Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11](I)=[C:10]([S:13][CH3:14])[N:9]=[C:8]([NH2:15])[N:7]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][O:20][C:16](=[O:19])/[CH:17]=[CH:18]/[C:11]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]([NH2:15])=[N:9][C:10]=1[S:13][CH3:14]
Reactant: C=CC(=O)OC
Reactant: CSc1nc(N)nc(-c2ccco2)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1c(SC)nc(N)nc1-c1ccco1
Temperature: 100 °C
Yield: 48.6 %

Procedure:
A stirred suspension of 457 mg (1,37 mmol) 4-furan-2-yl-5-iodo-6-methylsulfanyl-pyrimidin-2-ylamine, 0.25 ml (2.77 mmol) methyl acrylate, 96 mg (0.14 mmol) bis(triphenylphosphine)palladium(II) chloride and 0.67 g (2.06 mmol) cesium carbonate in 5 ml dioxane under argon in a sealed tube was heated at 100° C. for 16 h. After cooling to room temperature, the mixture was diluted with 50 ml ethyl acetate, filtered, and the filtrate was concentrated in vacuo. Flash chromatography (1/2-1/1 ethyl acetate/hexane) followed by trituration in ether/pentane afforded 194 mg (49%) (E)-3-(2-amino-4-furan-2-yl-6-methylsulfanyl-pyrimidin-5-yl)-acrylic acid methyl ester as an off-white crystalline solid. ES-MS m/e (%): 292 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]=[C:57]=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:57]([NH:56][CH3:55])=[O:58])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CN=C=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and methyl isocyanate as starting materials in 43% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.40 (m, 2H), 9.05 (s, 1H), 8.33 (m, 2H), 8.20 (s, 1H), 7.63 (m, 1H), 7.30 (m, 1H), 7.09 (m, 1H), 6.38 (m, 1H), 3.92 (m, 2H), 2.97 (s, 4H), 2.68 (m, 2H), 2.55 (s, 3H), 2.28 (m, 2H), 1.91 (m, 1H), 1.64 (m, 2H), 1.09 (m, 2H). LCMS for C26H30ClN8O2 (M+H)+: m/z=521.2.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1>ClCCl.C(N(CC)CC)C>[O:16]([CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH2:9][CH2:10]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC1CCN(CCOc2ccccc2)CC1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCC1CCN(CCOc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of propionyl chloride (2.37 g) in dichloromethane (10 ml) was added dropwise to a solution of 4-aminomethyl-1-(2-phenoxyethyl)piperidine (6.0 g) in dichloromethane (50 ml) and triethylamine (3.9 ml) at 0° C. The solution was allowed to warm up to ambient temperature with stirring and then stirred at this temperature for a further 2 hours. More propionyl chloride (0.3 ml) was added at ambient temperature and the solution stirred for a further half-hour. Further propionyl chloride (0.3 ml) was added and the mixture stirred for 1 hour. The mixture was extracted with 2M hydrochloric acid. The combined acidic extracts were washed with ethyl acetate, then basified with sodium hydroxide solution and extracted with dichloromethane to give an oil which solidified on standing to give N-[1-(2-phenoxyethyl)piperid-4-ylmethyl]propionamide, m.p. 85°-86° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH2:23]([O:33][C:34]([NH:36][C:37]1[N:45]=[CH:44][N:43]=[C:42]2[C:38]=1[N:39]=[CH:40][N:41]2[CH2:46][C:47](O)=[O:48])=[O:35])[C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:47](=[O:48])[CH2:46][N:41]1[CH:40]=[N:39][C:38]2[C:42]1=[N:43][CH:44]=[N:45][C:37]=2[NH:36][C:34]([O:33][CH2:23][C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1)=[O:35])[CH3:2]
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccc4c(c3)OCO4)ncnc21
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OCc3ccc4c(c3)OCO4)ncnc21
Yield: 85 %

