Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][C:19]3=[S:27])[C:6]=2[CH:28]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][C:19]3=[S:27])[C:6]=2[CH:28]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COC(OC)[C@]1(C)Oc2ccc(N)cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(OC)[C@]1(C)Oc2ccc(NC(C)=O)cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
100 mg (0.25 mmol) of the compound obtained in Example 17 was dissolved in 2 ml of dichloromethane, to which 23 μl (0.25 mmol) of acetic anhydride, 52 μl (0.37 mmol) of triethylamine and 9.1 mg (0.07 mmol) of 4-dimethylaminopyridine were added in that order. The reaction was stirred for 3 hours at room temperature, 10 ml of saturated NaHCO3 solution was added and extraction was performed with 40 ml of dichloromethane. The extract was washed with brine and dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), to give 96 mg (yield: 86%) of the target compound.
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=O)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][C:46]([CH3:48])([CH3:49])[CH3:47])=[O:44])=[O:26])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C)C(C)C
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)NC(C)(C)C)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
2 g (3.35 mmol) Z-Val-Val-MeVal-Pro-OH (SEQ ID NO: 2) and 0.692 g (3.35 mmol) H-Pro-NHC(CH3)3 were dissolved in 34 ml of dry dichloromethane. After cooling to 0° C., 1.35 ml (12.1 mmol) N-methylmorpholine, 0.114 g (0.84 mmol) HOBt and 0.645 g (3.35 mmol) EDCI were added and the reaction mixture stirred overnight at room temperature. 80 ml dichloromethane were added and the organic phase thoroughly washed with saturated aqueous NaHCO3 solution (3×), water (1×), 5% citric acid (3×) and saturated NaCl solution (1×). The organic phase was dried over sodium sulfate and evaporated to dryness to yield 1.8 g of the product which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[C:20]3[C:27]([OH:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O:32][C@@H:33]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@@H:34]1OC(=N)C(Cl)(Cl)Cl)(=[O:31])[CH3:30].C(=O)([O-])O.[Na+]>ClCCl>[C:29]([O:32][C@@H:33]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:34]1[O:28][C:27]1[C:20]2[C:19]([CH2:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])=[CH:12][CH:13]=3)=[CH:23][S:22][C:21]=2[CH:24]=[CH:25][CH:26]=1)(=[O:31])[CH3:30]
Reactant: O=C(OCc1ccccc1)c1ccc(CCc2csc3cccc(O)c23)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3scc(CCc4ccc(C(=O)OCc5ccccc5)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of 3-[2-(4-benzyloxycarbonylphenyl)ethyl]-4-hydroxybenzo[b]thiophene (35 mg) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (53 mg) in dichloromethane (3 mL) was added boron trifluoride-diethyl ether complex (0.006 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-3/2) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-benzyloxycarbonylphenyl)ethyl]benzo[b]thiophene (38 mg). This material was dissolved in dichloromethane (1 mL). To the solution were added dimethyl sulfide (0.15 mL) and boron trifluoride-diethyl ether complex (0.067 mL), and the mixture was stirred at 35° C. for 4 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give the title compound (25 mg).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].C[C@]12CC[C@H]3[C@@H](CCC4[C@]3(C)C=CC(=[O:41])C=4)[C@@H]1CCC2=O.C[C@]12CC=C3[C@@H](CCC4[C@]3(C)CCC(=O)C=4)[C@@H]1CCC2=O>>[OH:41][C@:17]12[CH2:18][CH2:19][C@@:2]3([CH3:1])[C@@H:6]([CH2:5][CH2:4][C:3]3=[O:21])[C@@H:7]1[CH2:8][CH2:9][C:10]1[C@:15]2([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O

Procedure:
We have carried on investigations with attention to the fact that corticoids can be prepared through fewer steps from the aforementioned androst-4-ene-3,17-dione, androsta-1,4-diene-3,17-dione or androsta-4,9(11) -diene-3,17-dione which has recently be produced inexpensively and in a large scale from 9α-hydroxy-androst-4ene-3,17-dione which has also recently be produced by a fermentative process.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:24])[NH:9]2)(=[O:3])[CH3:2].[Br-:25].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>O1CCCC1>[Br:25][CH2:2][C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:24])[NH:9]2)=[O:3]
Reactant: [Br-]
Reactant: COc1ccc(COc2ccc(C(C)=O)c3ccc(=O)[nH]c23)cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(C(=O)CBr)c3ccc(=O)[nH]c23)cc1
Temperature: 0 °C
Yield: 33.1 %

Procedure:
5-Acetyl-8-[(4-methoxyphenyl)methoxy]-1,2-dihydroquinolin-2-one (1.25 g, 3.87 mmol) was dissolved in tetrahydrofuran (10 mL) and the solution was cooled to 0° C. Pyridinium tribromide (1.51 g, 4.25 mmol) was added in portions thereto and the reaction mixture was heated under reflux overnight. The precipitate was collected by filtration and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure and, thereafter, the residue was suspension-washed with purified water (20 mL). The precipitate was collected by filtration and washed with purified water. The solid was suspension-washed with ethyl acetate (20 mL), collected by filtration, and dried under reduced pressure to obtain 5-(2-bromoacetyl)-8-[(4-methoxyphenyl)methoxy]-1,2-dihydroquinolin-2-one (515 mg).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl.O>[Cl-].[NH+]1C=CC=CC=1>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C

