Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=[O:4].O.[ClH:23].[CH2:24](O)C>>[ClH:23].[ClH:23].[N:9]1([CH2:8][CH2:7][O:6][CH2:5][C:3]([O:2][CH2:1][CH3:24])=[O:4])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: COC(=O)COCCN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCOC(=O)COCCN1CCNCC1
Reaction time: 4 h
Yield: 97.3 %

Procedure:
2 g (0.0066 mol) of tert-butyl 4-(2-methoxycarbonylmethoxyethyl)piperazine-1-carboxylate prepared in Example I.4.3. are dissolved in 10 ml of ethanol in a 50 ml three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. 11 ml of a 3.8M solution of hydrochloric acid in ethanol are added in a single portion with stirring. The mixture is stirred at room temperature for 30 minutes and a further 11 ml of a 3.8M solution of hydrochloric acid in ethanol are added. The mixture is brought at the reflux temperature for 4 hours. The solvent is removed on a rotary evaporator under reduced pressure. 1.86 g (97.3%) of ethyl 2-(1-piperazinyl)-ethoxyacetate dihydrochloride are obtained in the form of a pale yellow oil which crystallizes. NMR: δ: 1.21 (3H, t, 7.1 Hz); 3.37 (2H, t, 4.8 Hz); 3.46 (1H, m); 3.55 (4H, m); 3.91 (2H, t, 4.8 Hz); 4.14 (2H, q, 7.1 Hz); 4.18 (2H, s); 10.1 (1H, bs); 12 (1H, bs). Mass spectrum: 216 (M+·).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.O>C(#N)C>[C:23]1([CH:18]2[CH2:17][CH2:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([O:12][C:9]4[N:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:11][CH:10]=4)[CH:14]=3)[O:19]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(CN1CCCC1)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-Chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and pyrrolidine (51 μl). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. N-[6-(2-Phenyl-chroman-6-yloxy) pyridin-3-yl]-2-pyrrolidin-1-yl acetamide was isolated as its hydrochloride salt. 1H-NMR (400 MHz; d6-DMSO) δ: 10.8 (s, 1H), 8.35 (d, 1H, J 2.7 Hz), 8.02 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.32 (m, 5H), 7.00 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 1.9, 10.0 Hz), 4.25 (d, 2H, 5.4 Hz), 3.67-3.55 (m, 2H), 3.20-3.06 (m, 2H), 3.06-2.90 (m, 1H), 2.80-2.65 (m, 1H), 2.23-2.12 (m, 1H), 2.10-1.85 (m, 5H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl.C(N=C=NCCCN(C)C)C.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:18]([NH:28][C@H:29]([C:31]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:32])[CH3:30])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@H](C)NC(=O)OCc1ccccc1)C2
Yield: 75.8 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.3 g, 10 mmol) was dissolved in dimethylformamide (100 ml) while cooled on ice. To the obtained mixture, carbobenzyloxy-L-alanine (2.3 g, 10.5 mmol), a hydrochloric acid salt of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (hereinafter referred to as WSC.HCl) (2.3 g, 11.0 mmol), and 1-hydroxybenzotriazol (hereinafter referred to as HOBT) (1.4 g, 11.0 mmol) were added, and the resultant mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The obtained residue was extracted with chloroform, washed with 1N-HCl and saturated aqueous NaCl solution, and dried. The solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol =20:1) to obtain 3.3 g of the title compound as colorless powdery crystals (76.0%)
Reaction SMILES: C(O[C:4](=[NH:22])[CH2:5][C:6]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([OH:13])[CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)C.C(O[CH:26](OCC)[CH2:27][NH2:28])C.C(O)(=O)C.Cl>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:6]([OH:13])([CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)[CH2:5][C:4]1[NH:22][CH:26]=[CH:27][N:28]=1
Reactant: CCOC(=N)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CCOC(CN)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(Cc1ncc[nH]1)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 70 °C

Procedure:
A solution of 3-(2,4-dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrimidic acid ethyl ester free base (546 mg), aminoacetaldehyde diethylacetal (234 mg) and acetic acid (210 mg) in tetrahydrofuran (4 ml) was heated under reflux for 2 hours. Hydrochloric acid (4 ml, 5N) was added and the mixture heated to 70° C. for 30 minutes. The mixture was diluted with saturated sodium carbonate to pH8 and extracted with ethyl acetate (3×20 ml). The organic extracts were dried over magnesium sulphate and evaporated to yield a gum which was chromatographed on silica eluting with a mixture of methylene chloride, isopropanol and concentrated ammonium hydroxide (85:15:1 by volume). Fractions containing the desired product were pooled and evaporated to yield a gum which solidified on trituration with diethyl ether (246 mg). Recrystallisation from isopropanol gave the title compound as colourless crystals m.p. 168°-170° C. Found: C,49.8; H,3.9; N,20.9. C14H13Cl2N5O requires C,49.7; H,3.9; N,20.7%.
