Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:19])[C:11](=[O:18])[CH:12]=[CH:13][C:14]=2[C:15]([OH:17])=O)=[C:4]([F:20])[CH:3]=1.[CH:21]([O:23][CH2:24][CH2:25][O:26][NH2:27])=[CH2:22]>>[CH:21]([O:23][CH2:24][CH2:25][O:26][NH:27][C:15]([C:14]1[CH:13]=[CH:12][C:11](=[O:18])[N:10]([CH3:19])[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:20])=[O:17])=[CH2:22]
Reactant: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)ccc1=O
Reactant: C=COCCON
Product: C=COCCONC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Yield: 60 %

Procedure:
2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.020 g, 0.059 mmol) was coupled as described previously in Example 154 using O-(2-vinyloxy-ethyl)-hydroxylamine to yield 0.015 g (60%) pure desired product as a yellow solid.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:18](OCC)=[O:19].[H-].[Na+].O>COCCOC>[CH:18]([CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:19]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A mixture of ethyl 3-(1-naphthyl)propionate (18.01 g) and ethyl formate (8.88 g) was added to a suspension of sodium hydride (57% dispersion in oil, 4.43 g) in 1,2-dimethoxyethane stirred at 5°, and the mixture was stirred at 5° for one hour and allowed to warm to room temperature. Water (300 ml) was added and the mixture was extracted with chloroform and the residual aqueous phase adjusted to pH 4 with hydrochloric acid: the mixture was extracted with ether and the extracts evaporated to give ethyl 2-formyl-3-(1-naphthyl)propionate (16.05 g) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH:24]3[NH2:31])[CH2:22]1)[CH2:28]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:31][CH:24]2[CH:23]3[CH2:29][CH:27]4[CH2:28][C:21]([OH:20])([CH2:30][CH:25]2[CH2:26]4)[CH2:22]3)=[O:17])(=[O:11])=[O:12])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)NC(C)(C)C(=O)O)cc1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(S(=O)(=O)NC(C)(C)C(=O)NC2C3CC4CC2CC(O)(C4)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
2-(4-acetylphenylsulfonamido)-2-methylpropionic acid (109 mg, 0.38 mmol), 5-hydroxy-2-adamantanamine (127 mg, 0.76 mmol), and BOP (168 mg, 0.38 mmol) were charged, and CH2Cl2 (5 ml) was added thereto, followed by stirring for 30 minutes at room temperature. DIPEA (0.18 ml, 1.14 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated using CH2Cl2 and H2O, dried with MgSO4, and filtered. Then, through vacuum distillation, the solvent was removed, and the resultant product was purified with column chromatography to obtain 2-(4-acetylphenylsulfonamido)-N-(5-hydroxyadamantane-2-yl)-2-methylpropanamide (110 mg, 0.25 mmol, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](Cl)=[O:34]>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]([C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[O:34])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(Cl)c1ccco1
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)c3ccco3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 2-furoyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.68 (t, J=7.33 Hz, 3H) 1.25-1.36 (m, J=7.39, 7.39, 7.39, 7.39 Hz, 2H) 2.25 (t, J=6.69 Hz, 2H) 6.73-6.83 (m, 2H) 7.41 (d, J=3.28 Hz, 1H) 7.63 (t, J=7.58 Hz, 1H) 7.74 (d, J=8.59 Hz, 2H) 7.83-7.95 (m, 2H) 8.00 (s, 1H) 8.08 (d, J=8.59 Hz, 2H) 8.15 (d, J=8.08 Hz, 1H) 10.55 (s, 1H); ESI-MS: m/z calc'd for C26H22N4O3S 470.54. found 471.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.Cl.[CH3:22][O-:23].[Na+]>CN(C)C=O>[CH:22]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:23]
Reactant: C[O-]
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CNc1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Reaction time: 0.08 h

Procedure:
A stirred solution of 15.7 g of 1-(2-amino-4-trifluoromethylphenyl)indoline.HCl in 75 ml of dry dimethylformamide, kept under N2, is immersed in an oil bath preheated to 100° C. After 5 minutes, 8.1 g of fresh, solid sodium methoxide is added in one portion. The mixture is quickly (15 minutes) brought to reflux, and kept at reflux an additional 45 minutes. The heating bath is then removed and when the internal temperature falls to 100° C., 300 ml of water is added in portions, with vigorous stirring. The product separates first as an oil which then solidifies. This material is filtered, washed with H2O, with alcohol, and dried to afford 1-(2-formamido-4-trifluoromethylphenyl)indoline, m.p. 135°-357° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH3:20].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCCBr
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 64.3 %

