Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.[C:7]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)(=[O:9])[CH3:8].[Cl:19]C(OCC)=O.[C:25]1([C@H:35]([N:37]([CH2:45][CH:46]2[CH:50]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:49][NH:48][CH2:47]2)C(=O)OC(C)(C)C)[CH3:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>O.C(N(CC)CC)C>[ClH:19].[C:7]([N:10]1[CH2:11][CH2:12][CH:13]([C:16]([N:48]2[CH2:49][CH:50]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:46]([CH2:45][NH:37][C@@H:35]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH3:36])[CH2:47]2)=[O:18])[CH2:14][CH2:15]1)(=[O:9])[CH3:8]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CCOC(=O)Cl
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCC1c1ccccc1)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(=O)N2CC(CN[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An 8.0 ml ethyl acetate solution of 318 mg of 1-acetylpiperidine-4-carboxylic acid was mixed with 0.18 ml of ethyl chloroformate, 0.52 ml of triethylamine and 400 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl][(4-phenylpyrrolidin-3-yl)methyl]carbamate in that order and stirred at room temperature for 30 minutes. This was mixed with 10 ml of water and extracted with ethyl acetate. The solvent was evaporated, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol). This was treated with 4 M hydrogen chloride/ethyl acetate and concentrated to dryness to obtain 75 mg of (1R)—N-({1-[(1-acetylpiperidin-4-yl)carbonyl]-4-phenylpyrrolidin-3-yl}methyl)-1-(1-naphthyl)ethanamine hydrochloride as a pale pink solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[C:10]2=[O:20])=[CH:5][CH:4]=1.[C:23]([Mg]Br)([CH3:25])=[CH2:24].Cl[Ce](Cl)Cl>>[OH:19][C:16]1([C:23]([CH3:25])=[CH2:24])[CH2:15][CH2:14][C:11]2([C:10](=[O:20])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=3)[CH2:13][CH2:12]2)[CH2:18][CH2:17]1
Reactant: C=C(C)[Mg]Br
Reactant: O=C1CCC2(CC1)CCN(c1ccc(C(F)(F)F)cc1)C2=O
Agent: Cl[Ce](Cl)Cl
Product: C=C(C)C1(O)CCC2(CCN(c3ccc(C(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 55 from 2-(4-trifluoromethyl-phenyl)-2-aza-spiro[4.5]decane-1,8-dione (product of example 208, step 2) by reaction with isopropenylmagnesium bromide (0.5 M in THF), but without use of anhydrous cerous(III)-chloride in the reaction, as a light yellow solid. MS (m/e): 353 [M F].
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8]([Cl:20])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1

Procedure:
42 g of 3,5-diacetoxybenzoic acid are heated under reflux for 5 hours with 300 ml of benzene and 26 ml of thionyl chloride. The reaction mixture is concentrated by evaporation and the residue is taken up in benzene and again concentrated by evaporation. 3,5-diacetoxybenzoyl chloride having a melting point of 85°-87° is thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([O:19][CH2:20][CH2:21][NH:22]C(OCC1C=CC=CC=1)=O)[C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C.O1CCCC1>[C:1]([O:5][C:6]([N:8]([O:19][CH2:20][CH2:21][NH2:22])[C:9]([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=N)N(OCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(=N)N(OCCN)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
A mixture of [N,N′-di(tert-butoxycarbonyl)]2-(benzyloxycarbonylamino)ethoxyguanidine (730 mg, 1.5 mmol), as prepared in the preceding step, 10% palladium on carbon (70 mg) in ethanol (20 mL) and tetrahydrofuran (20 mL) was hydrogenated under hydrogen (balloon) for 30 min. The catalysts were removed by filtration through Celite and the filtrate was concentrated in vacuo. The residue was purified on a Waters Sep-Pak (10 g, 95:5 methylene chloride:methanol saturated with ammonia) to give the title compound as a colorless oil (290 mg, 61%). 1H-NMR (300 MHz, CDCl3) δ 9.08 (br s, 1H), 4.08 (t, J=5.2 Hz, 2H), 2.99 (q, J=5.1 Hz, 2H), 1.50 (s, 9H), 1.48 (s, 9H).
Reaction SMILES: [N:1]([C@H:4]([CH2:14][CH2:15][O:16]C1C=CC(OC)=CC=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[N+:2]=[N-:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl.O>[NH2:1][C@@H:4]([CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH2:14][CH2:15][OH:16].[N:1]([C@@H:4]([CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH2:14][CH2:15][OH:16])=[N+:2]=[N-:3]
Reactant: COc1ccc(OCC[C@H](CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-])cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CCO)N=[N+]=[N-]
Product: CC(C)(C)[Si](C)(C)OC[C@H](N)CCO