Reaction SMILES: [Na].C(O)(C)(C)C.C(OCC)(=O)C.[C:13]([O:17][C:18]([N:20]1[CH:24]2[CH2:25][CH2:26][CH:21]1[C:22](S(C1C=CC(C)=CC=1)(=O)=O)=[CH:23]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]>[Hg].C(O)(C)(C)C.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH:24]2[CH2:25][CH2:26][CH:21]1[CH:22]=[CH:23]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)C2=CC3CCC2N3C(=O)OC(C)(C)C)cc1
Agent: [Hg]
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2C=CC1CC2
Reaction time: 24 h
Yield: 45 %

Procedure:
A 2.5% Na amalgam was prepared by adding sodium (15.1 g, 657 mmol) slices to mercury (56 mL, 3.77 mol). This amalgam was added in portions to a vigorously stirring solution of NaH2PO4 (24.4 g, 203 mmol) and Na2HPO4 (28.9 g, 203 mmol) in a 1:1 tert-butanol:ethyl acetate mixture (100 mL). A solution of 7-tert-Butoxycarbonyl-2-p-tolylsulfonyl-7-azabicyclo[2.2.1]-hepta-2-ene (14.22 g, 40.7 mmol) in a 1:1 tert-butanol-ethyl acetate mixture (200 mL) was added to the stirring mixture at 0° C. After stirring for 24 h the mixture was decanted into a separatory funnel and extracted with ethyl acetate. The remaining mercury was washed thoroughly with ethyl acetate. The combined organic layers were dried with sodium sulfate, concentrated, then purified by flash chromatography with 4:1 hexane:ethyl acetate to provide 7-tert-Butoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene (3-56 g, 45% based on recovered starting material) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][O:40][CH2:41][CH:42]([NH:44][C:45](=[O:53])[CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:43]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:50]3[CH2:51][CH2:52][N:47]([CH2:46][C:45]([NH:44][CH:42]([CH3:43])[CH2:41][O:40][CH3:39])=[O:53])[CH2:48][CH2:49]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCC(C)NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)COC)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-(2-methoxy-1-methyl-ethyl)-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N-(2-methoxy-1-methylethyl)-2-piperazin-1-yl-acetamide (example 15) in an analogous manner as described in example 25. LR-MS: 719.4 [(M+H)+]
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=4)[CH2:19][CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])C(=O)OC(C)(C)C)[S:15][C:8]=23)=[C:4]([F:38])[CH:3]=1.C(O)C.C1(C)C=CC=CC=1.[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([N:59]=[C:60]=[S:61])=[O:58])=[CH:52][CH:51]=1.FC(F)(F)C(O)=O>ClCCl>[F:38][C:4]1[CH:3]=[C:2]([NH:1][C:60]([NH:59][C:57](=[O:58])[CH2:56][C:53]2[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=2)=[S:61])[CH:37]=[CH:36][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:35]=[CH:34][CH:33]=[C:18]([CH2:19][CH2:20][NH:21][CH2:29][CH2:30][O:31][CH3:32])[CH:17]=3)[S:15][C:8]=12
Reactant: COCCN(CCc1cccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COCCNCCc1cccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
To a solution of 156 (0.17 g, 0.32 mmol) in 1:1 absolute ethanol/toluene (20 mL), p-fluorophenylacetyl isothiocyanate (0.11 g, 0.56 mmol) in 1:1 absolute ethanol/toluene (5 mL) was added and the reaction was allowed to stir for 2 h at r.t. The solvents were removed under reduced pressure and the residue was purified by chromatography on silica gel (75% EtOAc/hexane) to give the intermediate Boc-protected product [not shown in the scheme] as a white solid. This material was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (3 mL) and stirred for 6 h at r.t. The mixture was then concentrated and the residue was purified by Gilson reverse phase HPLC (Aquasil C-18 column, 35-85% MeOH/H2O+HCO2H, 30 min. linear gradient elution) and lyophilized to afford title compound 157 (0.100 g, 50% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.55 (d, J=5.3 