Procedure:
The title compound (2.96 g, 85%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [6-N-(piperonyloxycarbonyl)-adenin-9-yl]-acetic acid (1.86 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.63 (s, 1H), 8.98 (brs, 0.6H), 8.77 (brs, 0.4H), 8.57 (s, 0.4H), 8.52 (s, 0.6H), 8.29 (d, 1H), 8.27 (m, 1H), 8.17 (d, 1H), 7.65 (m, 2H), 7.04 (s, 1H), 6.94 (d, 1H), 6.90 (d, 1H), 6.01 (s, 2H), 5.36 (s, 1.2H), 5.15 (s, 0.8H), 5.10 (s, 2H), 4.45 (s, 0.8H), 4.17 (q, 0.8H), 4.07 (s, 1.2H), 4.01 (q, 1.2H), 3.70 (t, 1.2H), 3.48 (t, 1.2H), 3.41 (t, 0.8H), 3.22 (t, 0.8H), 1.23 (t, 1.2H), 1.12 (t, 1.8H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.C(O[C:14]([N:16]1[CH2:21][CH2:20][O:19][CH:18]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:17]1)=O)(C)(C)C>CC(N(C)C)=O>[CH3:14][N:16]1[CH2:21][CH2:20][O:19][CH:18]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCOC(COc2ccccc2CCCCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: CN1CCOC(COc2ccccc2CCCCc2ccccc2)C1
Yield: 76.5 %

Procedure:
115 mg of potassium carbonate and 118 mg of methyl iodide were added to a solution of 300 mg of 2-[2-(4-phenylbutyl)phenoxymethyl]morpholine hydrochloride (prepared as described in Example 7) in 6 ml of dimethylacetamide, and the resulting mixture was allowed to react at room temperature for 3 hours. At the end of this time, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting yellow oily residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 183 mg (yield 65%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21]C)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8]C.[CH3:23]C1C(NC2C3C(=CC=CC=3)CCC2)=NC(C)=CN=1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:23]2)=[N:6][C:7]=1[CH3:8]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: Cc1cnc(C)c(NC2CCCc3ccccc32)n1
Product: Cc1nc(NC2CCCc3ccccc32)c(C)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.92, 2.08, 2.29, 2.53, 2.86, 4.48, 5.40, 7.21, 7.33; 13C NMR (CDCl3) δ 19.63, 20.32, 23.67, 29.81, 30.00, 49.20, 124.85, 126.66, 127.69, 129.23, 129.63, 137.17, 138.12, 138.25, 148.78, 151.23; MS (ESI+) for C16H18N3Br1 m/Z 333.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:29][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=2)=[O:9])=[CH:4][C:3]=1[O:41][CH3:42].[N:43]1([C@@H:49]2[CH2:54][CH2:53][CH2:52][CH2:51][C@H:50]2O)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH3:42][O:41][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[C:11]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:29][C:12]=3[S:13][C:14]=2[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:19][CH:20]=2)=[O:9])[CH:6]=[CH:7][C:2]=1[O:1][C@@H:50]1[CH2:51][CH2:52][CH2:53][CH2:54][C@H:49]1[N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1O
Reactant: O[C@@H]1CCCC[C@H]1N1CCCCC1
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1O[C@@H]1CCCC[C@H]1N1CCCCC1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield by essentially following the procedures outlined in Example 20, Part B, from 6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 4-hydroxy-3-methoxyphenyl ketone (Example 81, Part F) and (±)-trans-2-(1-piperidyl)cyclohexanol (Example 20, Part A).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH:9]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:26][CH:27]=1
Reactant: CCOP(=O)(OCC)C(Oc1ccc([N+](=O)[O-])cc1)P(=O)(OCC)OCC
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: CCOP(=O)(OCC)C(Oc1ccc(N)cc1)P(=O)(OCC)OCC
Reaction time: 3 h

Procedure:
A solution of tetraethyl (4-nitrophenoxymethylene)-bisphosphonate (11 g) in methanol (120 ml) in a nitrogen atmosphere was cooled in ice and treated with hydrazine hydrate (5.3 ml) and 10% palladium on carbon (2.4 g). Stirring was continued for 3 hours at room temperature, and the catalyst was removed by filtration. The filtrate was evaporated in vacuo, and the crude product was purified by column chromatography on silica gel to give a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][Si:11]([CH3:27])([CH3:26])[O:12][Si:13]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])([CH3:15])[CH3:14].[N:28]#[C:29]Br.[CH2:31]([N:33](CC)CC)C>C(Cl)Cl>[O:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][CH2:16][Si:13]([CH3:14])([CH3:15])[O:12][Si:11]([CH2:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C:29]#[N:28])([CH3:27])[CH3:26])[C:31]#[N:33]
Reactant: C[Si](C)(CCCc1ccccc1O)O[Si](C)(C)CCCc1ccccc1O
Reactant: N#CBr
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(CCCc1ccccc1OC#N)O[Si](C)(C)CCCc1ccccc1OC#N
Yield: 99.4 %

