Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][C@@H:14]([CH3:28])[C@@H:15]([CH3:27])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].C[O-].[Na+].[N+:32]([C:35]1[NH:36][CH:37]=[CH:38][N:39]=1)([O-:34])=[O:33]>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([CH2:16][C@H:15]([CH3:27])[C@H:14]([CH3:28])[CH2:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH2:3][CH2:2][N:36]3[CH:37]=[CH:38][N:39]=[C:35]3[N+:32]([O-:34])=[O:33])[CH:6]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCBr)c2)cc1OC
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCn3ccnc3[N+](=O)[O-])c2)cc1OC
Yield: 52.9 %

Procedure:
The Standard Procedure 2 was followed by use of 5a (57.9 mg, 0.129 mmol, 1.0 equiv), sodium methoxide (15.4 mg, 0.285 mmol, 2.2 equiv), and 2-nitroimidazole (6b, 29.3 mg, 0.259 mmol, 2.0 equiv). After workup and purification with column chromatography (80% EtOAc in hexanes as eluant), 7b (32.9 mg, 0.0682 mmol) was obtained in 53% yield as a yellow gummy oil: 1H NMR (CDCl3, 400 MHz) δ 0.79 (d, J=6.8 Hz, 3H, CH3), 0.82 (d, J=6.8 Hz, 3H, CH3), 1.70-1.72 (m, 2H, 2×CH), 2.21-2.31 (m, 2H, 2×ArCH), 2.67-2.73 (m, 2H, 2×ArCH), 3.75 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.30 (t, J=3.8 Hz, 2H, CH2N), 4.81 (t, J=4.6 Hz, 2H, CH2O), 6.56 (m, 1H, ArH), 6.63-6.68 (m, 2H, 2×ArH), 6.71-6.78 (m, 2H, 3×ArH), 7.13 (s, 1H, nitroimidazole C5-H), 7.35 (s, 1H, nitroimidazole C4-H); 13C NMR (CDCl3, 100 MHz) δ 15.95, 15.99, 38.27, 38.68, 38.94, 39.02, 49.41, 55.59, 55.62, 55.69, 67.78, 110.86, 111.68, 112.12, 115.69, 120.73, 122.78, 127.46, 127.87, 134.18, 134.46, 144.51, 146.72, 146.82, 147.68, 148.43; IR (neat) 2924 (s), 2851 (s), 1588 (w), 1537 (w), 1515 (s), 1488 (w), 1361 (s), 1260 (s), 1235 (s), 1028 (s) cm−1; HRMS (FAB) m/z calcd for C26H34N3O6 (M+H)+: 484.2448. found: 484.2433.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C@H](C3C=CC(OC)=CC=3)[O:8][C:7]([C:23]#[C:24][CH:25]3[CH2:27][CH2:26]3)([C:19]([F:22])([F:21])[F:20])[C:6]=2[CH:28]=1.CO.O.[BH4-].[Na+]>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:10])=[C:6]([C@@:7]([C:23]#[C:24][CH:25]2[CH2:26][CH2:27]2)([C:19]([F:21])([F:22])[F:20])[OH:8])[CH:28]=1
Reactant: COc1ccc([C@H]2Nc3ccc(Cl)cc3C(C#CC3CC3)(C(F)(F)F)O2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Crude (S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2-(4'-methoxyphenyl) -3, 1-benzoxazine (71 kg calculated dry weight) was charged to a mixture of methanol (301 kg), 30% NaOH (121 kg) and water (61L). The mixture was heated to 60° C. to give a clear solution then cooled to 30° C. A solution of sodium borohydride (3.2 kg, 84.2 mol) in 0.2 N NaOH (29L) was added to the methanolic solution over 20 min, keeping the temperature below 35° C. After 30 min, excess borohydride was quenched with acetone (5.8 kg) and the solution diluted with water (175L) then neutralized to pH 8 to 9 with acetic acid. The resulting slurry was cooled to about 0° C., filtered and the product washed with water then dried in vacuo at 40° C. The crude product was reslurried with a mixture of toluene (133 kg) and heptanes (106 kg) initially at 25° C., then with cooling below -10° C. The product was filtered, washed with heptanes (41 kg) and dried in vacuo at 40° C. to give 44.5 kg (88%) as an off-white/pale yellow crystalline solid. An analytical sample was recrystallized from t-butyl methyl ether/heptane: mp 141-143° C.; [a]25D -28.3° (c 0.106, MeOH); 1H NMR (300 MHz, CDCl3) δ7.54 (d, J=2 Hz, 1H), 7.13 (dd, J=9, 2 Hz, 1H), 6.61 (d, J=9 Hz, 1H), 4.61 (brs, 1H), 4.40 (brs, 1H), 1.44-135 (m, 1H), 0.94-0.78 (m, 2H): 13C NMR (75 MHz, DMSO-d6) δ146.7, 129.4, 129.0, 124.3, 118.4, 118.07, 118.05, 92.3, 72.6, 71.0, 8.2, 8.1, -1.1; 19F NMR (282 MHz CDCl3) δ-80.5.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O-:14])=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>CN(C)C=O>[O:18]1[CH2:19][CH2:20][N:15]([C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[NH:1][C:2](=[O:3])[CH2:4][CH2:5]3)=[O:14])[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: O=C1CCc2cc(C(=O)[O-])ccc2N1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(=O)N3CCOCC3)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.0 Gram of succenimide 3,4-dihydrocarbostyril-6-carboxylate and 0.37 g of morpholine were dissolved in 2 ml of dimethylformamide and stirred at room temperature for 3 hours. Then water was added to the reaction mixture and extracted with chloroform, the chloroform layer was washed with water and a saturated sodium chloride aqueous solution in this order. After drying the chloroform layer with anhydrous sodium sulfate, then chloroform was removed by distillation under a reduced pressure, then acetone was added to the thus obtained residue to crystallize the product. 150 Milligrams of 6-morpholinocarbonyl-3,4-dihydrocarbostyril was obtained. Colorless granular crystals. Melting point: 206°-207° C. (from ethanol).
Reaction SMILES: C(C1C=CC=CC=1O[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)CCC.[C:18]12([C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=3[OH:35])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1C=CCCC1>ClCCl>[C:18]12([C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=3[O:35][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH2:19][CH:20]3[CH2:26][CH:24]([CH2:23][CH:22]([CH2:21]3)[CH2:27]1)[CH2:25]2
Reactant: CCCCc1ccccc1OC1CCCCO1
Reactant: Oc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc(C23CC4CC(CC(C4)C2)C3)c(OC2CCCCO2)c1

