Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:11](=O)[CH3:12])[C:6](OCC)=[O:7])#[N:2].C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20]>N1C=CC=CC=1>[NH2:21][C:19]1[N:20]=[C:6]([OH:7])[C:5]([CH2:4][CH2:3][C:1]#[N:2])=[C:11]([CH3:12])[N:18]=1
Reactant: CCOC(=O)C(CCC#N)C(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: c1ccncc1
Product: Cc1nc(N)nc(O)c1CCC#N
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A mixture of ethyl 2-(2-cyanoethyl)-3-oxobutanoate (9 g, 49 mmol), guanidine carbonate (5.30 g, 29.4 mmol) and pyridine (49 ml) was kept at 100° C. for 8 hours. The procedure according to pro-treatment of Reference-example 6 was carried out to give the object compound (3.38 g, 38.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>C(#N)C>[CH3:17][C:13]1[CH:12]=[C:11]([C:9](=[O:10])[CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cccc(C(=O)Cc2ccnc(N)c2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
To a solution of 2-(2-amino-4-pyridyl)-1-(3-methylphenyl)ethanone (24.0 g, 0.106 mol) in acetonitrile (500 mL) was added benzoylchloride (27.0 mL, 0.233 mol) at 0° C. Triethylamine (35.6 mL, 0.256 mol) was added dropwise to the obtained mixture and the mixture was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the precipitated solids were collected by filtration. The aqueous layer was extracted with ethyl acetate and the extract was washed with aqueous sodium hydrogen carbonate solution. The extract was dried and concentrated. The obtained residue and the solid were dissolved in a mixture of tetrahydrofuran (450 mL) and methanol (110 mL) and 1N aqueous sodium hydroxide solution (256 mL) was added. The reaction mixture was stirred for 2 hrs. and concentrated. The residue was extracted with ethyl acetate, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1), and the obtained oil was crystallized from ethyl ether to give the title compound (19.5 g, yield 56%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][CH2:61]O)[CH:55]=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:61][CH2:60][C:56]4[CH:55]=[N:54][CH:59]=[CH:58][CH:57]=4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: OCCc1cccnc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCc1cccnc1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 133.5 %

Procedure:
Diethyl azodicarboxylate (236 μl, 1.5 mmol) was added dropwise to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (393 mg, 1.5 mmol) and 2-(3-pyridyl)ethanol (86 mg, 0.7 mmol), (J.Heterocycl. Chem. 1992, 29, 1663), in methylene chloride (6 ml) and the mixture stirred for 4 hours at ambient temperature. The mixture was poured directly on to a silica column and eluted with methylene chloride/acetonitrile/methanol (60/35/5). The purified solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (1.5 ml of a 4.5M solution) was added. The volatiles were removed by evaporation, the solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-pyridyl)ethoxy)quinazoline hydrochloride (154 mg, 52%). 1H NMR Spectrum: (DMSOd6; CF3COOD) 3.45(t, 2H); 4.01(s, 3H); 4.56(t, 2H); 7.44(s, 1H); 7.46(d, 1H); 7.61(t, 1H); 7.67(d, 1H); 8.13(t, 1H); 8.19(s, 1H); 8.71(d, 1H); 8.88(s, 1H); 8.9(d, 1H); 9.01(s, 1H) MS-ESI: 425 [MH]+
Reaction SMILES: [CH:1]([C:4]1[CH:28]=[CH:27][C:7]2[NH:8][C:9]3[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=3[N:11]=[C:12]([N:13]3[CH2:18][CH2:17][NH:16][C@@H:15]([CH2:19][CH2:20][O:21][CH3:22])[CH2:14]3)[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].[Cl:50]CCCl>>[ClH:50].[ClH:50].[CH:1]([C:4]1[CH:28]=[CH:27][C:7]2[NH:8][C:9]3[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=3[N:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH3:31])[C@@H:15]([CH2:19][CH2:20][O:21][CH3:22])[CH2:14]3)[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: ClCCCl
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(C)C)cc32)CCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(C)C)cc32)CCN1C
