Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]Br)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH3:26][C:27]1[NH:28][CH2:29][CH2:30][N:31]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:31]2[CH2:30][CH2:29][N:28]=[C:27]2[CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC1=NCCN1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2CCN=C2C)c1
Reaction time: 2 h

Procedure:
To (2′-bromomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.070 g, 0.17 mmol) and 2-methyl-2-imidazoline (0.017 g, 0.18 mmol) in DMF (1 mL) at 0° C. was added sodium hydride (60% in mineral oil; 0.011 g, 0.18 mmol), and the reaction was stirred for 2 hours. After work-up with EtOAc, H2O, and citric acid, the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[N:10]([CH2:16][CH3:17])[CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]/[CH:28]=[C:29]1/[C:30]2[CH:43]=[C:42]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:31]=2[O:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][C:35]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[N:10]([CH2:16][CH3:17])[CH:11]2[CH2:15][CH2:14][N:13]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Nc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(C(=O)Nc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(4-chloro-phenyl)-1-ethyl-1-pyrrolidin-3-yl-urea (0.21 g, 0.8 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.16 g, 0.8 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by flash chromatography on silica using gradient elution from ethyl acetate/methanol (5%) to ethyl acetate/methanol (10%) to give the desired product as yellow solid. 1H-NMR (CDCl3) δ: 1.05 (3H, t), 1.40 (6H, s), 1.80 (1H, m), 2.20-2.40 (3H, m), 2.50-3.00 (8H, m), 3.40 (4H, q and m), 4.20 (1H, m), 5.20 (2H, br, s), 6.20 (1H, t), 6.65 (1H, d), 7.00 (2H, dd), 7.20-7.40 (5H, m), 7.70 (1H, dd), 8.50 (1H, dd) 9.80 (1H, br s). ESI-MS m/z: 561 (M+1), UV retention time: 1.45 min.
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[CH-:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1.[Ti+2:29]>>[CH:19]1([Ti:29]([CH:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)([C:11]2[C:12]([F:15])=[CH:13][CH:14]=[C:9]([N:8]=[CH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[F:16])[C:11]2[C:12]([F:15])=[CH:13][CH:14]=[C:9]([N:8]=[CH:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:10]=2[F:16])[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: [Ti+2]
Reactant: c1cc[cH-]c1
Reactant: Fc1ccc(N=Cc2ccccc2)c(F)c1
Agent: [Cl-]
Product: Fc1ccc(N=Cc2ccccc2)c(F)c1[Ti](c1c(F)ccc(N=Cc2ccccc2)c1F)(C1C=CC=C1)C1C=CC=C1

Procedure:
477.9 g (2.2 mol) of N-benzal-2,4-difluoroaniline are reacted at -10° C. with 248.8 g (1.0 mol) of titanocene dichloride analogously to Example 1, method A, to give bis(cyclopentadienyl)bis[2,6-difluoro-3-(N -benzalamino)phenyl]titanium. When the yellow-brown suspension produced has reached room temperature, it is evaporated on a vacuum rotary evaporator. The residue is taken up in 3000 ml of methylene chloride and clarified over Hyflo. The filtrate is re-evaporated. The residue is dissolved in 2000 ml of ethyl acetate, and 2000 ml of 2N hydrochloric acid solution are added. After hydrolysis has been carried out by stirring the mixture for 3 hours, the phases are separated. The organic phase is extracted three times with 200 ml of 2N hydrochloric acid solution in each case. The aqueous phases are combined and washed once with 500 ml of ethyl acetate. 500 ml of ethanol are added to the water phase, and the mixture is then neutralized using 30% sodium hydroxide solution with cooling at 10°-15° C. The mixture is then cooled to 5° C. The red-brown suspension produced is filtered and dried at 40° C. in vacuo, to give 391.8 g (90.2% of theory) of orange-red crystals which melt at 250° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].N1CCCCC1>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:17]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1ccc(Br)cc1
Yield: 88.8 %

Procedure:
4-Bromobenzaldehyde (3 g, 16.21 mmol) and ethyl cyanoacetate (1.9 ml, 17.84 mmol) in toluene was added piperidine (27 μl) and the reaction mixture was refluxed for 1 hour with a Dean-Stark separator. The solvent was removed under reduced pressure, the residue triturated with warm ethyl acetate, filtered to yield the desired product as a yellow solid (4.03 g, 89% yield). LC/MS: (PS-A2) Rt 3.44.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C@H:9]1[CH2:13][NH:12][C@@H:11]2[C@@H:14]([OH:17])[CH2:15][O:16][C@H:10]12.[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33](Cl)=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>O.O1CCOCC1>[OH:17][C@@H:14]1[C@H:11]2[N:12]([C:33]([O:32][CH2:31][CH:29]3[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:22]4[C:30]3=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:34])[CH2:13][C@H:9]([O:8][CH3:7])[C@H:10]2[O:16][CH2:15]1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CO[C@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CO[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 0.67 h
Yield: 66 %