Procedure:
Using the same general procedure as for the preparation of of 4-bromo-2-t-butyl-1-(2-tetrahydropyranoxy)benzene (Compound H), but instead using 12.56 g (40.9 mmol) of 2-(1-adamantyl)-5-bromophenol (Compound G), 1.03 g (4.1 nunol) of pyridinium p-toluenesulfonate, 5.16 g (5.6 ml, 61.3 mmol) of 3,4-dihydro-2H-pyran and 50 ml of dichloromethane produced a clear, orange solution. During aqueous workup, the organic phase was washed with 3×150 ml-portions of sat. aqueous NaHCO3 solution to produce a light yellow solid. Purification by flash chromatography (silica, 3% ethyl acetate in hexane) yielded the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](OCC)=[O:14].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC>O1CCCC1>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](=[O:14])[CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: Cc1ccncc1
Reactant: CCOC(=O)c1ccco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cc1ccncc1)c1ccco1
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of 4-picoline (4.6 g, 49.4 mmol) and ethyl 2-furancarboxylate (7.7 g, 54.9 mmol) in tetrahydrofuran (40 ml) was dropwise added lithium bis(trimethylsilyl)amide (100 ml, 100 mmol) over 1 hour at 0° C. under an atmosphere of nitrogen gas, followed by stirring as it was for 2 hours. Hexane (140 ml) was added to the reaction mixture, and the resulting crystals were collected by filtration. The resulting crystals were dissolved in ethyl acetate and a saturated aqueous ammonium chloride solution. The organic layer was washed with a saturated aqueous ammonium chloride solution twice and brine, dried over anhydrous sodium sulfate and concentrated. Hexane was added to the residue, and the resulting precipitates were collected by filtration and washed with hexane, to give the title compound (6.5 g, 70%) as a pale yellow solid.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]1[C:12]([O:14]CC)=[O:13].Cl>[OH-].[Na+]>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C1C=Nc2cccnc2C1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1C=Nc2cccnc2C1O
Temperature: 25 °C

