Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.CC(C)([O-])C.[K+].I[C:17]1[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1.O>O1CCCC1>[Br:23][C:20]1[CH:19]=[N:18][C:17]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[N:22][CH:21]=1
Reactant: OC1CN2CCC1CC2
Reactant: Brc1cnc(I)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cnc(OC2CN3CCC2CC3)nc1
Reaction time: 0.5 h

Procedure:
3-Quinuclidinol (Aldrich, 254 mg, 2 mmol) in tetrahydrofuran (Aldrich, anhydrous, 10 mL) was treated with potassium tert-butoxide (224 mg, 2 mmol) at ambient temperature for 1 hour. 2-Iodo-5-bromo-pyrimidine (Aldrich, 568 mg, 2 mmol) was then added. After stirring for 30 minutes, the mixture was treated with water (5 mL) and extracted with CHCl3:isopropyl alcohol (10:1, 3×10 mL). The extracts were combined and concentrated under reduced pressure. The title compound was purified by flash chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.15) as a solid (287 mg, yield, 50%). 1H NMR (300 MHz, MeOH-d4) δ 1.52-1.65 (m, 1H), 1.66-1.93 (m, 2H), 2.00-2.15 (m, 1H), 2.22-2.31 (m, 1H), 2.79-3.09 (m, 5H), 3.38-3.49 (m, 1H), 5.06-5.15 (m, 1H), 8.64 (s, 2H) ppm. MS (DCl/NH3) m/z 284 (M+H)+ 286 (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:42][CH2:41][CH2:40][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][C@H:32]([O:34][CH3:35])[CH2:31][CH:30]4[C:36](OC)=[O:37])[N:28]=3)[CH:18]=2)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[NH:21][N:20]=[C:19]([NH:22][C:23]3[C:24]4[CH2:42][CH2:41][CH2:40][C:25]=4[N:26]=[C:27]([N:29]4[CH2:33][C@H:32]([O:34][CH3:35])[CH2:31][C@@H:30]4[C:36]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:37])[N:28]=3)[CH:18]=2)[CH2:15][CH2:16]1
Reactant: Nc1ccc(F)nc1
Reactant: COC(=O)C1C[C@@H](OC)CN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@H](C(=O)Nc2ccc(F)nc2)N(c2nc3c(c(Nc4cc(C5CC5)[nH]n4)n2)CCC3)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-fluoropyridin-3-amine (1.2 g, 11.30 mmol) in dry THF (20 mL) was added 2M solution of isopropylmagnesium chloride in THF (9.4 mL, 18.8 mmol) dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of (4R)-methyl 1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylate (3 g, 7.53 mmol) in THF (10 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT overnight. The reaction was quenched with saturated ammonium chloride solution (50 mL). The product was extracted with EtOAc (2×100 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded a diastereomeric mixture of Compound 21. The diastereomers were separated by reverse phase followed by chiral HPLC to afford (2R,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide (Compound No. 21a, 208 mg) and (2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide (Compound No. 21b, 193 mg). Compound No. 21a: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.78 (m, 2H), 0.82-0.98 (m, 2H), 1.78-1.82 (m, 1H), 2.08-2.20 (m, 2H), 2.38-2.62 (m, 2H), 2.78-2.91 (m, 4H), 3.40 (s, 3H), 2.70-2.81 (m, 1H), 3.90-4.02 (m, 1H), 4.15-4.21 (m, 1H), 4.72-4.78 (m, 1H), 6.21 (brs, 1H), 7.00 (dd, 1H), 8.00 (brs, 1H), 8.28 (brs, 1H). Compound No. 21b: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.78 (m, 2H), 0.82-0.98 (m, 2H), 1.78-1.82 (m, 1H), 2.08-2.20 (m, 2H), 2.38-2.62 (m, 2H), 2.78-2.91 (m, 4H), 3.40 (s, 3H), 3.80-4.01 (m, 2H), 4.15-4.21 (m, 1H), 4.72-4.78 (m, 1H), 6.21 (brs, 1H), 7.00 (dd, 1H), 8.00 (brs, 1H), 8.28 (brs, 1H).
Reaction SMILES: [I:1]I.[CH2:3]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH2:18])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([NH:10][C:11]1[C:16]([I:1])=[C:15]([CH3:17])[N:14]=[C:13]([NH2:18])[N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cc(NCc2ccccc2)nc(N)n1
Reactant: II
Solvent: CO
Product: Cc1nc(N)nc(NCc2ccccc2)c1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.7 %