Procedure:
To a solution of {[(2R)-2-azido-4-(4-methoxyphenoxy)butyl]oxy}(tert-butyl)dimethylsilane (4.7 g, 12.86 mmol) in 19:1 DCM/water at 0° C. was added DDQ (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone) (3.5 g, 15.43 mmol, 1.2 eq) and the mixture was stirred (from 0° C. to rt) until all starting material disappeared as indicated by TLC (thin layer chromatography) analysis. Most DCM was then removed in vacuo and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and saturated NaHCO3 repeatedly until a pale yellow organic solution was obtained. The organic solution was dried and the crude was purified by silica gel chromatography (5% acetone/toluene) to give the desired product (3R)-3-azido-4-{[tert-butyl(dimethyl)silyl]oxy}butan-1-ol. 1H NMR (400 MHz, Acetone-d6): δ3.89 (1 H, dd), 3.73-3.65 (5 H, m), 1.76-1.68 (1 H, m), 1.62-1.54 (1 H, m), 0.94 (9 H, s), 0.13 (6 H, s).
Reaction SMILES: C(OCC[CH2:7][CH2:8][CH2:9][N:10]=[N+:11]=[N-:12])(=O)C.[C:13]([O-:16])([O-])=O.[K+].[K+].[C:19]([O-])(=O)C.[K]>CO.O>[N:10]([CH:9]([CH3:19])[CH2:8][CH2:7][CH2:13][OH:16])=[N+:11]=[N-:12]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCCCCCN=[N+]=[N-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CO
Product: CC(CCCO)N=[N+]=[N-]
Yield: 65 %

Procedure:
5.1 g of 4-azido-1-pentylacetate (4.46) (33 mmol, 1.0 eq) from Example 19 was dissolved in 30 mL of MeOH and 2 mL of water. This solution was then saturated with K2CO3 and stirred overnight at room temperature. The reaction was then checked by TLC to confirm conversion of the acetate to the primary hydroxyl. Water (300 mL) was added to dissolve the potassium salt and extracted with diethyl ether 3×100 mL. The organic extracts were combined and dried with MgSO4. The solution was filtered and concentrated under vacuum with no external heat resulting in 4-azido-1-pentanol 4.47: 65% Yield; 1H NMR (500 MHz, Acetone-d6): δ: d 3.56 (t, J=4.2 Hz, 2H), 3.45 (t, J=7 Hz, 2H), 1.69-1.37 (m, 6H)13C NMR (100 MHz, Acetone): δ: 62.19, 52.01, 33.17, 29.42, 23.90
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:19]=[S:20]1(=[O:29])[CH2:25][CH2:24][N:23]([C:26](Cl)=[O:27])[CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:26]([N:23]2[CH2:24][CH2:25][S:20](=[O:29])(=[O:19])[CH2:21][CH2:22]2)=[O:27])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2)no1
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2C(=O)N2CCS(=O)(=O)CC2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (0.092 g; 0.337 mmol) in tetrahydrofuran (2.5 mL) is added 1,1-dioxo-1λ6-thiomorpholine-4-carbonyl chloride (0.067 g; 0.337 mmol) and N,N-diisopropylethylamine (0.123 mL; 0.708 mmol). The mixture is stirred at room temperature for 3 hours before diluting with ethyl acetate and washing with 1N hydrochloric acid and brine. The organics are concentrated in vacuo and purified by preparatory HPLC. The product fractions are pooled and concentrated in vacuo to afford title compound. ESI m/z 399 [M+H]+/397 [M−H]−
Reaction SMILES: [I:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:15]([C:17]1[N:18]([CH2:31][C:32]#[CH:33])[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH3:16]>CN(C=O)C.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.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[IH:1].[CH2:15]([C:17]1[N:18]([CH2:31][C:32]#[C:33][C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH3:16]
Reactant: C#CCn1c(CC)nc2c(N)nc3ccccc3c21
Reactant: Ic1cnccn1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CC#Cc1cnccn1
Product: I
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.5 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.12 mg, 0.03 eq.), 2-iodopyrazine (0.90 g, 1.1 eq), triethylamine (1.21 g, 3 eq.), and copper (I) iodide (46 mg, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinolin-4-amine (1 g, 4 mmol, 1.0 eq.) in DMF. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to provide crude product which was purified by column chromatography (silica gel eluting with 8/92 methanol/dichloromethane). The residue was purified by recrystallization from DMF to provide 100 mg of 2-ethyl-1-[3-(pyrazin-2-yl)-2-propynyl]-1H-imidazo[4,5-c]quinolin-4-amine hydroiodide as tan granules, mp 180-225° C. (dec). 1H NMR (300 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.70 (br s, 2H), 8.68 (d, J=1.4 Hz, 1H), 8.61 (m, 2H), 8.48 (dd, J=8.2, 0.9 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.73 (m, 1H), 7.62 (m, 1H), 5.93 (s, 2H), 3.14 (q, J=7.4 Hz, 2H), 1.43 (t, J=7.4 Hz, 3H); MS (APCI) m/z 329 (M+H)+; Anal. calcd. for C19H16N6.HI.0.06 DMF: C, 50.01; H, 3.81; N, 18.43. Found: C, 49.96; H, 3.84; N, 18.15.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:4]([CH:3]=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Cc1cccc(Nc2ccccn2)c1
Reactant: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])c(Nc2ccccn2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 18 %