Procedure:
Ethyl 4-hydroxy-3,4-dihydro-1,5-naphthyridine-3-carboxylate (1.8 g, 8.2 mmol) was dissolved in 4% aqueous sodium hydroxide (80 ml). The reaction mixture was heated to reflux for 4 hours, cooled to room temperature, and then adjusted to pH=4 with 2N hydrochloric acid. The reaction mixture was filtered to give 4-hydroxy-3,4-dihydro-1,5-naphthyridine-3-carboxylic acid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[N:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1>N1C=CC=CC=1>[Br:5][C:6]1[N:10]2[N:11]=[C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH:20]([CH3:22])[CH3:21])[C:1](=[O:3])[CH3:2])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CC(C)NCCCNc1ccc2ncc(Br)n2n1
Solvent: c1ccncc1
Product: CC(=O)N(CCCNc1ccc2ncc(Br)n2n1)C(C)C
Reaction time: 17 h
Yield: 103.1 %

Procedure:
Acetyl chloride [75-36-5] (1.0 mL, 14.1 mmol) was added, in portions, to an ambient temperature solution of N1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-N3-isopropylpropane-1,3-diamine (196.9 mg, 0.6 mmol) in pyridine (6.5 mL), and stirred under N2 blanket for 17 h. Pyridine was evaporated from the reaction mixture and the residue partitioned between aqueous 5% (w/v) sodium bicarbonate and ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and evaporated to afford 219.2 mg of dark oil. LRMS (ESI) m/z 354.1/356.1 [(M+H)]+, calc'd for C14H20BrN5O: 354.25.
Reaction SMILES: [CH2:1]([C:3](=[CH:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)[CH3:2].S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[Na].[C:33]1([SH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:1]([C:3](=[CH:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([S:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCC(=CSc1ccccc1)C(=O)Nc1ccccc1
Agent: [Na]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCC(=CSc1ccccc1)C(=Nc1ccccc1)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
A mixture of 3.68 g (13 mmol) of 2-ethyl-N-phenyl-3-(phenylthio)-2-propenamide, 1.9 ml (26 mmol) of thionyl chloride, 10 mg of DMF, and 20 ml of toluene was refluxed for 1 hour. After concentration of the mixture under vacuum, the residue was dissolved in 35 ml of DMF and then 2.0 g (15.1 mmol) of a benzenethiol sodium salt was added portionwise under ice cooling and stirred at room temperature for 1 hour. After dilution with tert-butyl methyl ether, the mixture was washed sequentially with water (three times) and saturated NaCl solution, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 2.03 g of phenyl 2-ethyl-N-phenyl-3-(phenylthio)-2-propenimidothioate (hereinafter referred to as the present compound 14).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[I:15]CI.N(OCCC(C)C)=O>C(OCC)C>[I:15][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CCOCC
Product: CCOC(=O)CCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 42 %

Procedure:
To a solution of Part (2) compound (7.2 g, 32 mmol) in diiodomethane (10.3 mL, 128 mmol) under argon at RT was added isoamyl nitrite (6.5 mL, 64 mmol) over 10 min. The brownish solution was stirred at RT for 40 min and then heated to 80° C. for 2 h. Ethyl ether (300 mL) was added to the reaction and the organic layer was washed with 1N hydrochloric acid (70 mL×2), water (70 mL), saturated sodium bicarbonate (70 mL×2), 10% sodium bisulfite solution (30 mL) and dried over magnesium sulfate. Purification was performed by flash chromatography on 800 g silica gel, loaded and eluted with 7% ethyl acetate in hexane. Pure, fractions were combined and evaporated to give the title compound (4.1 g, 42%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[Br:24][C:25]1[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=1>>[Br:24][C:25]1[N:30]=[C:29]([C:31]2[NH:21][C:3]3[C:2]([N:1]=2)=[N:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:15])[CH2:9]2)=[CH:5][CH:4]=3)[CH:28]=[CH:27][CH:26]=1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Reactant: O=Cc1cccc(Br)n1
Product: O=C([C@@H]1CCCN(c2ccc3[nH]c(-c4cccc(Br)n4)nc3n2)C1)N1CCCC1

