Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[CH3:15])[C:7](=[CH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:41]1[C:49]2[N:48]=N[NH:46][C:45]=2[CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[CH3:15])[C:7](=[CH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:46][C:45]3[CH:44]=[CH:43][CH:42]=[CH:41][C:49]=3[NH2:48])=[O:26])=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1-c1c(C)cccc1C2=CC(=O)NCCCCCC(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc2c1-c1c(C)cccc1C2=CC(=O)NCCCCCC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
6-(2-(4,5-dimethyl-9H-fluoren-9-ylidene)acetamido)hexanoic acid (363 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2 mmol), hydroxyl-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (326 mg, 72% yield) as a brown solid. LC-MS (m/z) 454 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[F:18][C:19]([F:25])([F:24])[S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[F:18][C:19]([F:25])([F:24])[S:20]([O:10][CH:8]1[CH2:9][CH:3]2[N:2]([CH3:1])[CH:6]([CH2:5][CH2:4]2)[CH2:7]1)(=[O:22])=[O:21]
Reactant: CN1C2CCC1CC(O)C2
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C2CCC1CC(OS(=O)(=O)C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tropine (14.2 g, 0.10 mol) was dissolved in methylene chloride (210 mL) and triethylamine (23 mL, 0.16 mol). Trifluoromethanesulfonyl chloride (9.3 mL, 0.12 mol) was added dropwise at a rate such that the methylene chloride boiled gently. The reaction was stirred at ambient temperature for 1 h; then it was washed with cold 0.5 N sodium hydroxide, water, and brine. The organic phase was dried and concentrated to a yellow solid which had: NMR δ4.88 (t, 1 H), 3.10-3.05 (m, 2 H), 2.94 (s, 3 H), 2.22 (s, 3 H), 2.20-2.10 (m, 2 H), 2.02-1.88 (m, 6 H).
Reaction SMILES: [H][H].[BrH:3].[CH:4]([NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[C:14]=2[OH:18])[C:9]1=[O:20])([CH3:6])[CH3:5]>O.[Pd]>[BrH:3].[OH:20][CH:9]1[C:10]2[C:15](=[C:14]([OH:18])[C:13]([OH:19])=[CH:12][CH:11]=2)[CH2:16][CH2:17][CH:8]1[NH:7][CH:4]([CH3:6])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)NC1CCc2c(ccc(O)c2O)C1=O
Agent: [Pd]
Agent: Br
Solvent: O
Product: CC(C)NC1CCc2c(ccc(O)c2O)C1O

Procedure:
In 10 volume parts of water is dissolved 0.180 part of 3,4-dihydro-2-isopropylamino-5,6-dihydroxy-1(2H)-naphthalenone hydrobromide and with the addition of 0.2 part of 5 % palladium-on-carbon, catalytic reduction is carried out in a current of hydrogen gas. The absorption of hydrogen ceases when 9 volume parts of hydrogen has been absorbed. The catalyst is filtered off and the filtrate is freeze-dried. Finally, the residue is recrystallized from ethanol-ethyl ether. The procedure gives colorless prisms of 1,5,6-trihydroxy-2-isopropylamino-1,2,3,4-tetrahydronaphthalene hydrobromide. Melting point: 169° C.(decomp.)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH:16](OS(C)(=O)=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:14][Cl:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CS(=O)(=O)OC(CCCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: ClCCC(c1ccccc1)n1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a RT solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (424 mg, 2.76 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 121 mg, 3.03 mmol). The reaction mixture was stirred for 30 min at RT and then a solution of methanesulfonic acid 3-chloro-1-phenyl-propyl ester in DMF (2 mL) was added at 0° C. The resulting mixture was stirred overnight at RT and then diluted with H2O and EtOAc. The organic layer was separated, washed 3 times with water, dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc), affording 4-Chloro-7-(3-chloro-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine as a colorless oil (480 mg, 56% yield).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI.O>CN(C=O)C>[CH3:24][N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1
Reactant: c1ccc(COc2ccc(-c3n[nH]c4cccnc34)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1nc(-c2ccc(O)cc2)c2ncccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.4 %