Procedure:
A solution of sodium carbonate (239 mg, 2.26 mmol) in water (10 mL) was added whilst stirring to a solution of (3R,3aR,6S,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol in 1,4-dioxane (7 mL). A solution of 9-fluorenylmethoxycarbonyl chloride (319 mg, 1.23 mmol) in 1,4-dioxane (3 mL) was added then the mixture stirred for 40 minutes then water (30 mL) was added and the product extracted into dichloromethane (1×40 mL then 2×30 mL). The organic layer was washed with brine (50 mL), then dried (MgSO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 7:93 to 45:55 gave bicyclic alcohol (6b) (270 mg, 66%) as a white solid. TLC (Rf=0.34, EtOAc:heptane 3:2), analytical HPLC single main peak, Rt=15.990 min., HPLC-MS 382.1 [M+H]+, 404.1 [M+Na]+, 785.3 [2M+Na]+; [α]D18.5 −35.4° (c=2.758, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers major:minor 3:2; 1.02 (0.6H, d, J=3.55 Hz, OH major), 2.59 (0.40H, d, J=3.19 Hz, OH minor), 3.10 (0.6H, dd, J=12.54 and 3.89 Hz, FmocNCH2 major), 3.26 (1.8H, s, OCH3 major), 3.30 (0.4H, dd, J=12.21 and 4.19 Hz, FmocNCH2 minor), 3.35 (1.2H, s, OCH3 minor), 3.49 (0.6H, m, OCH2CHOH major), 3.52 (0.6H, dd, J=10.04 and 1.81 Hz, OCH2CHOH major), 3.55-3.59 (1.2H, m, OCH2CHOH major and FmocNCH major), 3.64 (0.6H, d, J=3.69 Hz, CHOCH3 major), 3.65-3.70 (1H, m, FmocNCH2), 3.75-3.79 (0.8H, m, OCH2CHOH minor and CHOCH3 minor), 3.85 (0.4H, dd, J=9.85 and 4.46 Hz, OCH2CHOH minor), 4.22-4.26 (1.4H, m, FmocNCH minor and Fmoc CH), 4.37 (0.6H, d, J=4.64 Hz, OCHCHOCH3 major), 4.40-4.44 (1.2H, m, Fmoc CH2 minor and OCH2CHOH minor), 4.60 (0.4H, d, J=4.94 Hz, OCHCHOCH3 minor), 4.70 (0.6H, dd, J=10.80 and 3.96 Hz, Fmoc CH2 major), 4.82 (0.6H, dd, J=10.80 and 4.25 Hz, Fmoc CH2 major), 7.29-7.80 (8H, Fmoc aromatic CH); δC (125 MHz, CDCl3) 47.248/47.378 (Fmoc CH), 49.754/50.177 (FmocNCH2), 56.868/56.996 (OCH3), 65.736/67.270 (Fmoc CH2), 68.262/69.085 (FmocNCH), 73.760/74.008 (OCH2CHOH), 75.812/76.145 (OCH2CHOH), 81.509/82.286 (OCHCHOCH3), 83.496/84.166 (OCHCHOCH3), 119.805, 119.982, 120.003, 124.494, 124.576, 124.958, 124.975, 127.019, 127.034, 127.404, 127.488, 127.637, 127.726, 127.754 and 127.865 (Fmoc aromatic CH), 143.633, 143.909, 143.943 and 144.037 (Fmoc quaternary), 154.255/155.025 (Fmoc C═O).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1F.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: Oc1ccc(F)cc1F
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2ccc(C(F)(F)F)cc2Br)c(F)c1
Temperature: 80 °C
Yield: 80.5 %

Procedure:
A mixture of 3-bromo-4-fluorobenzotrifluoride (0.5 mL, 3.52 mmol), 2,4-difluorophenol (0.337 mL, 3.52 mmol), and potassium carbonate (0.486 g, 3.52 mmol) in dimethylformamide (7 mL) was heated at 80° C. for 16 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (silica gel, 0-10% ethyl acetate/hexanes gradient) to provide the title compound (1.0 g, 80% yield).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10](O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.ClC(OC)=O.N1C=CC=CC=1.CO.C(=O)([O-])OC>C1(C)C=CC=CC=1>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH2:13][C:14]4[C@:20]3([CH3:21])[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=4)[C@@H:7]1[CH2:8][CH:9]=[CH:10]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: COC(=O)Cl
Agent: COC(=O)[O-]
Solvent: CO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1CC2
Yield: 90 %