Procedure:
To a 750 ml methylene chloride solution containing 40.2 g (0.1 mole) of 1,3-bis-(3'-(2-hydroxylphenyl)-propyl)-1,1,3,3-tetramethyldisiloxane from A above is added 25.42 g (0.24 mole, 97% purity) of cyanogen bromide (CNBr) at -30° C. and 26.31 g (0.26 mole, 98% purity) of triethylamine is then added at -30° C. in 15 minutes. An exothermic reaction is observed. After completion of addition, the reaction temperature is maintained at -25° C. to -15° C. for 30 minutes and -15° C. to -5° C. for 30 min. The mixture is then hydrolyzed with 150 ml H2O and washed once with 0.2N HCl and three times with 150 ml portions of H2O. The solution is dried over MgSO4, resulting in 45 g of a viscous liquid after stripping off solvent at <145° C./<10 mm Hg. The structure is confirmed by IR and 1H NMR. IR(neat): 3350 cm-1 (aromatic hydroxyl disappeared), 2250 cm-1 (strong --CN); 1H NMR (CDCl3): 0 to 0.8 ppm (m, Si--CH3 and Si--CH2 --), 1.6-2.0 ppm (m, --CH2 --), 2.8 p pm(t, --CH2 --), 7.3-7.6 ppm (m, Ar--H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:13]2[NH:14][C:15](=[O:22])[NH:16][C:17](=[O:21])[C:18]=2[CH2:19][CH3:20])[C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[I-].[Li+].CS([CH2:29]/[CH:30]=[CH:31]/[CH3:32])(=O)=O>CN(C=O)C.CCOCC>[CH2:29]([N:14]1[C:13]([N:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[C:10](=[O:12])[CH3:11])=[C:18]([CH2:19][CH3:20])[C:17](=[O:21])[NH:16][C:15]1=[O:22])[CH:30]=[CH:31][CH3:32]
Reactant: CCc1c(N(C(C)=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: C/C=C/CS(C)(=O)=O
Agent: [I-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC=CCn1c(N(C(C)=O)c2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Reaction time: 13 h
Yield: 40.9 %

Procedure:
To a stirred solution of N-(3,5-dimethyl-phenyl)-N-(5-ethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-acetamide (109) (602 mg, 2 mmol) anhydrous powdered K2CO3 (276 mg, 2 mmol), and lithium iodide (268 mg, 2 mmol) in DMF (6 mL), was added 1-methanesulfonyl-trans-2-butene (283 μL, 2.4 mmol). After stirring for 13 hr., the reaction mixture was diluted with ether, washed with water, dried with MgSO4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:1)) to afford 291 mg (40%) of a white solid. m.p. 218-220° C.; m/z (EI) 355(M+).
Reaction SMILES: [CH3:1][O:2][C:3]1S[CH:5]=[CH:6][C:7]=1Br.C([Li])CCC.[NH:14]1[C:22](=[O:23])[C:20](=[O:21])[C:18](=[O:19])[NH:17][C:15]1=[O:16].CC[O:26]CC>O1CCCC1>[OH:21][C:20]1([C:7]2[CH:6]=[CH:5][O:26][C:3]=2[O:2][CH3:1])[C:18](=[O:19])[NH:17][C:15](=[O:16])[NH:14][C:22]1=[O:23]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: CCOCC
Reactant: COc1sccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1occc1C1(O)C(=O)NC(=O)NC1=O
Temperature: 25 °C