Procedure:
To a stirred mixture of 3-[4-(benzyloxy)phenyl]-1H-pyrazolo[4,3-b]pyridine (300 mg) and Cs2CO3 (649 mg) in DMF (4 mL) was added MeI (0.093 mL) at 0° C. The mixture was stirred at room temperature for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in EtOH (20 mL) and 10% Pd—C (50% wet, 200 mg) was added. The mixture was stirred for 1 h under H2 atmosphere, filtered and evaporated. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (160 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:35]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:31][C:30]1[CH:29]=[CH:28][C:27]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:37]=[C:36]([N:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)[CH:35]=2)=[CH:26][C:25]=1[NH:24][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:16]=1
Reactant: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Product: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 77 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 50, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-morpholino-5-trifluoromethylbenzamide to give N-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamide in 77% yield; NMR Spectrum: (DMSOd6) 1.37 (s, 9H), 1.55 (m, 2H), 1.95 (m, 2H), 2.19 (s, 3H), 3.2 (m, 2H), 3.25 (t, 4H), 3.63 (m, 2H), 3.77 (t, 4H), 4.63 (m, 1H), 7.18 (m, 1H), 7.22 (d, 1H), 7.37 (s, 1H), 7.41 (t, 1H), 7.5 (s, 2H), 7.57 (m, 1H), 7.62 (s, 1H), 7.7 (s, 1H), 7.78 (d, 1H), 9.83 (s, 1H), 10.31 (s, 1H); Mass Spectrum: M+H+ 683.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:40])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].[OH2:59].S([O-])([O-])(=O)=[O:61].[Al+3].[K+].S([O-])([O-])(=O)=[O:68]>O1CCOCC1>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@@:14]2([OH:40])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].[OH2:61].[OH2:68].[OH2:59]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Reactant: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Temperature: 27.5 °C
Reaction time: 0.46 h
Yield: 70 %

Procedure:
Crude docetaxel (1.0 g,) was dissolved in 1,4-dioxane (5 ml) at 25-30° C. under constant stirring. Demineralised water (7 ml) containing 0.02 g of potassium aluminum sulfate was added slowly at 25-30° C. with constant stirring. The precipitated solid was stirred for 25-30 minutes at 25-30° C., then filtered, washed with a 1:1 solution of 1,4-dioxane and demineralised water (1 ml), dried under vacuum under humid atmosphere (until the moisture content was between 5-7% by Karl Fischer method) to afford Docetaxel trihydrate in 70-90% yield
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:32]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:32][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[F:1])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(C)cc1F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: O
Product: Cc1ccc(C(=O)CBr)c(F)c1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a chloroform (7.5 mL) solution of 1-(2-fluoro-4-methylphenyl)ethanone (0.50 g), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (0.65 mL) and trimethylsilyl trifluoromethanesulfonate (0.71 mL) were added, and the resultant was stirred for 30 minutes. Then, N-bromosuccinimide (0.64 g) was added thereto, and the resultant was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, and the resultant was stirred for 10 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=99/1→95/5) to obtain the title compound (0.72 g) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]2[N:9]=[C:10]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:22])[NH:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[Cl:22][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([F:20])([F:21])[F:19])[C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:24]=[CH:23][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester (430 mg, 1.2 mmol) in MeOH (5 mL) was added 1N NaOH (5 mL). The solution was stirred at ambient temperature overnight and carefully acidified to pH 3 with 1N HCl. The resulting suspension was filtered and washed with water. The pale yellow solid was dried under reduced pressure give 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13]C(=O)C)[C:10]([Cl:17])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH2:13])[C:10]([Cl:17])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1C(=O)O
Yield: 84 %