Procedure:
Iodine (3.04 g, 12.0 mmol) was added to a solution of N4-benzyl-6-methylpyrimidine-2,4-diamine (2.33 g, 10.9 mmol) in anhydrous MeOH (50 mL) at 0° C. The reaction was allowed to warm to room temperature overnight. After 12 hours, an additional 0.5 equiv of iodine was added, and the reaction warmed to 50° C. After four hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (200 mL) and washed with 10% NaHSO3 (200 mL). The aqueous phase was separated and washed once more with ethyl acetate (200 mL). The organic phases were combined, washed with brine, separated and dried over Na2SO4. The filtrate was concentrated in vacuo to afford the product N4-benzyl-5-iodo-6-methylpyrimidine-2,4-diamine (3.14 g, 85% yield).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.Cl>C1COCC1>[NH2:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:15][CH2:16]1)=[O:10]
Reactant: COc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccccn2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a solution of (R)-{2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-2-oxo-1-pyridin-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester (3.16 g.; 7.18 mmol from Example 11) in THF (30 mL) at 0° C. was added HCl (4M/Dioxane) (30 mL; 0.12 mol). The mixture was stirred at ambient temperature for 3 hours, and the solvent removed in vacuo. The residue was dissolved in water (35 mL), washed with ether (20 mL). The aqueous layer was rendered basic (pH 9–10) with saturated aqueous Na2CO3, and the product extracted into dichloromethane (3×60 mL). The combined dichloromethane layers were washed with brine, dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (5% methanol/chloroform) to afford the free base of the title compound as a light yellow oil (2.07 g.; 85%); MS (+) FAB, [M+H]+ @ m/z 341, [M+Na]+ @ m/z 363; 1H NMR, 400 MHz, DMSO-d6.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27](=[O:41])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=O)=[C:30]([CH3:40])[CH:29]=1.Cl.[CH3:43][C:44]([CH3:54])([CH3:53])[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:25][O:26][C:27](=[O:41])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][C:37]([N:50]2[CH2:51][CH2:52][N:47]([CH2:46][CH2:45][C:44]([CH3:54])([CH3:53])[CH3:43])[CH2:48][CH2:49]2)=[O:39])=[C:30]([CH3:40])[CH:29]=1
Reactant: CC(C)(C)CCN1CCNCC1
Reactant: COC(=O)c1ccc(CCCC(=O)O)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CCCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
HBTU (910 mg, 2.4 mmol) was added to a solution of 4-(3-carboxy-propyl)-3-methyl-benzoic acid methyl ester from Example E30 (378 mg, 1.6 mmol) and 1-(3,3-dimethyl-butyl)-piperazine hydrochloride from Example E4 (467 mg, 1.9 mmol) in dichloromethane (15 ml) and DIEA (0.836 ml, 4.8 mmol). The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 5% methanol:95% dichloromethane) to yield the title compound (582 mg, 94%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([F:10])[CH:9]=1)[NH2:6])#[CH:2].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:7]=[C:8]([F:10])[CH:9]=1)#[CH:2]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: C#Cc1cc(N)cc(F)c1
Agent: Br
Product: C#Cc1cc(F)cc(NC(C)c2cc(C(=O)N(C)C)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 86.3 %

Procedure:
3-ethynyl-5-fluoroaniline (165 mg, 1.22 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-ethynyl-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (80 mg, 56%) as a white solid. Mass Spectrum: M+H+ 464. NMR Spectrum (DMSOd6): 1.52 (d, 3H), 2.72 (bs, 3H), 2.94 (bs, 3H), 3.50-3.63 (m, 4H), 3.69-3.78 (m, 4H), 4.12 (s, 1H), 4.98-5.07 (m, 1H), 5.66 (s, 1H), 6.31 (d, 1H), 6.40 (d, 1H), 6.46 (s, 1H), 6.81 (d, 1H), 7.54 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1([CH3:14])[CH2:13][O:12][CH2:11]1.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:14][C:10]1([CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:13][O:12][CH2:11]1
Reactant: CC1(COCCCCCCBr)COC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(COCCCCCCOc2ccc(C=O)cc2)COC1
Temperature: 150 °C
Yield: 82 %