Procedure:
This synthesis is depicted in FIG. 1. Several methods are known for the conversion of testosterone into Androsta-4,16-dien-3-one (Brooksbank et al., Biochem. J. (1950) AZ:36). Alternatively, thermolysis (460°) of the methyl carbonate of testosterone gives Androsta-4,16-dien-3-one in 90% yield. 17B-MethoxyCarbonyioxy-androst-4-en-3-one (IV) was prepared from testosterone (III. Fluka) with methyl chloroformate/pyridine (a) in 76% yield (after recrystallization from MeOH). M.p. 140-°141°, [a]D =+95.4° (c=1.10) - IR. (CDCl3): 1740s, 1665s, 1450s, 1280s, - 1H-NMR. (360 MHz): 0.87 (s, 3 H); 1.20 (s, 3H); 3.77 (s, 3H); 4.53 (br. t, J 8, 1H); 5.75 (s, 1H). A solution of the methyl carbonate IV in toluene was pyrolyzed (b) as described for I. Recrystallization of the crude product from acetone at RT. gave pure ketone 4 in 90% yield. M.p. 127°-129.5°, (a)D +118.9° (C=1.32) ([3]: m.p. 131.5°-133.5° (hexane), [a]D16 =+123°±3.5° (C=1.03)). - IR. (CDCl3): 3050w, 1660s, 1615m. - 1H-NMR. (360 MHz): 0.82 (s, 3H); 1.22 (s, 3H); 5.70 (m, 1H); 5.73 (s, 1H); 5.84 (m, 1H).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:21]=[CH:22][C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:32])(C)(C)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:15][C:14]1[CH:13]=[C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:21]=[CH:22][C:23]=3[N:24]=2)[CH:11]=[C:10]([CH3:32])[C:9]=1[O:8][CH2:7][C:6]([OH:33])=[O:5]
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4)nc3o2)cc(C)c1OCC(=O)O

Procedure:
A solution of 77 mg of [2,6-dimethyl-4-(5-phenoxy-oxazolo[5,4-d]pyrimidin-2-yl)-phenoxy]-acetic acid tert-butyl ester in 0.7 ml of trifluoroacetic acid was stirred at room temperature for 2 h. Then 5 ml of toluene were added and the solvents were distilled off in vacuo. The residue was triturated with 2 ml of acetonitrile, and the title compound was isolated by filtration. Yield: 26 mg of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Cl[C:37]1[CH:38]=[CH:39][C:40]2[O:45][CH2:44][N:43]3[C:46]4[N:52]=[CH:51][CH:50]=[CH:49][C:47]=4[CH:48]=[C:42]3[C:41]=2[N:53]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:37]4[CH:38]=[CH:39][C:40]5[O:45][CH2:44][N:43]6[C:46]7[N:52]=[CH:51][CH:50]=[CH:49][C:47]=7[CH:48]=[C:42]6[C:41]=5[N:53]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Clc1ccc2c(n1)-c1cc3cccnc3n1CO2
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5cccnc5n3CO4)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (40 mg, 0.08 mmol), 2-chloro-6H-pyrido[2,3-e]pyrido[3′,2′:4,5]pyrrolo[1,2-c][1,3]oxazine (27 mg, 0.10 mmol) and K3PO4.3H2O (64 mg, 0.24 mmol) in 1,4-dioxane/water (1.5 mL/0.2 mL), Pd2(dba)3 (5 mg), X-Phos (10 mg) were added under N2 protection. After stirred overnight at 80° C., the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (dichloromethane:MeOH=20:1) to provide the product of Compound 48 (30 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 8.34˜8.37 (m, 1H), 8.04 (s, 1H), 7.93˜8.00 (m, 3H), 7.68 (s, 1H), 7.48˜7.56 (m, 2H), 7.17˜7.24 (m, 2H), 7.10˜7.16 (m, 2H), 6.22 (s, 2H), 5.96 (br s, 1H), 3.53 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 2.76 (s, 3H). MS (M+H)+: 598.
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([NH:28][CH:29]=[O:30])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[CH:29]([NH:28][C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:51])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16]1)=[O:30]
Reactant: C[C@]12CCCCC1[C@@H](NC=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1[C@@H](NC=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 96 %