Procedure:
2-Methoxy-3-bromothiophene is reacted with n-butyl lithium in ether at 0° to 5° C., following the method of Sornay et al. [Bull. soc. chim. Fr. (3), p. 999 (1971)]. The organolithium reagent is cooled to -10° to -20° C. and reacted with an equivalent of alloxan in tetrahydrofuran. The reaction mixture is allowed to warm to room temperature and 5-hydroxy-5-(2-methoxy-3-furyl)-2,4,6(1H,3H,5H)pyrimidinetrione isolated according to the method of Example 5.
Reaction SMILES: [CH3:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C@@H:12]2[C@H:17]3[CH2:18][O:19][C@H:15]([O:16]3)[C@H:14]([O:20][S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C@H:13]2[OH:31])=[CH:7][CH:6]=1>CN(C)C=O.[Ag]=O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C@@H:12]2[C@H:17]3[CH2:18][O:19][C@H:15]([O:16]3)[C@H:14]([O:20][S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C@H:13]2[O:31][CH3:1])=[CH:7][CH:6]=1
Reactant: COc1ccc(O[C@H]2[C@H](O)[C@@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]3OC[C@H]2O3)cc1
Reactant: CI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COc1ccc(O[C@H]2[C@H](OC)[C@@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]3OC[C@H]2O3)cc1
Reaction time: 16 h
Yield: 93.1 %

Procedure:
Methyl iodide (54 ml, 954 mmol) and silver oxide (18.4 g, 79.5 mmol) are added to a solution of compound 88 (3.36 g, 7.95 mmol) in dry N,N-dimethylformamide (8 ml). After stirring for 16 h, the mixture is filtered (Celite), diluted with ethyl acetate (300 ml), washed with water (3×100 ml), dried (sodium sulphate), filtered, concentrated and purified by chromatography on silica to give the derivative 89 (3.23 g, 80%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCOCc1ccccc1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1ccc(CNCCCOCc2ccccc2)cc1

Procedure:
A solution of 6.0 g (22 mmol) of 4-bromomethyl-2'-cyanobiphenyl, 5.8 g (35 mmol) of 3-benzyloxypropylamine (Synthesis 1975, 590) and 3.6 g of triethylamine in 50 ml of 1,4-dioxane is heated to boiling under reflux for 18 hours. After working up analogously to Example 23 a), an oil is obtained which, after flash-chromatographic purification (ethanol:ethyl acetate: 1:4), gives the title compound (TLC system B7; Rf value 0.39).
Reaction SMILES: CO[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C@@H]3[C@@H](CC[C:20]=2[CH:21]=1)[C@H]1[C@@](C)([C@@H](OCOC)CC1)CC3.COCCl.[CH3:31][C@@:32]12[C@@H:40]([OH:41])[CH2:39][CH2:38][C@H:37]1[C@@H:36]1[CH2:42][CH2:43][C:44]3[CH:49]=[C:48]([OH:50])[CH:47]=[CH:46][C:45]=3[C@H:35]1[CH2:34][CH2:33]2.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:3][O:4][CH2:5][CH2:21][CH2:20][CH2:8][CH2:7][CH2:6][C@@H:43]1[CH2:42][C@@H:36]2[C@H:35]([CH2:34][CH2:33][C@@:32]3([CH3:31])[C@H:37]2[CH2:38][CH2:39][CH:40]3[OH:41])[C:45]2[CH:46]=[CH:47][C:48]([OH:50])=[CH:49][C:44]1=2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: COCOc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OCOC)CC[C@@H]12
Agent: COCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCCC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(O)CC[C@@H]23)c2ccc(O)cc21
Reaction time: 18 h

Procedure:
(8R,9S,13S,14S,17S)-3,17-bis(methoxymethoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene—Chloromethyl methyl ether (7.0 mL, 92.0 mmol) is added to a solution of β-estradiol (5 g, 18.4 mmol) and diisopropylethylamine (16.0 mL 92 mmol) in 100 mL of THF. The reaction mixture is heated to reflux and stirred for 18 hours. The THF is removed in vacuo, and the yellow/brown oil is partitioned between water and CH2Cl2. The organic layer is separated, washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo to give a golden oil. Purification by silica gel column chromatography (10% EtOAc/Hex) affords the title compound as a viscous, clear oil (5.7 g, 86%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH:18](Cl)(Cl)Cl>>[CH3:17][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH:10]2[CH2:11][CH2:13][CH2:18]2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH3:17][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[O:8])[CH:3]1[C:14]([O-:16])=[O:15]
Reactant: ClC(Cl)Cl
Reactant: CC(C)COC(=O)C=CC1C(C(=O)O)C1(C)C
Product: CC(C)COC(=O)C=CC1C(C(=O)[O-])C1(C)C
Product: CC1(C)C(C=CC(=O)OC2CCC2)C1C(=O)O