Hz, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 8.03-8.00 (m, 1H), 7.76 (s, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.57-7.53 (m, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.40-7.35 (m, 2H), 7.32 (d, J=7.6 Hz, 1H), 7.21-7.16 (m, 2H), 6.67 (d, J=5.5 Hz, 1H), 3.84 (s, 2H), 3.43 (t, J=5.5 Hz, 2H), 3.24 (s, 3H), 2.92-2.82 (m, 4H), 2.79 (t, J=5.5 Hz, 2H) (presumably as a formate salt). MS (m/z): 633.2 (M+H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Br:44].C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Br:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:33]1[C:32]([C:19]2[CH:20]=[CH:21][C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:17][CH:18]=2)=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)OC1(C)C
Reactant: Brc1ccccc1-c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccccc1-c1ccccc1-c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 61.6 %

Procedure:
A mixture of Compound 2 (3.00 g, 7.57 mmol), 2,2′-dibromo-1,1′-biphenyl (4.72 g, 15.1 mmol), tetrakis(triphenylphosphine)palladium(0) (0.350 g, 0.303 mmol), Na2CO3 (3.18 g, 30.0 mmol), H2O (30 mL) and tetrahydrofuran (THF) (50 mL) was degassed with argon for about 44 min while stirring. The reaction mixture was then maintained under argon at about 80° C. while stirring. Upon confirming consumption of the starting material by TLC (SiO2, 19:1-CH2Cl2:acetone), the reaction was cooled to RT and poured over CH2Cl2 (ca. 250 mL). The organics were then washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified via flash chromatography (SiO2, 100% CH2Cl2 to 39:1-CH2Cl2:acetone) to yield Compound 3 (2.34 g, 62%) as an off-white foam: confirmed by LCMS (APCI): calculated for C31H21BrN2 (M+): 501; Found: 501.
Reaction SMILES: [Si:1]([CH3:5])([CH3:4])(Cl)[Cl:2].[CH:6]1[CH2:10][CH:9]=[CH:8][CH:7]=1.[Na]>C(OCC)C>[Cl:2][Si:1]([C:7]1[CH2:6][CH:10]=[CH:9][CH:8]=1)([CH3:5])[CH3:4]
Reactant: C[Si](C)(Cl)Cl
Reactant: C1=CCC=C1
Agent: [Na]
Solvent: CCOCC
Product: C[Si](C)(Cl)C1=CC=CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
A solution of Me2SiCl2 (225 mL, 1.86 mol) in 450 mL of diethyl ether was cooled to 0° C., after which a sodium cyclopentadiene (compound 1) solution (1.68 M, 950 mL, 1.60 mol) was added dropwise. A white precipitate formed immediately. The reaction was allowed to warm up to room temperature and was stirred for an additional 4 hours. The resulting reaction mixture was centrifuged to separate precipitate from supernatant. The volatiles of the isolated supernatant were removed in vacuo. Fractional distillation yielded 122.76 g (48%) of the desired product as a colorless liquid (48-52° C./15 mmHg).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]([CH3:26])[CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:16]=[CH:15][C:14]=1[O:27][CH3:28])=[S:11])(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[CH3:28][O:27][C:14]1[CH:15]=[CH:16][C:17]([N:19]([CH3:26])[CH:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:18][C:13]=1[NH:12][C:10]([NH2:9])=[S:11]
Reactant: COc1ccc(N(C)C2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N(C)C2CCOCC2)cc1NC(N)=S
Reaction time: 18 h
Yield: 48.4 %

Procedure:
To a stirred suspension of 1.7 g (4.2 mmol) 1-benzoyl-3-{2-methoxy-5-[methyl-(tetrahydro-pyran-4-yl)-amino]-phenyl}-thiourea in 13 ml methanol was added dropwise 0.78 ml (6.35 mmol) 5.4 M sodium methylate solution and stirring continued for 18 hrs at room temperature. The mixture was then concentrated in vacuo and the residue subjected to column chromatography (1/1 hexane/ethyl acetate) to afford 0.6 g (51%) {2-methoxy-5-[methyl-(tetrahydro-pyran-4-yl)-amino]-phenyl}-thiourea as a yellow solid. ES-MS m/e (%): 296 (M+H+, 100).