Procedure:
The title compound II-bc was prepared in 96% yield from 3,3:17,17-bis(ethylendioxy)-6α-formamidoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 8.02-7.56 (m, 2H), 3.74 (m, 1H), 2.54-0.70 (m, 20H), 1.04 (s, 3H), 0.80 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].C(N(CC)CC)C>C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: OCC(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)OCC(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 110.5 g of o-nitrobenzenesulfonyl chloride and 50.0 g of 2,2,2-trifluoroethanol in 600 ml of diethyl ether was added 52.0 g of triethylamine at 5°-15° over a 45 minute period. The reaction mixture was stirred at 25° for 1 hour then washed with water, dried over MgSO4, and stripped in vacuo to give 2,2,2-trifluoroethyl 2-nitrobenzenesulfonate as an oil weighing 110.3 g.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([CH3:27])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH:24]3[CH2:26][CH2:25]3)[CH3:23])[CH:16]=2)=[CH:9][CH:8]=1)C.[OH-].[K+]>C(O)C.O1CCCC1>[CH:24]1([N:22]([CH2:21][C:17]2[CH:16]=[C:15]([C:14]#[C:13][C:10]3[CH:11]=[CH:12][C:7]([CH:6]=[C:5]([CH3:27])[C:4]([OH:28])=[O:3])=[CH:8][CH:9]=3)[CH:20]=[CH:19][CH:18]=2)[CH3:23])[CH2:25][CH2:26]1
Reactant: CCOC(=O)C(C)=Cc1ccc(C#Cc2cccc(CN(C)C3CC3)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=Cc1ccc(C#Cc2cccc(CN(C)C3CC3)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A solution of 3-(4-{3-[(cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-2-methyl-acrylic acid ethyl ester (Intermediate 94, 0.15 g, 0.4 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 3M solution of potassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature for overnight. The reaction mixture was concentrated, neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to a solid. The solid was subjected to flash column chromatography using 5% methanol in ethyl acetate as the eluent to afford the title product as an amorphous solid (0.115 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:22]3[CH2:27][CH:26]([CH3:28])[O:25][CH:24]([CH3:29])[CH2:23]3)[CH:8]=2)[N:3]=1.[S:30]([O:40][NH2:41])([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>CN(C)C=O.ClCCl>[S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)([O-:40])(=[O:32])=[O:31].[NH2:41][N+:3]1[C:4]2[C:9](=[CH:8][C:7]([N:22]3[CH2:23][CH:24]([CH3:29])[O:25][CH:26]([CH3:28])[CH2:27]3)=[CH:6][CH:5]=2)[C:10]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([C:12]#[N:13])[C:2]=1[NH2:1]
Reactant: CC1CN(c2ccc3nc(N)c(C#N)c(NCc4ccccc4)c3c2)CC(C)O1
Reactant: Cc1ccc(S(=O)(=O)ON)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CN(c2ccc3c(c2)c(NCc2ccccc2)c(C#N)c(N)[n+]3N)CC(C)O1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 5 h

Procedure:
To the solution of 3.2 g of 2-amino-3-cyano-4-benzylamino-6-(2,6-dimethylmorpholin-4-yl)quinoline in 20 ml dimethylformamide, 2.2 g of O-tosylhydroxylamine in 25 ml dichloromethane is dropped at 20° C. in 15 minutes. After 5 hours of stirring the precipitated crystalline material is filtered off. After drying 3.4 g of the title compound is obtained (MH+:403).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=1[Cl:30])[C:10]([CH2:17][CH3:18])=[N:11]2.CO.[OH-].[Li+].O>C(O)(=O)C>[Cl:30][C:21]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[CH2:19][C:9]1[C:10]([CH2:17][CH3:18])=[N:11][C:12]2[C:7]([C:8]=1[O:31][CH:32]([F:34])[F:33])=[C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A mixture of [3-(2-chloro-4-methanesulfonylbenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (1.0 g), methanol (38 mL), 5.0 M aqueous lithium hydroxide solution (0.8 mL) and water (1.6 mL) was stirred at room temperature for 35 minutes. The pH of the mixture was adjusted to 4 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water (4.0 mL) and the solid collected by filtration, washed with water and dried to afford to title compound as a cream solid, 0.66 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.C([N:13]([CH2:16]C)CC)C.[C:18](C1NC=CN=1)(C1NC=CN=1)=[O:19]>C1COCC1>[CH3:18][O:19][N:13]([CH3:16])[C:8]([C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=1)=[O:10]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
To a solution of commercially-available 4-bromopicolinic acid (10.0 g, 49.5 mmole) in 200 mL of anhydrous THF at room temperature is added N,O-hydroxylamine hydrochloride (4.83 g, 49.5 mmol), triethylamine (6.9 mL, 49.5 mmol), carbonyl diimidazole (CDl) (12.0 g, 74.3 mmol) and N,N-dimethyl amino pyridine (DMAP) (20 mg, 0.16 mmol). After stirring at room temperature for 4 hours, an aliquot is taken and injected on LC-MS to check the reaction progress. Upon completion of the reaction, the reaction mixture is quenched with 100 mL of water and extracted with 2×150 mL of ethyl acetate. The combined organic layers are concentrated and purified by chromatography (hexanes 95%, EtOAc 5% step gradient) to give 4-bromo-pyridine-2-carboxylic acid methoxy-methyl-amide (1) as a thick yellow oil (10.4 g, yield 86%) MS ES+247.02.