Procedure:
Nitric acid (100 ml) and 3-methyl-N-(2-pyridyl)aniline (Hirota, M.; Kobayashi, K. Bull. Chem. Soc. Jpn. 1981, 54, 1583) (16.8 g, 91.2 mmol) was mixed with ice cooling, the ice bath was removed and the reaction mixture was stirred for 40 h at room temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (200 ml), the aqueous mixture was basified with the addition of potassium carbonate and the resulting basic solution was extracted with ethyl acetate (500 ml). The organic extracts were washed with water (50 ml) and brine (50 ml), dried (magnesium sulfate) and concentrated to dryness. The residue was purified by column chromatography (silica gel, 350 g; n-hexane/ethyl acetate (9/1)) to give 3.85 g (18%) of the titled compound as yellow solids.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[CH:9]1)(OC(C)(C)C)=O.[CH3:52][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[CH3:1][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:39])[CH3:40])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[CH:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3cn(C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 295 mg (0.43 mmol) of 2-[3-(N-BOC-indol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Example 23, in 10 mL of DMF at 0° C. is added 690 μL (0.69 mmol, 1.6 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 10 min, then 53 μL (0.86 mmol, 2.0 equiv) of methyl iodide is added. The reaction mixture is stirred 2 h at RT and then heated to 50° C. for 14 h, then quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. The crude material is then resubjected to the same conditions as stated above to ensure complete alkylation. The crude material is then dissolved in 10 mL of 4N HCl in dioxane and the reaction mixture is stirred 6 h at RT. The reaction mixture is diluted with 40 mL of EtOAc and extracted with NaHCO3 (1×30 mL) and H2O (1×30 mL). The organic layer is dried (MgSO4) and the solvents removed in vacuo. The resulting crude oil is purified via reverse phase MPLC using a C-18 column and 65% acetonitrile/35% H2O as eluent followed by lyophilization to afford 51 mg of 2-[3-(N-methyl-indol-3-ylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide as a white amorphous solid. 1H NMR (DMSO-d6, 300 MHz) δ7.61-6.88 (m, 18H), 4.86 (m,1H), 4.28 (m, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 2.71 (dd, 2H, J=14.9, 35.4), 1.25 (s, 3H), 1.00 (m, 6H); low resolution MS (FAB)m/e 615 (MH+), 614 (M+).
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[S-:26][C:27]#[N:28].[Ba+2].[S-]C#N>CC(C)=O.O>[OH:24][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH2:2][S:26][C:27]#[N:28])[CH2:12]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reactant: N#C[S-]
Agent: [Ba+2]
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CSC#N)[C@@]3(C)CC(=O)[C@@H]12
Yield: 96.4 %