Product: Cl
Reaction time: 0.17 h

Procedure:
Combine (S)-2-isopropyl-11-[3-(2-methoxy-ethyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.405 g, 1.07 mmol) and 37% formaldehyde solution (0.1 mL, 1.12 mmol) in 1,2-dichloroethane (25 mL). Stir for 10 minutes and add sodium triacetoxy borohydride (0.343 g, 1.60 mmol). Stir an additional 30 minutes and then pour solution onto saturated sodium bicarbonate solution. Extract with methylene chloride to give 0.489 g of the crude product. Silica gel chromatography, eluting with methylene chloride:methanol (100:10), gives 0.354 g of the title compound as the free base. The dihydrochloride salt precipitates in ethyl acetate as a solid: mp=210° C.; mass spectrum (ion spray): m/z=393 (M+1); Analysis for C24H34Cl2N4O: calcd: C, 61.93; H, 7.36; N, 12.04; found: C, 61.74; H, 7.47; N, 11.86.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23].[NH2:24][C:25]1[CH:36]=[CH:35][C:28]2[N:29]([CH3:34])[C:30](=[O:33])[CH2:31][S:32][C:27]=2[CH:26]=1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:24][C:25]3[CH:36]=[CH:35][C:28]4[N:29]([CH3:34])[C:30](=[O:33])[CH2:31][S:32][C:27]=4[CH:26]=3)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23]
Reactant: CN1C(=O)N(c2ccccc2Br)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CN1C(=O)CSc2cc(N)ccc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CSc2cc(Nc3ncc4c(n3)N(C)C(=O)N(c3ccccc3Br)C4)ccc21
Temperature: 140 °C

Procedure:
320 mg 3-(2-bromo-phenyl)-3,4-dihydro-7-methanesulphonyl-1-methylpyrimido-[4,5-d]pyrimidin-2(1H)-one and 626 mg 7-amino-4-methyl-4H-benzo[1,4]thiazin-3-one (starting material k)) in 4 ml NMP were treated with 92 mg TFA and heated to 140° C. for 12 hrs. The mixture was diluted with aqueous HCl and the precipitated product collected by filtration.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])[CH2:3][CH2:2]1.[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20](=[C:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O>[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20](=[C:30]3[CH2:31][CH2:32][N:33]([C:12](=[O:14])[CH2:11][NH:10][C:8](=[O:9])[O:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH2:34][CH2:35]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CNC(=O)OC1CCOCC1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)OC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{[(Tetrahydro-2H-pyran-4-yloxy)carbonyl]amino}acetic acid, 563 mg (2.06 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine and 563 mg (1.65 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were suspended in 10 ml of dichloromethane. 0.23 ml (1.65 mmol) of triethylamine was added to the obtained suspension, and they were stirred at room temperature overnight. 20 ml of dimethylformamide was added to the reaction mixture, and they were stirred at 50° C. for 3 hours. 263 mg (1.37 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, 50 mg (0.41 mmol) of 4-dimethylaminopyridine and 0.19 ml (1.37 mmol) of triethylamine were added to the reaction mixture, and they were stirred at 50° C. overnight. The resultant mixture was concentrated under reduced pressure and then ethyl acetate was added to the residue. The resultant mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by the silica gel chromatography (hexane:ethyl acetate=3:1 to 1:2) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[C:8]([O:16]CC2C=CC=CC=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[C:8]([OH:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(Cc2cccc(C(=O)O)c2O)c(OC)c(OC)c1OC
Yield: 98.3 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (0.52 g, 1.15 mmol) was dissolved in ethanol (10 ml) and after adding thereto an ethanol suspension (3 ml) of 5% Pd—C (0.15 g), the solution was stirred at room temperature for 16 hours in a hydrogen stream. The reaction solution was filtered, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.41 g, 1.13 mmol, 98%).