Procedure:
A mixture of JYC-I-143-A (5 g, 18.9 mmol), 4-hydroxybenzaldehyde (2.53 g, 20.7 mmol), and K2CO3 (5.21 g, 37.7 mmol) in 50 mL of DMF was heated at 150° C. for 5 h. The reaction mixture was allowed to cool down to room temperature and poured into a separatory funnel containing H2O. The mixture was extracted with CH2Cl2 and the organic phase was washed with H2O and a saturated NaCl aqueous solution. The organic phase was dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give brown oil. The crude product was purified by column chromatography (silica gel, hexanes:ethyl acetate:=4:1 (v/v)) to give light yellow liquid (4.75 g, 82%). 1H NMR (300 MHz, CDCl3, δ): 9.84 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.47 (d, J=5.5 Hz, 2H), 4.32 (d, J=5.5 Hz, 2H), 4.01 (t, J=6.4 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 3.44 (s, 2H), 1.80 (m, 2H), 1.60 (m 2H), 1.44 (m, 4H), 1.27 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3, δ): 190.66, 164.13, 131.88, 129.72, 114.66, 80.09, 76.00, 71.33, 68.20, 39.85, 29.38, 28.94, 25.85, 25.73, 21.30. HRMS-FAB (m/z): [M+H]+ calcd for C18H27O4, 307.1909; found, 307.1905.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:69]1([NH2:73])[CH2:72][CH2:71][CH2:70]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:73][CH:69]2[CH2:72][CH2:71][CH2:70]2)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=1)=[O:4]
Reactant: CCOC(=O)c1cc(C(=O)OC)cc(Cl)n1
Reactant: NC1CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(=O)OC)cc(NC2CCC2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
Add 6-chloropyridine-2,4-dicarboxylic acid 2-ethyl ester 4-methyl ester (0.500 g, 2.05 mmol), palladium acetate (0.0461 g, 0.205 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.128 g, 0.205 mmol), cesium carbonate (0.801 g, 2.46 mmol) and toluene (5 mL), to a sealed vessel flushed with nitrogen. Slowly add cyclobutylamine (0.210 mL, 2.46 mmol) and heat and stir the sealed vessel at 90° C. overnight. Cool to room temperature, filter through a pad of filtering agent, concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes) to give the title compound (0.223 g, 39%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[S:10][C:11]3[CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][C:16]=3[C:3]=12.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[F:32])[NH2:28].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>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].C1COCC1.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[S:10][C:11]4[CH2:12][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:14][CH2:15][C:16]=4[C:3]=23)[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Cl)c23)C1
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: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 90 °C
Yield: 68 %

Procedure:
To a solution of tert-butyl 4-chloro-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate from Example 53A (150 mg, 0.43 mmol) in a degassed mixture of DMF (1.5 mL) and THF (1.5 mL) were added 3-chloro-4-fluoroaniline (62 mg, 0.43 mmol), XPHOS (4.1 mg, 0.009 mmol), caesium carbonate (196 mg, 0.60 mmol) and tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol). The mixture was heated to 90° C. for 1 h. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (eluent: DCM/MeOH 50:1) to yield 190 mg (70% purity, 68% yield) of the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=C1CCCCCCCCC(C2CCCCCCCCCC=2)=C1)=[N-].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>O1CCCC1>[CH:1]1([NH:7][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: COC(=O)CBr
Agent: [N-]=[N+]=C1C=C(C2=CCCCCCCCCC2)CCCCCCCC1
Solvent: C1CCOC1
Product: COC(=O)CNC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of cyclohexylamine (34.3 ml) and diazobicycloundecene (DBU, 44.8 ml) in dry tetrahydrofuran (500 ml) under a nitrogen atmosphere was cooled to 0° C. and was treated dropwise with a solution of methyl bromoacetate (28.4 ml) in tetrahydrofuran (50 ml). After stirring at room temperature overnight, the mixture was filtered to remove precipitated DBU-hydrobromide and the solvent evaporated. The resulting residue was dissolved in ether (200 ml), washed with water (2×100 ml), and brine (2×100 ml). The organic extract was dried, filtered and evaporated. Fractional distillation provided 21.1 g., b.p. 160°-170° C. (0.2 mm).
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16]([NH2:28])[CH2:17][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])[O:2]1.[CH2:29]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](NC=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:30]1>>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16]([NH:28][CH:29]=[O:30])[CH2:17][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])[O:12]1
Reactant: C[C@]12CCCCC1C[C@@H](N)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCCCC1[C@@H](NC=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCCCC1C[C@@H](NC=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 92 %

Procedure:
17,17-Bis(ethylendioxy)-7α-formamidoandrostane was prepared in 92% yield from 3,3:17,17-bis(ethylendioxy)-7α-aminoandrostane by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6α-formamidoandrostane (II-bc, Prepn. 28). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 8.23 (dd, 1H), 7.97 (d, 1H), 4.00-3.70 (m, 8H), 1.85-1.05 (m, 20H), 0.76 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:40])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([OH:39])=O)=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:50]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN1CCOCC1>CN(C=O)C.O>[C:37]([C:21]1[C:22]2[NH:23][C:24]3[C:29]([C:30]=2[C:18]([C:14]2[C:13]([CH3:40])=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:17]=[CH:16][CH:15]=2)=[CH:19][N:20]=1)=[CH:28][C:27]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[CH:26][CH:25]=3)(=[O:39])[NH2:50]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3ccc(N4CCOCC4)cc3c12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(N)=O)c2[nH]c3ccc(N4CCOCC4)cc3c12
Yield: 88.2 %