Procedure:
Using the procedure of Example 9, the product of Step C and (3-propyn-2-yl-2,5-dioxo-imidazolidinyl)-methanol were reacted to obtain (3-propyn-2-yl-2,5-dioxo-imidazolidinyl)-methyl (1R, cis, ΔZ) 2,2-dimethyl-3-(3-isobutoxy-3-oxo-1-propenyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =+20.5°±1.5° (c=1% in chloroform).
Reaction SMILES: [F:1][C:2]1[C:11]([C:12](=[O:29])[CH2:13][N:14]2[CH2:19][CH2:18][C:17]([OH:28])([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:30])[NH:7]2.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[C:11]([CH:12]([OH:29])[CH2:13][N:14]2[CH2:15][CH2:16][C:17]([OH:28])([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[CH2:18][CH2:19]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:30])[NH:7]2
Reactant: COc1cccc(C2(O)CCN(CC(=O)c3ccc4c(c3F)CCC(=O)N4)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc(C2(O)CCN(CC(O)c3ccc4c(c3F)CCC(=O)N4)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
The mixture of 5-Fluoro-6-[[4-hydroxy-4-(3-methoxyphenyl)-1-piperidinyl]acetyl]-3,4-dihydroquinolin-2(1H)-one (630 mg, 1.5 mmol) and sodium borohydride (57 mg, 1.5 mmol) in ethanol (17 ml) was stirred at room temperature overnight. To the mixture was added water and extracted with dichloromethane. The extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane/methanol=10/1) to afford 5-Fluoro-6-[1-hydroxy-2-[4-hydroxy-4-(3-methoxyphenyl)-1-piperidinyl]ethyl]-3,4-dihydroquinolin-2(1H)-one as a yellow solid (220 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:6]([SH:15])[CH:5]=1.F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:18]=1[C:27]([F:30])([F:29])[F:28]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:6]([S:15][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][C:18]=2[C:27]([F:28])([F:30])[F:29])[CH:5]=1
Reactant: CS(=O)(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(O)CCc1ccc(Cl)cc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2CCC(=O)O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% wt. disp. oil, 0.063 g) was added to a solution of the product from step (iii) (0.180 g) in dry DMF (10 ml) and stirred at RT for 1 h before adding the product from example 44 step (i) (0.188 g). The mixture was heated at 80° C. for 1 h, then partitioned between 2M hydrochloric acid/ethyl acetate. The organics were dried, concentrated under reduced pressure to give an oil. The residue was purified by reverse phase HPLC.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH:21]=[CH:22][C:23]=1[Cl:24].FC(F)(F)C(O)=O>C1COCC1.CCCCCCC>[CH2:10]([N:4]1[CH2:3][CH:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH:26]([C:27]([OH:29])=[O:28])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (16.87 g, 0.071 mol) and (E)-3-(3,4-Dichloro-phenyl)-acrylic acid (7.71g, 0.036 mol) in THF (50 mL) was added trifluoroacetic acid (0.19 mL, 0.002 mol) at 0° C. The mixture was gradually warmed to room temperature and stirred overnight. It was then diluted with n-heptane (250 mL). The resulted white precipitation was collected and washed with heptane affording 11.6 g (94%) of the title compound as a white solid. ES-MS m/e: 350.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[O:8]=[S:9]1(=[O:26])[CH2:14][CH2:13][N:12]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:11]2=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:11]3=[N:10][S:9](=[O:26])(=[O:8])[CH2:14][CH2:13][N:12]3[CH:15]=[CH:16][CH:17]=2)=[CH:24][CH:23]=1
Reactant: Clc1ccccn1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccn4)cc3)C2=N1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
2-Chloropyridine (0.132 mL) was added to a solution of 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (300 mg) and potassium carbonate (390 mg) in DMSO (6 mL). The mixture was stirred at 120° C. under nitrogen overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and crystallized from THF—IPE to give the title compound (3.3 mg) as colorless crystals.