Procedure:
25.75 grs (0.1 mol) methyl 2-methoxy-4-acetamido-5-chlorobenzoate were introduced into a 500 ml flask, suspended in 100 ml ethanol. 40 grs NaOH, dissolved in 150 cc of water, were added and the mixture was heated under reflux for 2.5 hours. The mixture was diluted with water and made acid with concentrated HCl. The white solid which precipitated was collected and recrystallized from methanol. Weight: 17 grs m.p. = 213°-215° C. Yield = 84%.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[CH:10]([N:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH:15]([OH:20])[CH2:14][C:13]1([CH3:22])[CH3:21])[CH3:11]>>[CH3:22][C:13]1([CH3:21])[N:12]([CH2:10][CH2:11][O:5][C:4]([CH2:3][CH2:2][C:1]([OH:8])=[O:7])=[O:6])[C:17]([CH3:19])([CH3:18])[CH2:16][CH:15]([OH:20])[CH2:14]1
Reactant: CC(O)N1C(C)(C)CC(O)CC1(C)C
Reactant: O=C(O)CCC(=O)O
Product: CC1(C)CC(O)CC(C)(C)N1CCOC(=O)CCC(=O)O

Procedure:
This is an oligo ester of succinic acid and 1-hydroxyethyl-4-hydroxy-2,2,6,6-tetramethylpiperidine of Ciba-Geigy, Basel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:2]2[CH:7]=[CH:6][C:5]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)(=[O:26])=[O:25])=[CH:21][CH:22]=4)[CH:17]=[CH:16][N:15]=3)=[C:4]([O:11][CH3:12])[CH:3]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(Cl)nccc2c1
Reactant: COc1cc(Cl)ccc1B(O)O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(Cl)ccc1-c1ccc(-c2nccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4 %

Procedure:
A solution of Pd(Amphos)2Cl2 (0.442 g, 0.624 mmol), (4-chloro-2-methoxyphenyl)boronic acid (1.278 g, 6.86 mmol), 1-chloro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (2.000 g, 6.24 mmol), and potassium phosphate (5.29 g, 24.94 mmol) in 30 mL dioxane/12 mL water was heated to 110° C. for 2 hours. LC/MS showed product, so the reaction mixture was allowed to cool to room temperature. The aqueous layer was removed, and the reaction mixture was treated with HCl (4N in dioxane) (6.24 ml, 24.94 mmol). After stirring for 10 minutes, the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [RediSep Gold C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(4′-chloro-2′,3-dimethoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.073 g, 0.137 mmol, 2.197% yield). 1H NMR (MeCN-d3) δ: 8.69 (m, 1H), 8.62 (s, 1H), 8.44-8.52 (m, 1H), 8.21 (d, J=6.4 Hz, 1H), 7.89-7.99 (m, 2H), 7.81 (d, J=9.0 Hz, 1H), 7.42 (m, 1H), 7.32-7.39 (m, 1H), 7.29 (s, 1H), 7.24 (m, 1H), 7.16 (d, 1H), 7.03-7.12 (m, 2H), 3.84-3.88 (m, 3H), 3.64-3.67 (m, 3H); (M+H)+=533.0.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[CH2:10]([NH:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C.CCCCCC>C(O)C>[NH2:9][C:8]1[N:17]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: CCOC=C(C#N)C#N
Reactant: NNCc1ccccc1
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cnn(Cc2ccccc2)c1N

Procedure:
A procedure analogous to that described in Example 1 was followed except 1.55 g (12.7 mM) of ethoxymethylene malononitrile was added to 1.70 g (13.9 mM) of benzylhydrazine in ethanol. Following completion of the reaction 0.82 g (33%) of the product was obtained as a tan solid; tlc, Rf =0.24, silica gel, ethyl acetate:hexane (1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19].C(=O)(O)[O-].[K+]>C1C=CC=CC=1>[CH3:27][O:26][C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([O:14][CH3:13])[C:23]=1[O:24][CH3:25])[C:18]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:19]
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc(C(=O)Nc2cccc3c2CCN(C)C3)cc(OC)c1OC
Yield: 52.3 %