Procedure:
A mixture of 3.0 g of 6-fluoro-3-(4-piperidinyl)-1H-indazole, 1.8 g of 1-bromopropane, 2.5 g of sodium bicarbonate and 30 ml of dimethylformamide was stirred and heated at 60° for 2 hr. After stirring at ambient temperature for 14 hr, the reaction was poured into water and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. Recrystallization of the residue from ethyl acetate yielded 2.3 g (63%) of product. This material was combined with a sample from another experiment and recrystallized from ethyl acetate to yield the analytical sample, mp 175°-177° C.
Reaction SMILES: S[C:2]1[N:3]=[C:4]([OH:11])[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.N>O.[Ni]>[N:7]1[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=2[C:4]([OH:11])=[N:3][CH:2]=1
Reactant: Oc1nc(S)nc2c1CCC2
Agent: [Ni]
Agent: N
Solvent: O
Product: Oc1ncnc2c1CCC2
Yield: 100 %

Procedure:
To a solution of 2-mercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12.2 g, 72.5 mmol) in water (200 ml) was added Raney Ni (8 g, slurry in water) and followed by concentrated ammonia solution (27 mmol). The mixture was refluxed for 6 hour. The catalyst was filtered off. The solvent was removed under vacuum to afford 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.87 g, 99%). 1H NMR (CD3OD, 400 MHz) δ 8.07 (s, 1H), 2.89-2.85 (m, 2H), 2.80-2.76 (m, 2H), 2.23 (m, 1H), 2.13-2.05 (m, 2H), 1.64 (m, 1H).
Reaction SMILES: Cl[C:2]1C=CC(C(N=C=O)(C)C)=C[CH:3]=1.[C-]#N.C1(NO)C=CC=CC=1.[Cl:24][C:25]1[CH:44]=[CH:43][C:28]([C:29]([NH:32][C:33](=[O:42])[N:34]([OH:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([CH3:31])[CH3:30])=[CH:27][CH:26]=1.[O-]CC.[Na+].C(Br)C>C(OCC)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:32][C:33](=[O:42])[N:34]([O:41][CH2:2][CH3:3])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([CH3:30])[CH3:31])=[CH:43][CH:44]=1
Reactant: CC(C)(N=C=O)c1ccc(Cl)cc1
Reactant: CC(C)(NC(=O)N(O)c1ccccc1)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: ONc1ccccc1
Agent: [C-]#N
Solvent: CCBr
Solvent: CCOCC
Product: CCON(C(=O)NC(C)(C)c1ccc(Cl)cc1)c1ccccc1
Temperature: 60 °C

Procedure:
A solution of 19.6 g of p-chloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, in 10 ml of diethyl ether was added dropwise to a solution of 10.9 g of N-phenylhydroxylamine in 10 ml of diethyl ether. After completion of the addition, the mixture was stirred for 30 minutes whereby 3-(p-chloro-α,α-dimethylbenzyl)-1-hydroxy-1-phenylurea precipitated. The resulting crystals were separated by filtration and dried. A 3.0 g portion of the crystals thus obtained was added to 10 ml of an ethanolic solution of 750 mg of sodium ethoxide, and, after the crystals had been completely dissolved, 1.2 g of ethyl bromide was added thereto followed by heating at 60° C. for 2 hours. The solvent was then removed by distillation under reduced pressure, and the resulting residue was extracted with water and benzene. The benzene layer was washed successively with 2N aqueous sodium hydroxide and water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to precipitate crystals which were then recrystallized from a mixture of benzene and hexane to obtain 3.1 g of the title compound as white crystals.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[F:4][C:5]([F:15])([F:14])[C:6]([F:13])([F:12])[C:7](OCC)=[O:8].C([Li])CCC.CCCCCC>>[F:12][C:6]([F:13])([C:5]([F:15])([F:14])[F:4])[C:7]([CH2:2][C:1]#[N:3])=[O:8]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Product: N#CCC(=O)C(F)(F)C(F)(F)F
Yield: 77.8 %

