Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A mixture of 3-hydroxybenzaldehyde (6.71 g), 2-(chloromethyl)quinoline (8.88 g) and potassium carbonate (8.28 g) in N,N-dimethylformamide (25 ml) was stirred at 60° C. for 3 hours. The mixture was allowed to cool and concentrated in vacuo. The residue was treated with water. The separated oil was extracted with ethyl acetate. The organic layer was washed with brine, dried, and evaporated to give an oil, which was crystallized from n-hexane to yield 2-[[3-(formyl)phenoxy]methyl]quinoline (12.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:36]1([CH2:39]O)[CH2:38][CH2:37]1.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:39][CH:36]3[CH2:38][CH2:37]3)=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Reactant: OCC1CC1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2OCC2CC2)cc1

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting cyclopropylmethanol in place of isobutanol (yield: 0.117 g, 83%). mp 166-167° C. 1H NMR (300 MHz, DMSO d6) δ 0.22 (m, 2H), 0.46 (m, 2H), 1.10 (m, 1H), 3.31 (s, 3H), 4.30 (d, J=7 Hz, 2H), 7.36 (m, 2H), 7.66 (m, 2H), 7.96 (m, 2H), 8.07 (m, 2H), 8.20 (s, 1H). MS (DCI/NH3) m/z 415 (M+H)+, 432 (M+NH4)+. Anal. calc. for C23H25ClN2O4S: C, 60.86; H, 4.62; N, 6.76. Found: C, 60.76; H. 4.72; N, 6.61.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.Cl.[NH2:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1.C(N(CC)CC)C>C(O)C.CO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH:22]1[NH:21][C:5]1[C:4]2[N:8]=[CH:9][N:10]([C:3]=2[N:2]=[CH:1][N:6]=1)[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4Cc5ccccc5C4)ncnc32)[C@H](O)[C@@H]1O
Yield: 72.9 %

Procedure:
Two grams 6-chloropurine riboside, 1.48 grams 2-aminoindane hydrochloride and 1.74 g triethylamine are refluxed in ethanol under nitrogen for 20 hours. Upon cooling, solid material crystallizes. The reaction mixture is diluted with 70 ml ethanol, filtered and washed with ethanol. Solid thus obtained is suspended in approximately 25 to 30 ml methanol, filtered, and washed with methanol and dried affording 1.95 g (73%) N(6)-(2-indanyl)adenosine having a melting point of 166°-168° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32](Cl)=[O:33].CCN(C(C)C)C(C)C>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:32]([C:28]2[N:27]([CH3:26])[CH:31]=[CH:30][N:29]=2)=[O:33])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: Cn1ccnc1C(=O)Cl
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ccnc1C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 22.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol), 1-methyl-1H-imidazole-2-carbonyl chloride (0.026 g, 0.283 mmol), dry THF (5 mL), DIPEA (2 mL). The obtained crude was purified by column chromatography using 2% ammonia in 20% MeOH:DCM as mobile phase to afford 0.020 g of the desired title product. 1H NMR (300 MHz, DMSO d6): δ 3.50 (s, 3H), 4.41 (d, J=18.0 Hz, 1H), 6.99 (s, 1H), 7.43 (br, 2H), 7.67 (d, 1H), 7.78 (s, 1H), 8.28 (d, J=4.5 Hz, 2H), 8.30 (s, 1H), 9.08 (t, 1H); MS (m/z): 477.10 (M+H)+.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Cl>CO>[OH:4][C@H:3]([CH3:5])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@@H](O)CC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
tert-Butyl acetoacetate [15] (14.5 g, 90 mmol) and methanol (30 mL) were mixed and deoxygenated with flowing nitrogen for 5 minutes in a septum covered Parr shaker bottle. The catalyst prepared as described above (36 mg, 0.02 mmol) was added along with 2N HCl (0.041 mL, 0.082 mmol). The mixture was transferred to a standard Parr shaker apparatus and flushed by evacuating and refilling with nitrogen and then hydrogen several times. The apparatus was heated at 40° C. with shaking under 50 psi of hydrogen. After 20 min the reaction became a homogeneous clear yellow solution which took up hydrogen for approximately eight hours. At this time the reaction was complete and the mixture was cooled and diluted with hexane (30 mL) to precipitate the catalyst, which was filtered away. The filtrate was concentrated to give tert-butyl 3(R)-hydroxybutyrate [16] (14.5 g, 97%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[O:4]([CH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl)[Si:5]([C:18]([CH3:21])([CH3:20])[CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[O:4]([CH2:22][C:23]1[CH:24]=[C:25]([CH2:26][C:1]#[N:2])[CH:28]=[CH:29][CH:30]=1)[Si:5]([C:18]([CH3:21])([CH3:20])[CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](OCc1cccc(CCl)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1cccc(CC#N)c1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 72.8 %