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (3.76 g) was dissolved in anhydrous benzene (100 ml) and treated with 3,4,5-trimethoxybenzoyl chloride (5 g) under reflux for 16 hours in the presence of 0.25 g of anhydrous potassium bicarbonate. The precipitated solid was filtered and washed with sodium carbonate solution. The solid was recrystallized from benzene to yield 4.04 g of fine needles; mp 142.8-143.1° C.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[CH:54]=[CH:53][N:52]([CH2:55][CH2:56][O:57][CH3:58])[C:51](=[O:59])[C:50]=4[O:60][C:61]=3[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:68])[C:49]4[CH:54]=[CH:53][N:52]([CH2:55][CH2:56][O:57][CH3:58])[C:51](=[O:59])[C:50]=4[O:60][C:61]=3[C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: COCCn1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1=O
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COCCn1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1=O
Yield: 72 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[7-(2-methoxy-ethyl)-4,8-dioxo-2-phenyl-7,8-dihydro-4H-pyrano[2,3-c]pyridin-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was reacted to give the title compound as an off-white solid (48 mg, 72%). 1H NMR (400 MHz, DMSO-d6): δ 7.64 (d, J=7 Hz, 1H), 7.42-7.32 (m, 7H), 7.16-7.12 (m, 2H), 6.67 (d, J=7 Hz, 1H), 4.22 (t, J=5 Hz, 2H), 3.65 (t, J=5 Hz, 2H), 3.26 (s, 3H), 2.42-2.35 (m, 2H), 2.18-2.10 (m, 2H), 2.06-1.96 (m, 2H). LCMS (Method E): RT=2.93 min, [M+H]+=443.
Reaction SMILES: [Br:1][C:2]1[C:13]([F:14])=[CH:12][C:5]2[C:6]([C:9]([OH:11])=[O:10])=[N:7][S:8][C:4]=2[CH:3]=1.OS(O)(=O)=O.[C:20]([O-])([O-])=O.[Na+].[Na+]>CO.O>[Br:1][C:2]1[C:13]([F:14])=[CH:12][C:5]2[C:6]([C:9]([O:11][CH3:20])=[O:10])=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1nsc2cc(Br)c(F)cc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nsc2cc(Br)c(F)cc12
Temperature: 25 °C

Procedure:
6-Bromo-5-fluorobenzo[d]isothiazole-3-carboxylic acid (I-25D) (57 mg, 0.21 mmol) was suspended in dry methanol (5 mL) and H2SO4 (0.2 mL) and refluxed for 3 hours. After this time the reaction was cooled to room temperature and diluted with water (3 mL) and neutralized with 5% aquesou Na2CO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to yield methyl 6-bromo-5-fluorobenzo[d]isothiazole-3-carboxylate (I-25E). MS 289.9 and 291.9 (M+1; Br79/Br81 isotope pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Br[CH2:12][CH:13](Br)C.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:9]#[N:10])[CH2:13][CH2:12]1
Reactant: N#CCc1ccccc1Cl
Reactant: CC(Br)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2ccccc2Cl)CC1