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:13][CH2:12][C@@H:11]([O:14]/[N:15]=[C:16]2\[CH2:17][CH:18]3[C@:31]([CH3:35])([CH2:32][C@H:33]\2[F:34])[C@@H:30]2[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]2)([CH3:27])[C@@H:25]([OH:36])[CH2:24][CH2:23]4)[CH2:20][C:19]3=O)[CH2:10]1.Cl.[NH2:39][OH:40]>>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH:9]1[CH2:13][CH2:12][C@@H:11]([O:14]/[N:15]=[C:16]2\[CH2:17][CH:18]3[C@:31]([CH3:35])([CH2:32][C@H:33]\2[F:34])[C@@H:30]2[C@H:21]([C@H:22]4[C@@:26]([CH2:28][CH2:29]2)([CH3:27])[C@@H:25]([OH:36])[CH2:24][CH2:23]4)[CH2:20]/[C:19]/3=[N:39]\[OH:40])[CH2:10]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC(=O)C4C/C(=N\O[C@@H]5CCNC5)[C@H](F)C[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: NO
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Product: C[C@]12CC[C@H]3[C@@H](C/C(=N\O)C4C/C(=N\O[C@@H]5CCNC5)[C@H](F)C[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
The title compound was obtained in 74% yield following the procedure described in Example 34 starting from (E)-3-[3-(R)-pyrrolidinyl]oxyimino-2α-fluoro-17β-hydroxyandrostan-6-one fumarate (Example 35, 73 mg) and hydroxylamine hydrochloride (11 mg). After evaporation of the solvent the crude reaction mixture was purified by flash chromatography (SiO2, CHCl3/MeOH/26% NH4OH 90/10/1). To the concentrated fractions, a stoichiometric amount of fumaric acid in MeOH was added. The resulting precipitate was rinsed with heptane and filtered to give the title compound I-bj.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.CCCCCC.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[S:29][C:28]3=[CH:30][N:31]([CH2:42]O)[C:32](=[O:41])[C:33]([C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)=[C:27]3[NH:26][C:25]=2[CH:44]=1>N1C=CC=CC=1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[S:29][C:28]3=[CH:30][N:31]([CH2:42][O:4][C:3](=[O:5])[CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH3:9])[C:32](=[O:41])[C:33]([C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)=[C:27]3[NH:26][C:25]=2[CH:44]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccc(Cl)cc1N2
Reactant: CCCCC(C)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCCCC(C)C(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1cc(Cl)ccc1S2
Reaction time: 16 h
Yield: 76 %

Procedure:
A mixture of 1.4 g. of 2-methylhexanoic acid (10.8 mmol.) and 3 ml. of thionyl chloride (41.1 mmol.) in 20 ml. of Skellysolve B was refluxed on a steam bath for five hours. The mixture was then concentrated under reduced pressure and the residue azeotroped twice with 30 ml. of cyclohexane to yield a colorless oil. The oil was then added dropwise to a cold, stirred suspension of 1.2 g. of 7-chloro-4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (3.1 mmol.) in 20 ml. of pyridine. After stirring for 35 minutes, the reaction mixture was poured onto ice-water and allowed to stand for 16 hours at room temperature, resulting in formation of a yellow solid, which was collected, washed with water, air-dried, then purified using flash chromatography on silica gel, employing a mixture of 2% ethyl acetate: 98% methylene chloride as the eluent. Fractions containing the product were combined and triturated with ether to yield 7-chloro-4-(4-chlorophenyl)-2-[(2-methyl-1-oxohexyloxy)methyl]-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a yellow crystalline solid (1.17 g; 76% yield) having the structural formula, ##STR19## a melting point in the range of 140°-146° C. and the following elemental analysis:
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc2nnc(Cl)n2n1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc2nnc(Cl)n2n1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