Procedure:
Sodium cyanide (1.57 g, 32.0 mmol) and tetrabutylammonium iodide (0.11 g, 0.30 mmol) were added to a stirred solution of 24 (11.8 g, 29.9 mmol) in anhydrous DMF (90 mL) at room temperature under argon. The reaction mixture was heated to 80° C. for 2 h. The solution was allowed to cool to room temperature and was poured into saturated ammonium chloride solution and extracted twice with diethyl ether. The organic layers were combined, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 11.0 g of a clear, brown oil. Purification by column chromatography (20:1 ratio silica gel/crude product; gradient elution with 1% to 10% ethyl acetate/hexanes) provided 8.39 g (73%) of 25 as a pale yellow, clear oil. 1H NMR (300 MHz, CDCl3) δ7.64-7.67 (m, 4H, ArH), 7.19-7.41 (m, 10H, ArH), 4.74 (s, 2H, CH2OSi), 3.70 (s, 2H, CH2CN), and 1.08 (s, 9H, SiC(CH3)3); 13C NMR (75 MHz, CDCl3) δ142.24, 135.57, 133.31, 129.81, 129.04, 127.78, 126.41, 125.69, 125.54, 117.87 (CN), 65.13 (CH2OSi), 26.85 (SiC(CH3)3), 23.65 (CH2CN), and 19.31 (SiC(CH3)3); IR (film) 2960, 2930, 2890, 2860, 2250 (CN), 1470, 1430, 1150, 1110, and 1080 cm-1 ; MS (DCI) m/e 386 (MH+).
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH:5](OC)OC.Cl.[C:13]([NH:17][NH2:18])([CH3:16])([CH3:15])[CH3:14].Cl>C(O)C.O>[CH3:14][C:13]([N:17]1[CH:5]=[CH:4][CH:3]=[N:18]1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)NN
Reactant: COC(CC(OC)OC)OC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)n1cccn1
Yield: 72 %

Procedure:
To a mixture of 1,1,3,3-tetramethoxypropane (3.82 kg, 23.27 mol) and tert-butylhydrazine hydrochloride (2.9 kg, 23.27 mol) in ethanol (24.54 kg), conc HCl (4.72 kg, 46.55 mol) was added, keeping the temperature below 50° C. The reaction mixture was then rapidly heated to reflux. After ca. 2 h the reaction was sampled and analysed by NMR. Pass criteria was <3.0% starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29 kg) and evaporated in vacuo (T<50° C., p<−0.08 MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (11.11 kg×2) and the organic phase washed with saturated ammonium chloride solution (4.3 ml/g×2) and brine (4.3 ml/g), then evaporated to give the title compound (2.08 kg, 72% yield) as a brown liquid (GC purity 99.70% a/a).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>C(O)(=O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: C=CC(=O)OCC
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Product: CCOC(=O)CCNc1ccc(C(=O)O)cc1
Yield: 63.2 %

Procedure:
A solution of 4-aminobenzoic acid (6.85 g, 0.05 mol) and ethyl acrylate (15 g, 0.15 mol) in acetic acid (40 mL) was heated to 100° C. for 15 h. The solid which formed was filtered, washed with hexane and dried to give the title compound (7.5 g, 63%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:19]3[N:18]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:31][CH:30]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2ncccn2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyrimidin-2-yl-benzaldehyde, of Preparation 21, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 8.89 (d, 2H), 8.38 (d, 2H), 7.46 (d, 2H), 7.23 (m, 1H), 7.17 (m, 1H), 6.95 (m, 2H), 6.78 (dd, 1H), 4.51 (s, 2H), 3.86 (s, 2H), 3.79 (s, 2H), 1.47 (s, 9H); MS 406 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][NH:9][C:10]1[C:11]([NH2:19])=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1)[CH3:21].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(Cl)(Cl)Cl>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:19][C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[O:31])=[CH:25][CH:24]=1)[CH3:21]
Reactant: CCOc1ccc(CC(=O)O)cc1
Reactant: CN1CCCC1CCNc1ccc([N+](=O)[O-])cc1N
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2NCCC2CCCN2C)cc1
Temperature: 35 °C
Yield: 18 %