Procedure:
trans-7-Methoxy-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane (2 g) was dissolved in melted pyridinium chloride, prepared from a mixture of pyridine (10 ml) and conc. hydrochloric acid where the water has been removed by distillation at 140° C. The mixture was heated for 75 min. Cooled down to room temperature. Water was added (15 ml) and pH adjusted to 12 with sodium hydroxide (32.5%). The mixture was extracted with toluene (15 ml). The organic phase was separated, dried over potassium carbonate and evaporated.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH:8]3[C:13](=O)[CH:11]([CH2:12][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH2:10][CH2:9]3.Cl.[NH2:16][OH:17]>N1C=CC=CC=1.CCO>[CH:1]1[C:6]2[CH2:7][CH:8]3[C:13](=[N:16][OH:17])[CH:11]([CH2:12][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH2:10][CH2:9]3
Reactant: O=C1C2CCC1Cc1ccccc1C2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1C2CCC1Cc1ccccc1C2

Procedure:
To a solution of 34.3 g of 5,6,7,8,9,10-hexahydro-6,9-methano-benzo[a][8]annulen-11-one (0.184 mol) in 100 mL of pyridine and 100 mL of EtOH was added 29.7 g of hydroxylamine hydrochloride (0.460 mol). The resultant solution was refluxed for 4 hours prior to concentration in vacuo. The residue was partitioned between CH2Cl2 and 10% aqueous citric acid. The aqueous layer was extracted with CH2Cl2 (4×200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford the oxime.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:6]=2[N:7]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[N:30]1[C:34]([CH3:35])=[N:33][CH:32]=[N:31]1)[NH2:26]>C(O)(=O)C.C1COCC1>[F:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[N:3]=[C:4]([NH:20][CH3:21])[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=4)[C:6]=3[N:7]=2)[CH:27]=[CH:28][C:29]=1[N:30]1[C:34]([CH3:35])=[N:33][CH:32]=[N:31]1
Reactant: CNc1nc(Cl)nc2c1CCC2c1cc(F)c(F)c(F)c1
Reactant: Cc1ncnn1-c1ccc(N)cc1F
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3ncnc3C)c(F)c2)nc2c1CCC2c1cc(F)c(F)c(F)c1
Temperature: 80 °C

Procedure:
2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (65.3 mg, 0.208 mmol) was added to a solution of 3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (40 mg, 0.208 mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80° C. overnight. Partial formation of the desired product was observed. The reaction mixture was heated at 130° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (5.3 mg, 8.99 μmol, 4.32% yield). LC-MS (M+H)+=470.0. 1H NMR (500 MHz, CDCl3) δ ppm 12.17 (1H, s), 8.75 (1H, d, J=1.8 Hz), 8.05 (1H, dd, J=13.7, 2.1 Hz), 7.80 (1H, t, J=8.7 Hz), 7.44-7.65 (1H, m), 6.74-6.99 (2H, m), 5.33-5.66 (1H, m), 4.34-4.67 (1H, m), 3.42-3.74 (2H, m), 3.29 (3H, d, J=4.9 Hz), 2.70-2.99 (2H, m), 2.57 (2H, s), 2.14-2.38 (1H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]1=2.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>C1(C)C(C)=CC=CC=1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][N:50]([C:2]2[CH:20]=[CH:19][CH:18]=[C:4]([CH2:5][N:6]3[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]4[CH:14]=[CH:15][CH:16]=[CH:17][C:7]3=4)[CH:3]=2)[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: O=C1CCCc2ccccc2N1Cc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(CN3C(=O)CCCc4ccccc43)c2)CC1
Yield: 97.3 %

Procedure:
A mixture of 0.5 g (1.51 mmole) 1-(3-bromo-benzyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, 0.203 g sodium tert-butoxide, 0.04 g (0.16 mmole) tri-tert-butyl phosphine, 0.04 g (0.16 mmole) palladium(II)acetate, and 0.3 g piperazin-1-yl carboxylic acid tert-butyl ester in 5 mL xylene was heated at 105° under N2 for 1.5 hrs. The mixture was diluted with 5 mL ethyl ether and then filtered through a pad of 10 g silica gel 230-400 mesh. 4-[3-(2-Oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester was eluted with 20% ethyl acetate/hexane to yield 0.64 g of a heavy syrup. M+H=436.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:11]([C:18]1[C:23]([I:24])=[CH:22][CH:21]=[C:20]([N:25]2[CH2:29][C@H:28]([O:30][CH3:31])[C@@H:27](OS(C3C=CC=C([N+]([O-])=O)C=3)(=O)=O)[CH2:26]2)[N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CS(C)=O>[CH2:11]([C:18]1[C:23]([I:24])=[CH:22][CH:21]=[C:20]([N:25]2[CH2:29][C@H:28]([O:30][CH3:31])[C@@H:27]([O:3][C:1](=[O:4])[CH3:2])[CH2:26]2)[N:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)O
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1OS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1OC(C)=O
Reaction time: 6 h