Procedure:
A solution of 13.1 g of 2-chlorophenylacetonitrile and 20.3 g of 1,2-dibromopropane in 142 ml of DMF is mixed with 9 g of sodium hydride [55–65% in oil] at room temperature. It is stirred for several hours and carefully added to water. After extraction with ethyl acetate and filtration by silica gel, the desired product is obtained: 13.1 g
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:18]C)=[C:11]([O:16]C)[CH:12]=2)[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([OH:18])=[C:11]([OH:16])[CH:12]=2)[CH:7]=1
Reactant: COc1cc2ccc(CCCCCl)cc2cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc2ccc(CCCCCl)cc2cc1O
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To 17.0 g (0.061 mole) of 2-(4-chlorobutyl)-6,7-dimethoxynaphthalene in 350 mL of methylene chloride cooled at -70° C. under an argon atmosphere was added 122 mL (0.122 mole) of 1M boron tribromide in methylene chloride, dropwise over 30 minutes. The reaction mixture was stirred for 30 minutes at -70° C. and then kept at -20° C. for 17 hours. Workup as in Example 7 gave 2-(4-chlorobutyl)-6,7-dihydroxynaphthalene as a colorless solid (15.3g). This solid, 21.8g (0.18 mole) of benzyl bromide and 25.3g (0.18 mole) of potassium carbonate in 300 mL of acetone was stirred at reflux for 18 hours. Workup as in Example 7 and purification of the crude product by HPLC using 5% ethyl acetate-hexane gave a solid which was recrystallized from ether-hexane, to give 13.0 g (49% yield), mp 54°-59 °, of 2-(4-chlorobutyl)-6,7-bis(phenylmethoxy)-naphthalene.
Reaction SMILES: [P:1](Cl)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:17]([CH2:20][CH3:21])CC>C(Cl)Cl>[P:1]([N:17]([P:1]([N:17]([P:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH3:21])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCN(P(c1ccccc1)c1ccccc1)P(c1ccccc1)N(CC)P(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 130 %

Procedure:
A solution of PPh (NHEt)2 (0.301 g, 1.5 mmol) in CH2CH2 (20 cm3) was added to PPh2Cl (0.677 g, 3.0 mmol) dissolved in CH2Cl2 (5 cm3) containing NEt3 (0.466 g, 4.6 mmol) and stirred for two hours. The solvent was removed in vacuo affording an off white solid. The solid was washed with 3×20 cm3 aliquots of diethylether, the washings combined and the solvent then removed in vacuo yielding a white solid characterised as Ph2PN(Et)P(Ph)N(Et)PPh2 (0.540 g, 1.3 mmol) 31P [H] NMR (CD2Cl2)=53.5 [d, PPh2, 2P, J (PP)25]. 105.1 [t, PPh, J(PP) 25 Hz] ppm.
Reaction SMILES: [CH3:1][C@@:2]12[C@:19]([OH:23])(CC#N)[CH2:18][CH2:17][C@H:16]1[C@H:15]1[C:5](=[C:6]3[C:12]([CH2:13][CH2:14]1)=[CH:11][C:9](=[O:10])[CH2:8][CH2:7]3)[CH2:4][CH2:3]2.N1C=CC=C[CH:25]=1>>[CH3:25][O:10][C:9]1[CH2:11][C:12]2[CH2:13][CH2:14][C@@H:15]3[C@@H:5]([C:6]=2[CH2:7][CH:8]=1)[CH2:4][CH2:3][C@@:2]1([CH3:1])[C@H:16]3[CH2:17][CH2:18][CH:19]1[OH:23]
Reactant: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CC[C@@]2(O)CC#N
Reactant: c1ccncc1
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)C(O)CC[C@@H]32)C1

Procedure:
According to the German patent application DD 132,497 3-methoxy-17β-spiro-1′,2′-oxirane-estra-2,5(10)-diene is reacted with an alkali metal cyanide to yield a 17α-cyanomethyl-17β-hydroxy-3-enolether derivative. Then the so obtained compound is hydrolyzed, brominated and dehydrobrominated to furnish the dienogest of formula (I) hi 32% yield. The purity of the obtained dienogest is characterized by the melting point (204-214° C.) and optical rotation ([α]25D=290°, pyridine, c=0.5%). According to the method described in the patent application DD 80,023 3-methoxy-17β-spiro-1′,2′-oxirane-estra-2,5(10)-diene used as starting material can be synthesized by reacting dimethylsulfonium methylide and the 17-oxo derivative obtained by Oppenauer oxidation of the 17-hydroxy group of 3-methoxy-17-hydroxy-estra-2,5(10)-diene of formula (V)—latter synthesized by known methods.