Procedure:
(R)-(1-(2-(6-Bromopyridin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone was prepared using a method analogous to the one used for Example 112, but using (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone and 6-bromopicolinaldehyde as starting materials. MS (ES+APCI) (M+H) 455.0; LCMS retention time 3.238 min (Method C1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[N:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[N:4][CH:3]=1
Reactant: CCOC(=O)CCc1ncc(C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(CCC(=O)O)s1
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of ethyl 3-(5-methylthiazol-2-yl)propanoate (0.2 g, 1 mmol) in THF/water (3 mL/3 mL) was added lithium hydroxide (61 mg, 1.5 mmol) portionwise at room temperature. The resulting mixture was stirred for 3 h. The solvent was evaporated and the residue was acidified with conc. HCl to adjust the pH to 1-2. The mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate and concentrated to afford 3-(5-methylthiazol-2-yl)propanoic acid (0.17 g, 87.7% yield) as a colorless oil. LCMS retention time 0.436 min; LCMS MH+ 172.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:10]=[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)(C)(C)C.Cl.O1CCOCC1>C1COCC1>[C:20]1([CH3:23])[CH:19]=[CH:18][C:17]([N:9]2[C:8]([NH2:7])=[CH:12][C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[N:10]2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(-n2nc([Si](C)(C)C)cc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc([Si](C)(C)C)cc2N)cc1
Temperature: 60 °C
Yield: 48.8 %

Procedure:
Place (2-p-tolyl-5-trimethylsilanyl-2H-pyrazol-3-yl)-carbamic acid tert-butyl ester (504 mg, 1.46 mmol) in THF (10 mL). Add 4 M HCl in dioxane (4 mL, 16 mmol) and heat to 60° C. for 3 hours. Cool the reaction to room temperature and load onto a Varian™ SCX column. Wash the column with MeOH and then flush off the product with 2 M NH3 in MeOH. Collect filtrate and concentrate under reduced pressure to yield 175 mg (49%) of 2-p-tolyl-5-trimethylsilanyl-2H-pyrazol-3-ylamine.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-:3].[Cl-].[C:5]1([OH:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.O>ClC1C=CC=C(Cl)C=1>[Cl:1][C:5]1[CH:14]=[C:9]([Cl:3])[CH:8]=[CH:7][C:6]=1[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH2:6][CH2:7]1
Reactant: Oc1cccc2ccccc12
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1cccc(Cl)c1
Solvent: O
Product: O=C1CCC(c2ccc(Cl)cc2Cl)c2ccccc21
Temperature: 65 °C
Yield: 142.5 %

Procedure:
In a suspension of 60 g (0.45 mole) of aluminium chloride in 100 ml of metadichlorobenzene, 28.8 g (0.2 mole) of α-naphthol are introduced in 10 minutes: the temperature rises from 20° to 45° C. The medium is heated for 1 hour 30 mins at 65° C. then hydrolysed with 400 ml of water. After decantation, the organic phase is separated and concentrated in a vacuum from 2 to 5 torrs at 80° C. The residue is dissolved in 100 ml of isopropanol and the resultant solution cooled at 0° C. for 2 hours. The light beige solid formed is separated by filtration and dried to obtain 41.5 g of the expected compound.
Reaction SMILES: C([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.[OH-].[K+]>O1CCOCC1.O>[OH:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 3β-acetoxy-5α-pregn-16-ene-11,20-dione (Chamberlin et al., J. Amer. Chem. Soc., 1951, 73, 2396) (25.7 g.) in dioxan (500 ml.) was treated with potassium hydroxide (10 g.) and water 250 ml. and the mixture allowed to stand at room temperature for 1 hour. After a further 1 hour at 40° the mixture was diluted with water and the product filtered off. The crude material was dissolved in chloroform and filtered through a column of grade III neutral alumina (ca. 100 g.). The material obtained was crystallised from acetone petroleum to give pure title compound (17.65 g.), as small plates, m.p. 217.5°, [α]D +82.9° (c 1.1), λmax. 234 nm. (ε 10,100).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([NH:21][CH2:22][CH2:23]N1CCOCC1)=[O:20]>CO.[Pd]>[NH2:15][C:13]1[CH:14]=[C:10]([C:8]([NH:7][C:5]2[CH:4]=[C:3]([C:19]([NH:21][CH2:22][CH2:23][CH2:1][N:2]([CH3:6])[CH3:3])=[O:20])[N:2]([CH3:1])[CH:6]=2)=[O:9])[N:11]([CH3:18])[CH:12]=1
Reactant: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)NCCN1CCOCC1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCNC(=O)c1cc(NC(=O)c2cc(N)cn2C)cn1C
Reaction time: 5 h