Procedure:
4.2 ml of acetic acid was added to a mixture of 7.9 g of cesium carbonate and 15 ml of dimethyl sulfoxide. After foaming stopped, a mixture of 14.4 g of 2-benzyl-3-iodo-6-[(3S,4S)-3-(3-nitrobenzenesulfonyl)oxy-4-methoxypyrrolidine-1-yl]pyridine and 35 ml of dimethyl sulfoxide was added thereto, followed by heating under stirring for 6 hours in an oil bath kept at 70° C. in a nitrogen atmosphere. The reaction solution was cooled and then subjected to extraction with ethyl acetate-water. The organic phase was washed with water and brine brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 10-15% ethyl acetate/hexane, to give 7.5 g of the target compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]([C:40]([O:42]C(C)(C)C)=[O:41])([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:14])(C)(C)C>C(Cl)Cl>[CH2:25]([C:26]([OH:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([C:40]([OH:42])=[O:41])([C:13]([OH:14])=[O:12])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39]
Reactant: C=CCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (2 mL) is added to a compound from step 4 (0.022 mmol) and the reaction is stirred at r.t. for 1 hour. The mixture is diluted with DCM (10 mL) and concentrated. The material is taken up in EtOAc (10 mL) and washed with H2O (20 mL). The organic layer is dried over Na2SO4, filtered and concentrated. The crude material is dissolved in 1 mL MeOH and purified via MS-triggered HPLC (Sunfire 30×50 mm 5 um column ACN/H2O w/ 0.1% TFA 75 ml/min, 1.5 ml injection, 45-70% ACN over 3.5 min).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[CH3:27][O:28][CH2:29][CH2:30][NH:31][S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: COCCN
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: COCCNS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and 2-methoxy-ethylamine. MS (ESI): 452.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]([C:22]([NH2:24])=O)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:11]([CH2:22][NH2:24])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N2CCN(Cc3ccccc3)C(C(N)=O)C2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cccc(N2CCN(Cc3ccccc3)C(CN)C2)c1

Procedure:
In a manner similar to Preparation 2, react 4-(3-methoxyphenyl)-1-(phenylmethyl)-2-piperazinecarboxamide (0.9 g, 27 mmol) with lithium aluminum hydride (2.1 g, 55 mmol) to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].CN1CCCC1=O.Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>O>[CH:6]([C:2]1[N:1]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[CH:4][N:3]=1)=[O:7]
Reactant: CCOC(=O)CCl
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)Cn1ccnc1C=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To 1H-imidazole-2-carboaldehyde (2.0 g), N-methylpyrrolidone (25 mL) was added, followed by dissolution with heating. To the resultant solution, ethyl chloroacetate (11.1 mL) and potassium carbonate (2.9 g) were added. The reaction solution was stirred at room temperature for 14 hours. To the reaction solution, water (30 mL) was added. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated saline and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration and the solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane) to obtain the title compound having the following physical properties (1.3 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[O:5])[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=1[OH:20]
Reactant: COc1cccc(OC)c1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2c(F)cccc2F)c(O)c1
Reaction time: 1 h

Procedure:
To a mixture of 20 g of 2,6-difluorobenzoyl chloride and 15.5 g of 1,3-dimethoxybenzene in 200 ml of 1,2-dichloroethane, 15.28 g of aluminum chloride is added in portions with the internal temperature maintained at 0°-10° C. The mixture is stirred 1 hour and then refluxed 45 min. The reaction mixture is poured into concentrated hydrochloric acid and ice. The organic layer is separated, washed, dried over anhydrous sodium sulfate and evaporated. Trituration with hexane followed by recrystallization from 95% ethanol gives 2',6'-difluoro-2-hydroxy-4-methoxybenzophenone, mp 71°-72° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:16]2[CH2:15][C@H:14]([CH3:13])[O:19][C@H:18]([CH3:20])[CH2:17]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2C[C@@H](C)O[C@@H](C)C2)cc1
Yield: 11.8 %

Procedure:
A solution of 4-fluorobenzoic acid ethyl ester (3 g), cis-2,6-dimethylmorpholine (2.26 g) and potassium carbonate (2.47 g) in dimethylsulfoxide (60 ml) was stirred for 18 hours at 80° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (5:1 hexane-ethyl acetate elution) to give 4-(cis-2,6-dimethylmorpholin-4-yl)benzoic acid ethyl ester (555 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:33])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C=NC1CCCCC1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)NC1CCCCC1
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
A solution of the compound of Example 47, 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (980 mg, 2.98 mmol) in 20 mL of CH2Cl2 was chilled in an ice water bath. With vigorous stirring, the solution was treated with cyclohexyl isocyanate (0.400 mL, 3.13 mmol). After 30 min, the reaction was concentrated to yield a yellow foam. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) followed by recrystallization from acetonitrile gave 400 mg of N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-cyclohexylurea as an off white solid.