Procedure:
Acetonitrile (4.1 g, 0.10 mole), ethyl pentafluoropropionate (9.61 g, 0.05 mole) and a solution of n-butyllithium in n-hexane (70 ml, 0.11 mole) were reacted according to the same procedure as described in Example 1 to give 7.28 g (77.8%) of the title compound. When the resulting compound was dissolved in CDCl3 and its NMR was measured, the ratio of the keto form/the enol form was found to be 26/74, m.p. 47°-54° C. (deliquescence), b.p. 69°-71° C./18 mmHg.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2].[BH4-].[Li+].CCOC(C)=O>C1COCC1>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2]
Reactant: COC(=O)c1ccc(C#N)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the ester from Step D (48.8 g, 255 mmol) in 400 mL of dry THF under argon at room temperature was added lithium borohydride (255 mL, 510 mmol, 2M THF) over 5 minutes. After 1.5 hours, the reaction was warmed to reflux for 0.5 hours, then cooled to room temperature. The solution was poured into EtOAc/1N HCl soln. [CAUTION], and the layers were separated. The organic layer was washed with water, sat Na2CO3 soln. and brine (4×), dried (Na2SO4), and concentrated in vacuo to provide the titled product.
Reaction SMILES: Br[C:2]1[C:3](=[O:22])[N:4]([C:9]2[CH:10]=[C:11]([CH:17]=[C:18]([F:21])[C:19]=2[CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:23][C:24]([CH3:40])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:25].C(N(C(C)C)C(C)C)C>O1CCOCC1.O>[Br:8][C:6]1[N:7]=[C:2]([NH:25][C:24]([CH3:40])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:23])[C:3](=[O:22])[N:4]([C:9]2[CH:10]=[C:11]([CH:17]=[C:18]([F:21])[C:19]=2[CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=1
Reactant: CC(C)(N)c1ccccc1OCc1ccccc1
Reactant: CCOC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 99.9 %

Procedure:
3-(3,5-Dibromo-2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methyl-benzoic acid, ethyl ester (Example 169d, 1.137 g, 2.62 mmol) was dissolved in dioxane (10 mL). α, α-Dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example 134a, 0.63 g) and N-ethyldiisopropylamine (0.67 mL, 3.93 mmol) were added under nitrogen and the resulting solution was stirred at 100° C. for 10 h. The reaction mixture was diluted with water (50 mL), and extracted with ethyl acetate (100 mL×2). The combined organics were dried (MgSO4), filtered and evaporated to afford the crude product. This was purified by (SiO2 chromatography eluting with dichloromethane) to afford the subtitle product (1.55 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O>O1CCOCC1.O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:4]2([C:4]3[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=3)[CH2:5][CH2:6][CH:1]([OH:7])[CH2:2][CH2:3]2)=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(C2(c3ccc(O)cc3)CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
A mixture of ketal intermediate (2.8 g, 17.7 mmol) and phenol (5.64 g, 60 mmol) in dioxane (10 mL) and water (10 mL) at 0° C. was treated dropwise with conc. H2SO4 (20 mL). The mixture was allowed to warm to room temperature and stirred at this temperature for the next 6 h. The reaction mixture was then poured into ice-water and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried with anhydrous MgSO4 and concentrated in vacuo to provide 4,4-bis(4-hydroxyphenyl)cyclohexanol (5 g) contaminated with phenol.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:12][C@@H:13]1[CH2:18][CH2:17][C@H:16](O)[CH2:15][CH2:14]1>>[Cl:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14]1
Reactant: O[C@H]1CC[C@@H](Cl)CC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@H](Cl)CC1)C(C)=O