Procedure:
N1-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-4-nitro-benzene-1,2-diamine 32 (0.396 g, 1.498 mmol) was dissolved in anhydrous chloroform (20 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. (4-Ethoxy-phenyl)-acetic acid 5 (0.284 g, 1.573 mmol) followed by 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.455 g, 1.841 mmol) are added quickly as solids and resulting solution heated in an oil bath at 35° C. for 18 hours. After cooling to room temperature the solvent was removed under reduced pressure and the resulting residue partitioned between H2O and chloroform and 2M ammonium hydroxide solution added to adjust pH to 10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with chloroform and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to afford crude solid. The product was purified using silica gel dry column chromatography with a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) to afford a yellow powder 33 2-(4-Ethoxy-phenyl)-N-{2-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-5-nitro-phenyl}-acetamide Yield: 0.115 grams (18.0%). 1H NMR (DMSO) δ: 1.31 (t, 3H, J=7.0), 1.43-1.68 (2×m, 4-5H), 1.78-1.91 (m, 2H), 2.01-2.10 (m, 1H), 2.12-2.19 (m, 1H), 2.22 (s, 3H), 2.89-2.99 (m, 1H), 3.19-3.30 (m, 2H), 3.61 (s, 2H), 4.00 (q, 2H, J=6.9), 6.57 (br, 1H), 6.70 (d, 1H, J=9.1), 6.88 (d, 2H, J=8.4), 7.24 (d, 2H, J=8.6), 7.94 (dd, 1H, J=9.1, 2.6), 7.99 (d, 1H, J=2.5), 9.43 (br s, 1H); MS (ESI): 427 (MH+, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([C:16](OC)=[O:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C(O)C.C1COCC1.[OH-].[Na+].C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([CH2:16][OH:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn(Cc2ccccc2)cc1[N+](=O)[O-]
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])c1cn(Cc2ccccc2)nc1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.04 g (7.8 mmol) of methyl 1-benzyl-4-nitro-1H-pyrazole-3-carboxylate was dissolved in a mixture of 10 ml of ethanol, 10 ml of THF and 5 ml of 1 N sodium hydroxide, and the obtained solution was stirred at room temperature for 4 hours. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the solvent was evaporated, and the obtained crude product was dissolved in 100 ml of THF. 1.5 ml (10.1 mmol) of triethylamine and 0.81 ml (8.5 mmol) of ethyl chloroformate were added to the obtained solution under cooling with ice, and they were stirred at room temperature for 30 minutes. Apiece of ice and 600 mg (15.6 mmol) of sodium borohydride were added to the obtained mixture. The temperature was elevated to room temperature, and the obtained mixture was stirred overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the crude product was obtained. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([C:15]2[O:16][C:17]3[C:18](=[C:20]([C:24](O)=[O:25])[CH:21]=[CH:22][CH:23]=3)[N:19]=2)[C@@H:10]([CH3:27])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:31][C@H:32]1[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1>>[N:34]12[CH2:33][C@@H:32]([NH:31][C:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:17]4[O:16][C:15]([N:11]5[C@@H:12]([CH3:14])[CH2:13][N:8]([CH2:1][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[C:9](=[O:28])[C@@H:10]5[CH3:27])=[N:19][C:18]=34)=[O:25])[CH:37]([CH2:38][CH2:39]1)[CH2:36][CH2:35]2
Reactant: C[C@H]1CN(Cc2ccccc2)C(=O)[C@H](C)N1c1nc2c(C(=O)O)cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: C[C@H]1CN(Cc2ccccc2)C(=O)[C@H](C)N1c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1