Procedure:
1-Methyl-4-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-N-[2-(4-morpholinyl)ethyl]-1H-pyrrole-2-carboxamide (150 mg, 0.371 mmol; see step (ii) above) was suspended in methanol (25 mL) to which Pd/C-10% (108 mg) was added at 0° C. under a nitrogen with stirring. The reaction mixture was hydrogenated for 5 h at room temperature and atmospheric pressure. The catalyst was removed over Kieselguhr and methanol was removed under reduced pressure to give the title compound, which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[CH2:11][C:10](=[O:14])[NH:9][C:8]2[C:15]3[C:20]([CH:21]=[CH:22][C:7]1=2)=[CH:19][CH:18]=[CH:17][CH:16]=3.[Cl:23][C:24]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CC1C(C)=CC=CC=1C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1OC)=O>>[O:14]=[C:10]1[NH:9][C:8]2[C:15]3[C:20]([CH:21]=[CH:22][C:7]=2[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:24]=2[Cl:23])[C:12](=[O:13])[CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: NCCCCN1C(=O)CC(=O)Nc2c1ccc1ccccc21
Reactant: COc1cccc(C(=O)Cl)c1Cl
Agent: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1NC(=O)c1cccc(C)c1C
Product: COc1cccc(C(=O)NCCCCN2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1Cl
Yield: 55.8 %

Procedure:
By using N-(tert-butoxycarbonyl)-1,4-diaminobutane as the starting material, 5-(4-aminobutyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione was obtained in the same manner as that of Example 42, (1) and (2). By using 5-(4-aminobutyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.1 mmol), and 2-chloro-3-methoxybenzoyl chloride (0.15 mmol), the title compound (26 mg, yield 56%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1>>[F:33][C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([F:34])[CH:30]=1)[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: Fc1cc(F)cc(OCCCBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cc(F)cc(F)c3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.820 g of 1-(3-bromopropoxy)-3,5-difluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.39.
Reaction SMILES: CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.[N:16]1([C:22]([N:24]2[CH2:29][CH:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[CH2:27][CH:26]([C:40]([NH2:42])=O)[CH2:25]2)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O1CCCC1>[N:16]1([C:22]([N:24]2[CH2:29][CH:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=3)[CH2:27][CH:26]([C:40]#[N:42])[CH2:25]2)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: NC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: N#CC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Under argon, 3.83 g (16.1 mmol) of Burgess reagent were added to a solution of 4.42 g (11.5 mmol) of the compound from Example 82A in 208 ml of tetrahydrofuran. The mixture was stirred at 70° C. for 1 h. For work-up, the solvent was removed under reduced pressure and the residue was taken up in ethyl acetate. The organic phase was washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. Yield: 4.19 g (99% of theory)
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16](C3C=CN=CC=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:39]([S:41](Cl)(=[O:43])=[O:42])[CH3:40]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])[N:17]=[C:16]([C:7]3[CH:6]=[CH:5][CH:4]=[CH:9][N:8]=3)[N:15]=2)(=[O:11])=[O:12])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccncc2)nc1OCCN
Product: CCS(=O)(=O)NCCOc1nc(-c2ccccn2)nc(NS(=O)(=O)c2ccc(C(C)C)cn2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a) 100 mg 5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with ethanesulfonylchloride to give 83 mg 5-isopropyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.28 min, [M+1]+=629.63, [M−1]−=627.73.