetophenone Derivatives
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:16])[N:4]([CH:13]([CH3:15])[CH3:14])[N:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[CH2:17]([C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1[OH:28])[CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(C(CC)=O)C>[Cl:1][C:2]1[C:3](=[O:16])[N:4]([CH:13]([CH3:15])[CH3:14])[N:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([OH:11])[CH2:12][O:28][C:21]1[CH:22]=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:20]=1[CH2:17][CH2:18][CH3:19]
Reactant: CC(C)n1ncc(OCC2CO2)c(Cl)c1=O
Reactant: CCCc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: CCCc1cc(C#N)ccc1OCC(O)COc1cnn(C(C)C)c(=O)c1Cl
Reaction time: 8 h

Procedure:
A mixture comprising 2.0 g of 4-chloro-5-(2-oxiranylmethoxy)-2-i-propyl-3(2H)pyridazinone prepared in Reference Example 5, 1.5 g of 2-n-propyl-4-cyanophenol, 1.35 g of potassium carbonate and 80 ml of diethyl ketone, was refluxed under stirring for 8 hours. Then, diethyl ketone was distilled off under reduced pressure, and the residue thereby obtained was extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography by using benzene-ethyl acetate (1:1, v/v) as the developer. The colorless crystals thereby obtained was recrystallized from ethyl ether to obtain 1.3 g of the above identified compound as colorless crystals having a melting point of from 118.5° to 121° C.