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][C:19]=3[Cl:24])[C:14]3[C:25](=[O:29])N[C:27](=[O:28])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]1=2.[CH3:31][O-:32].[Na+].Cl.C[OH:36]>O1CCOCC1>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[C:14]2[C:25](=[O:36])[O:29][C:27](=[O:28])[C:13]=2[C:12]2[C:11]3[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]=3[N:5]([CH2:4][CH2:3][CH2:2][O:32][CH3:31])[C:17]=2[CH:16]=1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCCBr
Reactant: CO
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COCCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)OC3=O

Procedure:
A solution of the bromide (58) (50 mg, 0.103 mmol) prepared as described in example 172 and sodium methoxide (35.2 mg, 0.65 mmol) in methanol (0.5 mL) and p-dioxane (8 mL) was refluxed for 3 h. The solution was acidified with 2N HCl, extracted with ethyl acetate and the organic layer was dried, the drying agent was removed and the solution was concentrated to dryness and chromatographed on silica. Elution with ethyl acetate gave the anhydride, 4-(2-chlorophenyl)-9-hydroxy-6-(3-methoxypropyl)-1H-furo[3,4-c]carbazole-1,3(6H)-dione as an orange powder. 1H NMR δ [(CD3)2SO] 9.57 (br, 1H), 8.24 (d, J=2.3 Hz, 1H), 8.00 (s, 1H), 7.66–7.61 (m, 2H), 7.58–7.48 (m, 3H), 7.22 (dd, J=9.0, 2.3 Hz, 1H), 4.56 (t, J=6.7 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H), 3.13 (s, 3H), 2.02 (m, 2H). The product was added to molten ammonium acetate (10 g) at 140° C. and the mixture was warmed at this temperature for 3 h. Water was added and the resultant precipitate was filtered off, adsorbed onto silica from a THF solution, and chromatographed. Elution with ethyl acetate/petroleum ether (1:1) gave (132) (32 mg, 71%) an orange powder, mp 260–262° C. 1H NMR δ [(CD3)2SO] 11.07 (br s, 1H), 9.42 (br s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 7.60–7.44 (m, 5H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 4.49 (t, J=6.6 Hz, 2H), 3.22 (t, J=6.0 Hz, 2H), 3.13 (s, 3H), 1.99 (m, 2H). FABMS found [M+H]+: 437.1088, 435.1090. C24H20ClN2O4 requires 437.1082, 435.1112.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1.[Br:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[Br:16][C:17]1[CH:22]=[C:21]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:15])[N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example A.11) (1.0 g, 4.18 mmol) and commercially available 3-bromo-benzeneboronic acid (1.09 g, 5.43 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.5 g, 33%). MS (ISP) 361.0 [(M+H)+]; mp 123° C.
Reaction SMILES: [OH-:1].[K+].[Cl-].[C:4]([C:13]([NH3+])([C:23](=[O:31])CCCCCCC)[C:14](=O)[CH2:15][CH2:16][CH2:17]CCCC)(=[O:12])[CH2:5]CCCCCC.S1(CCC[CH2:36]1)(=O)=O>>[C:23]([C:13]1[CH2:14][CH:15]([CH:16]=[CH2:17])[O:12][C:4]=1[CH3:5])([O:31][CH3:36])=[O:1]
Reactant: [OH-]
Reactant: O=S1(=O)CCCC1
Reactant: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: C=CC1CC(C(=O)OC)=C(C)O1

Procedure:
Following the procedure of Example XII, 4-carbomethoxy-2-ethyl-5-methyl-2,3-dihydrofuran was obtained by the reaction of 1,4-dichlorobutene-2 (500 grams) and methyl acetoacetate (500 grams). Five hundred grams potassium hydroxide and 30 grams tricaprylylmethylammonium chloride were also employed for the reaction which was carried out in sulfolane. One hundred thirty grams crude 4-carbomethoxy-5-methyl-2-vinyl-2,3-dihydrofuran obtained from the reaction was hydrogenated at 40 psig using 1 weight percent supported catalyst (5% Pd on carbon). Two distillations of the crude product afforded 4-carbomethoxy-2-ethyl-5-methyl-2,3-dihydrofuran in 99.4 percent purity (B.P. 124°-126° C. @ 37 mm Hg; nD25° 1.4708). The product had a very natural herbaceous odor making it suitable for lavender and chamomile formulations. The product also exhibited a very desirable safrole-like character which was not evident in the unhydrogenated precursor. The structure of the product ##STR19## was confirmed by infrared and nuclear magnetic resonance spectroscopic analysis.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C.[OH-].[Na+]>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([O:1][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
138 g. (1 mole) of 4-hydroxybenzoic acid was dissolved in 1 liter of 95% ethanol and 500 ml of 2N sodium hydroxide solution. To this solution was added 346 ml. (3 mole) of benzyl chloride and the mixture was boiled under reflux. 1 liter of 5N sodium hydroxide was added dropwise over a period of 2 hours and the mixture heated a further hour with stirring. The solvent was distilled to half its volume, 2 liters of water added, the warm aqueous solution acidified with hydrochloric acid and the precipitated product recrystallised from 80% ethanol, m.p. 188° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C1C=CN=CC=1)[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH:22]1(N=C=NC2CCCCC2)CCCCC1.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH3:4][C:1]([CH3:2])([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:40]1[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=1)[C:11]([O:13][CH3:22])=[O:12])=[O:7])[CH3:3]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: c1ccncc1