A mixture of 193 mg of 3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-amine and 0.14 cm3 of pivaloyl chloride in 5 cm3 of pyridine is stirred for 5 h at 20° C. 0.14 cm3 of pivaloyl chloride is again added and the mixture is left to stir overnight. The reaction medium obtained is concentrated to dryness under vacuum. The residue is washed with ethyl ether and pentane. The precipitate is taken up in a solution of ammonium chloride and then extracted with a 90/10 ethyl acetate/methanol mixture. The organic phase is evaporated to dryness. 157 mg of N-(3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2,2-dimethylpropanamide are thus obtained in the form of a brown powder, the characteristics of which are as follows:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].C([O-])(O)=O.[Na+].[O-]Cl.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.[K+].[Br-].CC1(C)N([O])C(C)(C)CCC1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:5]([C@@H:3]([CH3:4])[CH:2]=[O:1])[C:6](=[O:15])[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H](C)CO)cc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H](C)C=O)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of (S)-benzyl (1-hydroxypropan-2-yl)(4-methoxybenzyl)carbamate (11.8 g, 35.5 mmol) in CH2Cl2 was added NaHCO3 (3.28 g, 39 mmol), KBr (0.25 g, 2.1 mmol) and TEMPO 0.168 g, 1.07 mmol). The reaction mixture was cooled to 0-5° C. and the 5% aqueous NaClO solution (85 mL, 71 mmol) was added within 30 min. After stirring for 1 h at 0-5° C. the reaction mixture was added to Na2S2O3 solution and the product was extracted with EtOAc. Combined extracts were washed with aqueous NaH2PO4 solution, H2O and brine, dried over MgSO4, filtered and concentrated to provide the title compound as a yellow oil (11.2 g, 96%): TLC (hexane/EtOAc 1:1) Rf=0.55; tR=1.29 min (UPLC 1), tR, 1.15 min (LC-MS 3); ESI-MS: 328 [M+H]+ (LC-MS 3).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[N:26]=[N:27][C:28](Cl)=[CH:29][CH:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][NH:33][CH3:34]>C(O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[N:26]=[N:27][C:28]([N:33]([CH3:34])[CH3:32])=[CH:29][CH:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccc(Cl)nn4)ccc32)n1)c1ccccc1
Reactant: CNC
Solvent: CCO
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccc(N(C)C)nn4)ccc32)n1)c1ccccc1
Temperature: 60 °C

Procedure:
2-[(S)-1-phenylethylamino]-4-[5-(6-chloropyridazin-3-yl)benzimidazol-1-yl]pyrimidine (13.2 mg) was mixed with 33% dimethylamine in ethanol (1 mL) in a sealed tube, the system heated to 60° C. for 15 h. The mixture was cooled, concentrated and the residue purified on silica gel (2.5%MeOH in CH2Cl2) to yield 11.2 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.51 (br s, 1H); 8.41 (d, J=5.5 Hz, 1H); 8.27 (s, 1H); 8.19 (br s, 1H); 7.89 (br s, 1H); 7.73 (d, J=9.6 Hz, 1H); 7.46 (m, 2H); 7.41 (t, J=7.5 Hz, 2H); 7.30 (m, 1H); 6.93 (d, J=1H); 6.81 (d, J=5.5 Hz, 1H); 5.80 (br s, 1H); 5.22 (br s, 1H); 3.26 (s, 6H); 1.65 (d, J=6.9 Hz, 3H). Mass spectrum (ESI) 437.4 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[S:12]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13]1.[Cl-].[NH4+]>C1COCC1>[S:9]1[CH:10]=[CH:11][C:7]([CH:17]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)[OH:18])=[CH:8]1
Reactant: O=Cc1ccsc1
Reactant: Brc1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccsc1)c1ccsc1
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To 100 mL of THF cooled to -78° C. under nitrogen was added 2.5M n-butyllithium (36 mL), and 14.67 g (0.09 mol) of 3-bromothiophene was added and the resulting mixture was stirred for 30 min. To the above mixture was added 3-thiophenecarboxaldehyde (10 g, 0.089 mol) in 10 mL of THF and the mixture was stirred, allowing it to reach room temperature. Saturated ammonium chloride solution was added to the reaction mixture, the aqueous layer was extracted with ether, and the combined organic layer was concentrated in vacuo to yield 17.26 g (98.9%) of 1,1-di(3-thienyl)methanol, as an oil.