Procedure:
A solution of 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-6-morpholino-9H-pyrido[3,4-b]indole-1-carboxylic acid (0.1408 g, 0.262 mmol), ammonium chloride (0.056 g, 1.050 mmol), BOP (0.151 g, 0.341 mmol), DIPEA (0.220 mL, 1.260 mmol) and N-methylmorpholine (0.113 mL, 1.023 mmol) in DMF (2.187 mL) was stirred for 1 hr. Water (22 mL) was added, and the precipitate was filtered, washed with water, dried over Drierite to give the desired product (0.1277 g, 0.231 mmol, 88% yield) as a light tan solid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]1([CH2:18][O:19][C:20](=[O:60])[CH2:21][N:22]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:30][CH2:29][N:28]([CH2:45][C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:27][CH2:26][N:25]([CH2:56][C:57]([OH:59])=[O:58])[CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:62][C:63]([N:65]([CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH3:101])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])=[O:64]>C1(C)C=CC=CC=1>[C:12]1([CH2:18][O:19][C:20](=[O:60])[CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH2:56][C:57]([O:59][CH2:62][C:63]([N:65]([CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH3:101])=[O:64])=[O:58])[CH2:26][CH2:27][N:28]([CH2:45][C:46]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:47])[CH2:29][CH2:30][N:31]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[CH2:32][CH2:33]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CBr
Reactant: O=C(O)CN1CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COC(=O)CN1CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CC1
Yield: 68 %

Procedure:
DBU (820 μL; 5.5 mmol) was added to a suspension of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tris(phenylmethyl)ester (prepared according to Step E3 of Example 17) (3.71 g; 5.5 mmol) in toluene (350 mL) obtaining a clear solution, then 2-bromo-N,N-dioctadecylacetamide (prepared according to Example 5, Step A) (3.9 g; 6.05 mmol) dissolved in toluene (50 mL) was added dropwise. After 2 h the reaction mixture was filtered and the solvent was evaporated. The crude was suspended in CH3CN (50 mL) and the insoluble was filtered off with a paper filter. The solution was evaporated obtaining the desired product (4.63 g; 3.74 mmol). Yield 68%. The 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: C([O:3][CH:4](O)[CH:5]([F:7])[F:6])C.[CH3:9][N+:10]([O-:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>O>[F:6][CH:5]([F:7])[CH:4]([OH:3])[CH2:9][N+:10]([O-:12])=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(O)C(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])CC(O)C(F)F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 1-ethoxy-2,2-difluoroethanol (60 g, 0.47 mol), CH3NO2 (32.9 g, 0.56 mol) and Na2CO3 (3 g) was stirred at 60° C. for 3 hrs, then at rt overnight. The mixture was diluted with water (40 mL), extracted with tert-butyl methyl ether (200 mL) and the organic layer was dried over Na2SO4 and concentrated under low temperature to give the title compound, which was used for next step directly.
Reaction SMILES: CC([O:5][C:6](=[O:36])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([C:33]#[N:34])[CH:26]=2)[C:16]=1[F:35])C(OC(C)(C)C)=O)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:33]([C:27]1[CH:26]=[C:25]([O:24][C:17]2[C:16]([F:35])=[C:15]([CH2:7][C:6]([OH:36])=[O:5])[CH:20]=[CH:19][C:18]=2[N+:21]([O-:23])=[O:22])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)#[N:34]
Reactant: COc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(CC(=O)O)c2F)c1

Procedure:
A solution of bis(1,1-dimethylethyl)(3-{[3-cyano-5-(methyloxy)phenyl]oxy}-2-fluoro-4-nitrophenyl)propanedioate (12.79 g, 25.5 mmol) in CH2Cl2 (25 ml) and TFA (25 ml, 324 mmol) was stirred at RT overnight. The reaction mixture was evaporated and the residue was dissolved in water and EtOAc. The aqueous layer was extracted with EtOAc. The organic layers were dried (Na2SO4), filtered, evaporated to give (3-{[3-cyano-5-(methyloxy)phenyl]oxy}-2-fluoro-4-nitrophenyl)acetic acid as a brown solid that was used without further purification. A solution of the above acid and Cu2O (0.74 g, 5.2 mmol) in acetonitrile (50 mL) was heated under reflux overnight. The reaction mixture was brought to RT, filtered through celite, evaporated and purified by silica gel chromatography (0-25% EtOAc/hexanes) to afford the title compound (2.20 g, 29%) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.77 (dd, J=8.61, 1.56 Hz, 1H) 6.85-6.90 (m, 1H) 6.73 (t, J=2.06 Hz, 1H) 6.65 (d, J=0.73 Hz, 1H) 3.80 (s, 3H) 2.39 (d, J=2.20 Hz, 3H).