Procedure:
A solution of 21-bromo-3α-hydroxy-5α-pregnane-11,20-dione (0.75 g.) in acetone (50 ml.) was treated with a solution of barium thiocyanate (2.6 g.) in water (10 ml.). The resulting mixture was refluxed for 4 hr., cooled and then partitioned between water and ether. The organic layer was washed with water, dried (Na2SO4) and evaporated. The residue (720 mg.) was purified by preparative t.l.c. (EtOAc) to afford title compound (685 mg.) as a white foam, [α]D + 67°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:20][N:21]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[CH2:22][CH2:23][NH:24][C:25]([NH2:27])=O)[CH2:3]1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O.C(OCC)(=O)C>N1C=CC=CC=1>[C:25]([NH:24][CH2:23][CH2:22][N:21]([CH2:20][C@@H:4]1[CH2:3][C@@H:2]([O:1][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:6][N:5]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])#[N:27]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)NCCN(C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN(CCNC#N)C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (2S, 4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[N-(4-nitrobenzyloxycarbonyl)-N-(2-ureidoethyl)amino]methylpyrrolidine (1.75 g) in pyridine (17.5 ml) was added methanesulfonyl chloride (0.60 ml) at 0°~10° C. The mixture was stirred at the same temperature for 1 hour and at ambient temperature for 15 hours. The mixture was poured into a mixture of water (100 ml) and ethyl acetate (100 ml). The organic layer was washed in turn with 1N hydrochloric acid (100 ml×3), saturated sodium hydrogen carbonate (100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (30 g) and eluted with a mixture of methanol and chloroform (1:99 v/v) to give (2S, 4R)-2-[N-{2-(cyanoamino)ethyl}-N-(4-nitrobenzyloxycarbonyl)aminomethyl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.53 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[CH:35]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[O:38][N:37]=[C:36]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[CH:35]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)no2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)no3)c2)cc1F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-fluoro-phenyl)-carbamic acid tert.-butyl ester (Example J13) (269 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propionic acid tert.-butyl ester (Example K12) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (360 mg).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@H:6]([CH3:20])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:9]=1)=[O:4].CC(C)([O-])C.[K+].[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[OH:36])[CH3:28].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH2:2][C:3]([NH:5][C@H:6]([CH3:20])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:9]=1)=[O:4])[CH3:28]
Reactant: COc1ccc(C[C@@H](C)NC(=O)CBr)cc1S(N)(=O)=O
Reactant: CCOc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccccc1OCC(=O)N[C@H](C)Cc1ccc(OC)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
1.0 g of (R)-2-bromo-N-[2-(4-methoxy-3-aminosulfonyl-phenyl)-1-methyl-ethyl]-acetamide prepared in Example 2 was added to a stirring solution of 1.25 g of potassium t-butoxide and 1.5 g of 2-ethoxy phenol in 10 ml of tetrahydrofuran and stirred at 25° C. for 1 hour. After the reaction was completed, 50 ml of a 10% hydrochloric acid solution and then, 50 ml of ethyl acetate was added to the resultant solution and then, extracted. Next, the organic layer was separated and concentrated. 10 ml of methanol was added to the obtained concentrated residue and stirred for 12 hours. Then, the resultant product was filtered and dried to obtain the title compound as a white solid (0.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9](O)[CH3:10])[CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([CH:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[OH:8])[CH3:10])[CH:18]=1
Reactant: CC(O)c1cc(Cl)ccc1O
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Product: CC(c1cc(Cl)ccc1O)c1cc(Br)ccc1O
Yield: 43.5 %

Procedure:
4-Chloro-2-(1-hydroxyethyl)phenol (4 g) was added slowly to a melt of 4-bromophenol (7.9 g) and concentrated hydrochloric acid (3 drops) at 100° C. The melt was heated at this temperature for 3 hr and then cooled and the product crystallised from benzene/hexane to give 1-(5-bromo-2-hydroxyphenyl)-1-(5-chloro-2-hydroxyphenyl)ethane (3.3 g); m.p. 167° C.
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].[F:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(OC(O)C)C>N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cccc(F)c1
Agent: CCOC(C)O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(F)c3)c2cc1OC

Procedure:
A mixture of 1.00 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.89 g of 3-fluoroaniline, 0.32 ml of pyridine, and 12 ml of ethoxyethanol was stirred at reflux temperature for 4 h. The mixture was cooled and partitioned with dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate to give a solid, mp 226-230° C.
Reaction SMILES: [O-]CC.[K+].C(O)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:26](OCC)(=[O:32])[C:27]([O:29]CC)=[O:28]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:26](=[O:32])[C:27]([OH:29])=[O:28])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(O)C(=O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
Potassium ethoxide (505 g; 6 mole) was added to a solution of ethanol (710 ml) and diethyl ether (4.8 l) and the mixture was cooled to 0° C. 4-(Benzyloxy)-1-methyl-2-nitrobenzene (639.8 g; 3 mole) dissolved in diethyl oxalate (900 g; 6.16 mole) and toluene (1500 ml) was added slowly during 30 minutes. The reaction mixture was stirred for 3 hours at 0° C. and then allowed to stand cold over night. After 5 days at room temperature the reaction mixture was filtered and the filter cake was washed with diethyl ether (2 l). The cake was then treated with water (10 l), sodium hydroxide (5 M, 0.8 l) and extracted three times with diethyl ether (3×3 l). The water phase was cooled and acidified in two steps while stirring with hydrochloric acid:water (1:1, 0.9 l). First to pH 5 and the reaction mixture was then stirred for 1 hour before the acidification continued to pH 2. The reaction mixture was cooled in an ice:sodium chloride bath. Filtration after 1 hour gave 849.5 g (89.8%) of 3-(4-benzyloxy-2-nitrophenyl)-2-oxopropanoic acid.