Reactant: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccncc1)NC(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a flask was charged with phosphonic acid 1 (67 mg, 0.1 mmol), methanol (0.1 mL, 2.5 mmol) and 1,3-dicyclohexylcarbodiimide (83 mg, 0.4 mmol), then pyridine (1 mL) was added under N2. The resulted mixture was stirred at 60-70° C. for 2 h, then cooled to room temperature and diluted with ethyl acetate. The mixture was filtered and the filtrate was evaporated. The residue was diluted with ethyl acetate and the combined organic phase was washed with NH4Cl, brine and water, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (isopropanol/CH2Cl2, 1% to 7%) to give 2 (39 mg, 56%) as a white solid. 1H NMR (CDCl3) δ 7.71 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 5.65 (d, J=5.1 Hz, 1H), 5.10-4.92 (m, 4H), 4.26 (d, J=9.9 Hz, 2H), 3.96-3.65 (m overlapping s, 15H), 3.14-2.76 (r, 7H), 1.81-1.55 (m, 3H), 0.91 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H); 31P NMR (CDCl3) δ 21.7; MS (ESI) 723 (M+Na).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)[CH:10]=2)[NH:5][CH2:4]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.C(OCC)(=O)C>[CH3:2][C:3]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:4]1
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)CN2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)CN2S(C)(=O)=O
Reaction time: 3 h
Yield: 63.7 %

Procedure:
5-(3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile hydrochloride (288 mg, 1.0 mmol) was dissolved in methylene chloride (5 mL) and triethylamine (0.43 mL, 3.0 mmol) was added. The mixture was treated with methanesulfonyl chloride (0.078 mL, 1.1 mmol) and stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water, 2N HCl, water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 10-60% ethyl acetate in hexane) to afford 5-[3,3-dimethyl-1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile (0.21 g). MS (EI) m/z 329.8; HPLC purity 100.0% at 210-370 nm, 9.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: BrBr.[OH:3]CCC1CC2C(C)=C(OCC3C=CC=CC=3)C(C)=C(C)C=2O1.[C:26]1([P:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1C=CN=C1>C1(C)C=CC=CC=1>[C:39]1([P:32](=[O:3])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCO)O2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: BrBr
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.8 ml of bromine in 15 ml of toluene is added, dropwise, to a solution of 4.0 gr. of 2-(RS)-(2-hydroxyethyl)-2,3-dihydro-5-benzyloxy-4,6,7-trimethylbenzofurane, 5.1 g of triphenylphosphine and 1.3 gr of imidazol in 70 ml of toluene. The mixture is stirred at room temperature for 15 minutes, after which the imidazol*HBr is filtered out and the filtrate is evaporated. The residue is treated with ethylic ether to obtain a precipitate of triphenylphosphine oxide, which is filtered out. After the residue has been evaporated, the obtained 7.7 g of raw material is purified by means of the column chromatography (SiO2), which produces 4.0 g of a yellow solid. m.p. 66°-68° C.; IR(KBr): 1549 (νC--C), 1075 cm-1 (νC--O--C); 1H-NMR (CDCl3): δ7.4-7.1 (5H,m), 5.0-4.5 (1H,m), 4.6 (2H,s), 3.5 (2H,t), 3.3-2.6 (2H,m), 2.3-2.1 (2H,m), 2.05 (9H,s).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:30])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]I>O1CCCC1>[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:30])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([NH:2][CH3:1])[CH3:28]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCI)[C@H]3[C@@H]1CCC2=O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(C)CCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
718 mg of methylamine are condensed at −78° C. into a solution of 960 mg of 11β-fluoro-3-hydroxy-7α-(6-iodo-hexyl)oestra-1,3,5(10)-trien-17-one in 9 ml of anhydrous tetrahydrofuran and the mixture is stirred overnight at room temperature in a pressure reactor. After the pressure reactor has been opened at −20° C., it is allowed to come to room temperature in order to allow excess methylamine to evaporate. The reaction solution is then added to saturated sodium hydrogencarbonate solution, extracted 3 times with ethyl acetate, dried over sodium sulphate and concentrated in vacuo. 763 mg of 11β-fluoro-3-hydroxy-7α-[5-(methylamino)hexyl]oestra-1,3,5(10)-trien-17-one are obtained as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[CH3:46][C:47]1[N:48]=[C:49]([CH:53]([NH2:55])[CH3:54])[S:50][C:51]=1[CH3:52]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:55][CH:53]([C:49]2[S:50][C:51]([CH3:52])=[C:47]([CH3:46])[N:48]=2)[CH3:54])=[O:44])=[C:18]([C:23]([F:25])([F:26])[F:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nc(C(C)N)sc1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4nc(C)c(C)s4)c(C(F)(F)F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-(trifluoromethyl)aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4,5-dimethyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (14 mg, yield 31%).