Procedure:
Following the general procedure GP-C2, a mixture of 2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl) 2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxamide which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27]/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C@H:36]([CH2:53][CH2:54][C:55]([F:67])([F:66])[C:56]([F:65])([F:64])[C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])[C:37]([N:39]3[C@H:43]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C@H:42]([CH3:50])[N:41]([CH3:51])[C:40]3=[O:52])=[O:38])([CH3:20])[C@@H:18]([O:68]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OC1C=CC2C3[C@H]([C@H]4[C@@](CC=3C/C=C\CCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(N3[C@H](C5C=CC=CC=5)[C@H](C)N(C)C3=O)=O)(C)[C@@H](OCC3C=CC=CC=3)CC4)CCC=2C=1)C1C=CC=CC=1>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C@H:36]([CH2:53][CH2:54][C:55]([F:67])([F:66])[C:56]([F:64])([F:65])[C:57]([F:62])([F:63])[C:58]([F:59])([F:60])[F:61])[C:37]([N:39]3[C@H:43]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C@H:42]([CH3:50])[N:41]([CH3:51])[C:40]3=[O:52])=[O:38])([CH3:20])[C@@H:18]([OH:68])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)N(C(=O)[C@H](CCCCCC/C=C/CC2=C3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]3CC[C@H](OCc4ccccc4)[C@@]3(C)C2)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C
Agent: [Pd+2]
Agent: C[C@H]1[C@@H](c2ccccc2)N(C(=O)[C@H](CCCCCC/C=C\CC2=C3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]3CC[C@H](OCc4ccccc4)[C@@]3(C)C2)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1[C@@H](c2ccccc2)N(C(=O)[C@H](CCCCCCCCC[C@H]2C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]3CCc4cc(O)ccc4[C@@H]23)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
The mixture of (4S,5R)-1-{(2R,9E)-11-[3,17β-bis-(benzyloxy)estra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one and (4S,5R)-1-{(2R,9Z)-11-[3,17β-bis(benzyloxy)estra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one (283 mg, 0.27 mmol) was dissolved in a mixed solvent of methanol (12 ml) and tetrahydrofuran (1.2 ml), followed by addition of palladium hydroxide/carbon (85 mg) at room temperature. After purging with hydrogen, the reaction mixture was stirred for 1 day at room temperature. After the reaction mixture was filtered, the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/7) to give (4S,5R)-1-{(2R)-11-[3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one (164 mg, Yield 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]([C:9](=[O:11])[CH3:10])([CH3:8])[CH2:4][O:3]1.[H-].[Na+].[C:15](OC)(=[O:20])[C:16]([O:18][CH3:19])=[O:17].[Cl-].[NH4+]>C1COCC1>[O:20]=[C:15]([CH2:10][C:9](=[O:11])[C:5]1([CH3:8])[CH2:4][O:3][C:2]([CH3:12])([CH3:1])[O:7][CH2:6]1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: CC(=O)C1(C)COC(C)(C)OC1
Reactant: COC(=O)C(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C(=O)CC(=O)C1(C)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a mixture of 1-(2,2,5-trimethyl-1,3-dioxane5-yl)ethanone (0.76 g, 4.4 mmol) and THF (7.6 mL) was added sodium hydride (0.16 g, 6.6 mmol) under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 0.5 hour. To the resulting reaction mixture was added dimethyl oxalate (0.78 g, 6.6 mmol) and the mixture was heated at reflux for 2 hours. After the reaction was completed, saturated ammonium chloride aqueous solution was added to mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified on a silica gel column chromatography (ethyl acetate/n-hexane) to give methyl 2,4-dioxo-4-(2,2,5-trimethyl-1,3-dioxane5-yl)butanoate (1.0 g, yield: 88%) as colorless oil.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)(=[O:5])=[O:4]>[Pd].C(O)C>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[S:3]([NH:2][CH3:1])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNS(=O)(=O)c1ccccc1N
Reaction time: 1 h
Yield: 94.6 %

Procedure:
N-Methyl-2-nitrobenzenesulfonamide (1.0 g, 4.6 mmol), 10% palladium on carbon (100 mg) and absolute ethanol (30 mL) were placed in a Parr bottle, the bottle placed on a Parr apparatus under a hydrogen atmosphere (45 psi), and shaken for 1 hour, The Parr bottle was evacuated and flushed with nitrogen, then the mixture was filtered through a disposable syringe filter. The filtrate was concentrated in vacuo to yield 0.81 g of 2-amino-N-methylbenzenesulfonamide.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][N:15]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]1=[O:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:14][N:15]1[C:19](=[O:20])[CH2:18][CH:17]([S:12][C:10]2[CH:9]=[C:8]([CH3:13])[C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=2)[C:16]1=[O:21]
Reactant: CN1C(=O)C=CC1=O
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(SC2CC(=O)N(C)C2=O)cc(C(C)(C)C)c1N
Yield: 52.2 %

Procedure:
A stirred solution of 1.0 g (5 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline, 0.6 g (5 mmol) of N-methylmaleimide and 0.1 g (1 mmol) of triethylamine in 10 mL of toluene is heated at 50° C. for 18 hours. The solvent is removed in vacuo and the residue is purified by flash chromatography (silica gel, 3:2, heptane:ethyl acetate eluent) followed by recrystallization from a heptane:toluene solvent mixture to give 0.8 g (51%) of the title compound as a white solid melting at 92°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21]([OH:23])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][CH:26]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]([F:45])([F:44])[F:43])[C:27]([NH:29][C:30]([CH3:35])([C:32]([NH2:34])=[O:33])[CH3:31])=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:16])([F:17])[F:18])[C:11](=[O:19])[N:10]([CH2:20][C:21]([NH:25][CH:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]([F:43])([F:44])[F:45])[C:27]([NH:29][C:30]([CH3:35])([C:32]([NH2:34])=[O:33])[CH3:31])=[O:28])=[O:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)C(N)c1ccccc1C(F)(F)F)C(N)=O
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Agent: Cl
Product: CC(C)(NC(=O)C(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1ccccc1C(F)(F)F)C(N)=O

Procedure:
Analogously to Example 1, 25 mg (72 μmol) of the compound of Example 11A and 29 mg (79 μmol) of the compound of Example 62A were employed. Purification by HPLC [Method 7] gave 32 mg (70% of theory) of the title compound.