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (95 mg) was treated with cis-4-chlorocyclohexanol as described in Example 4a, Method 3, to give the title compound as a colourless liquid (37 mg, 21%), (Found: M+, 276.1011. C12H19NO4Cl requires M, 276.1002) νmax (film) 1735, 1685, 1360, 1310, and 950 cm-1, νH (CDCl3), 1.32 (3H, t, J 7. 1 Hz), 1.76 (4H, m), 2.14 (4H, m), 2.4 (3H, s), 4.19 (1H, m), 4.35 (2H, q, J 7.1 Hz), and 4.44 (1H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2
Reactant: Nc1cccc2cccnc12
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc4cccnc34)c2cc1OC
Temperature: 200 °C
Yield: 46.8 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.288 g of 8-aminoquinoline, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was heated under nitrogen in a sealed tube at 200° C. for 2 hours. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.167 g of 6,7-dimethoxy-4-(quinolin-8-ylamino)-quinoline-3-carbonitrile as a solid, mp 150° C. (decomposed); mass spectrum (EI, m/e): M 356.1271.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:10]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[O:23])[C:6]=2[CH2:5][CH2:4][CH2:3]1.C=O.[C:26](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CO.ClCCl.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:10]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:18][CH2:19][N:20]([CH3:26])[CH2:21][CH2:22]4)[CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[O:23])[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)O
Reactant: CN1CCCc2c1c1cc(OC3CCNCC3)ccc1[nH]c2=O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(Oc2ccc3[nH]c(=O)c4c(c3c2)N(C)CCC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
The compound (45 mg, 0.13 mmol) prepared in step 2 of Example 13 was dissolved in methanol (3 ml)/dichloromethane (3 ml), sequentially added with formaldehyde (29 μl, 0.38 mmol), acetic acid (12 μl, 0.22 mmol), and sodium triacetoxyborohydride (108 mg, 0.51 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature and poured into cold 2 N sodium hydroxide aqueous solution. The mixture was extracted with chloroform and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then by flash column chromatography (chloroform:methanol=5:1) to obtain the title compound (28 mg, yield: 66%, yellow oil).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)C(C)C>[CH2:4]([O:5][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH:3]([CH3:7])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: CC(C)CO
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to example B from 2-chloro-5-methanesulfonyl-benzoic acid and isobutanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([C:23]([N:25]3[CH2:29][C:28](=[O:30])[NH:27][CH2:26]3)=[O:24])=[CH:12][C:13]=2[C:14]2[CH:15]=[C:16]([C:21]#[N:22])[CH:17]=[C:18]([F:20])[CH:19]=2)[CH:5]=[CH:6][C:7]=1F.ClC1C=C(C2OC(C(OCC)=O)=CC=2C2C=C(F)C=C(C#N)C=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([C:23]([N:25]3[CH2:29][C:28](=[O:30])[NH:27][CH2:26]3)=[O:24])=[CH:12][C:13]=2[C:14]2[CH:15]=[C:16]([C:21]#[N:22])[CH:17]=[C:18]([F:20])[CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)oc2-c2ccc(F)c(Cl)c2)c1
Agent: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)c(-c2cccc(Cl)c2)o1
Product: N#Cc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)oc2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 31 starting with the compound from Example 16A. 29.9 mg (49% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)#[N:2].[NH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C(O)(=O)C.ClC(Cl)C.C([BH3-])#N.[Na+]>CO>[C:26]([O:25][C:24](=[O:30])[NH:23][CH2:22][CH2:21][NH:20][CH:16]1[CH2:17][CH2:18][N:13]([C:4]2[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=2[C:1]#[N:2])[CH2:14][CH2:15]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC1CCN(c2ccc(C(F)(F)F)cc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 25 (535 mg, 1.99 mmol), 1 (335 mg, 2.09 mmol), and acetic acid (629 mg, 10.48 mmol) in methanol(2 mL)/dichloroethane(1 mL) was treated with sodium cyanoborohydride (130 mg, 2.06 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium carbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 4 mm, 10% EtOH-90% CHCl3) afforded the title compound (26).
Reaction SMILES: [Cl:1][C@H:2]1[CH2:20][C@@:17]2([CH2:18][CH3:19])[C@@H:13]([CH:14]=[CH:15][C@:16]2([C:22]#[CH:23])[OH:21])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:24])[CH2:6][CH2:5]1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(O)(=O)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:25]([O:21][C@@:16]1([C:22]#[CH:23])[CH:15]=[CH:14][C@H:13]2[C@H:12]3[C@H:3]([C@@H:2]([Cl:1])[CH2:20][C@:17]12[CH2:18][CH3:19])[C@@H:4]1[C:9](=[CH:8][C:7](=[O:24])[CH2:6][CH2:5]1)[CH2:10][CH2:11]3)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3[C@@H](Cl)C[C@@]21CC
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: C#C[C@]1(OC(C)=O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3[C@@H](Cl)C[C@@]21CC
Temperature: 0 °C

Procedure:
700 mg of 11β-chloro-17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one in 10 ml of pyridine is reacted at room temperature with the addition of 100 mg of 4-dimethylaminopyridine with 6 ml of acetic anhydride. The mixture is introduced, after 4 hours, into ice/water which contains acetic acid. The thus-precipitated product is vacuum-filtered, dissolved in ethyl acetate, and washed with water. The crude product is chromatographed on silica gel with hexane/acetone (0-10%), thus obtaining 510 mg of 17β-acetoxy-11β-chloro-17α-ethynyl-18-methyl-4,15-estradien-3-one as a foam.
Reaction SMILES: [CH:1]([N:4]([CH3:30])[C:5]1[C:6]([C:19]2[O:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([N:4]([CH3:30])[C:5]1[C:6]([C:19]2[O:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3cc(-c4ccccc4)co3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc(-c2ccccc2)co1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(4-phenylfuran-2-yl)quinoxaline-6-carboxylate (70 mg, 0.17 mmol) in MeOH (20 mL) was added sodium hydroxide (28 mg, 0.70 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (3 mL) and adjusted to pH 6 with HCl (1N). The solids were collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(4-phenylfuran-2-yl)quinoxaline-6-carboxylic acid (43 mg, 64%).