Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br.CS(C)=[O:17]>O>[O:17]=[CH:2][C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: CS(C)=O
Agent: Br
Solvent: O
Product: COC(=O)c1ccc(C(=O)C=O)cc1

Procedure:
To a solution of methyl 4-acetylbenzoate (1.00 g, 5.61 mmol) in DMSO (5 mL) was slowly added 40% HBr (1.5 mL) at 20° C. under stirring. The mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water (10 mL) and the resulting mixture was extracted with DCM (10 mL×3), washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give methyl 4-(2-oxoacetyl)benzoate (150 mg), which was taken forward without further purification. To a solution of 4-methoxybenzene-1,2-diamine (107 mg, 0.78 mmol) in 5 mL of acetic acid was added the crude methyl 4-(2-oxoacetyl)benzoate (150 mg). The mixture was refluxed for 2.5 hours. The solvent was removed in vacuo. The crude product was purified by prep-TLC (PE/EA: 1/1) to separate the desired methyl 4-(6-methoxyquinoxalin-2-yl)benzoate (more polar) from the undesired methyl 4-(7-methoxyquinoxalin-2-yl)benzoate. The two structures were confirmed by HMBC spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][NH:28][CH:29]3[CH3:32])=[CH:24][CH:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][C:22]([C:21]5[C:16]([O:15][CH3:14])=[N:17][CH:18]=[CH:19][CH:20]=5)=[CH:23][CH:24]=4)[CH:29]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1ncccc1-c1ccc2c(c1)C(C)NCC2
Product: COc1ncccc1-c1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Cl)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[H-].[Na+].[CH3:14]I>CN(C)C=O>[OH:1][CH2:2][C:3]1[N:11]([CH3:14])[C:10]2[C:5]([N:4]=1)=[N:6][CH:7]=[CH:8][CH:9]=2
Reactant: OCc1nc2cccnc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2ncccc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 45 g of 2-hydroxymethyl-3H-imidazo[5,4-b]pyridine, 13.17 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 20.7 ml of methyl iodide and 1.43 liter of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 1:1 by volume as the eluent, to give 3.24 g of the title compound, melting at 130°-132° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:31])[C:28]#[C:29][CH3:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:31])[C:28]#[C:29][CH3:30])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CC#CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC#CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (64 mg, 65%), MS (ISP) m/z=395.3 [(M+H)+], mp 195° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and but-2-ynoic acid.
Reaction SMILES: CO[N:3]=[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.B.O1CCCC1.O>C1COCC1>[NH2:3][CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1
Reactant: CON=C(Cc1ccc(OC)cc1)c1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of a mixture of syn-and anti-isomers of 2-(4-methoxyphenyl)-1-phenyl-1-ethanone-O-methyl oxime (10. 1.65 g, 6.46 mmol) in THF (40 ml, freshly distilled from sodium benzophenone ketyl) under nitrogen was added borane-tetrahydrofuran solution (21.2 ml, 21.2 mmol, 1.0M solution, Aldrich) at room temperature. The resulting pale yellow solution was refluxed overnight, and cooled in an ice water bath. Water (50 ml) was carefully added to quench, followed by 20% NaOH (50 ml). The resulting colorless bi-phasic mixture was refluxed with vigorous magnetic stirring overnight, and allowed to cool to room temperature. Hexanes (40 ml) were added, and the layers separated. The aqueous portion was extracted with hexanes (1×40 ml). The combined organic portions were dried over potassium carbonate, and concentrated in vacuo to afford a colorless, slightly cloudy syrup. This syrup was purified by column chromatography on neutral alumina (I, 15 g) using an elution gradient of chloroform to 10% methanol/chloroform. The amine 15 was isolated as 1.263 g of a clear, colorless syrup (86% yield): Rf 0.20 (5% methanol/chloroform); IR (CDCl3) 3376 (w), 3316 (w), 3068 (w), 3031 (w), 3007 (w), 2965 (m), 2940 (m), 2910 (m), 2834 (m), 1614 (m), 1584 (m), 1514 (s), 1493 (m), 1466 (m), 1454 (m), 1441 (m), 1300 (m), 1245 (s), 1179 (m), 1106 (w), 1033 (m); 1H NMR (CDCl3) δ7.40-7.24 (m, 5H), 7.11 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.18 (dd, J=8.6, 4.9 Hz, 1H), 3.81 (s, 3H), 2.98 (dd, J=13.5, 4.9 Hz, 1H), 2.79 (dd, J=13.5, 8.7), 1.49 (s, 2H). Low resolution mass spec. 228(M+1, 26), 211(49), 121(44), 107(69), 106(100), 79(100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20]CC)=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([OH:20])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cc(Cl)ccn3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(Cl)ccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(4-chloropyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (8 mL, 1:1) was added aqueous NaOH (200 mg in 2 mL of water). After stirring at room temperature for two hours, the reaction mixture was evaporated and acidified to PH 5 using 1 M HCl and then concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (b, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.24 (dd, J=5.6, 2 Hz, 1H), 7.21 (d, m, 2H), 7.05 (d, J=1.6 Hz, 1H), 5.50 (dd, J=9.6, 2.4 Hz, 1H), 3.07 (dd, J=15.6, 2.8 Hz, 1H), 2.28 (s, 3H), 2.12 (dd, J=15.6, 9.6 Hz, 1H). 1 protons assumed to be exchanged with solvents. MS (ESI) m/z=334 [M+H]+.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][CH:5]([CH3:31])[CH2:6][C:7]1([CH:20]([C:28](C)=[CH2:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:19].N#N.[BH4-].[Na+]>CCO>[OH:1][CH2:29][CH2:28][CH:20]([C:7]1([CH2:6][CH:5]([CH3:31])[CH3:4])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]1=[O:19])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCN(Cc2ccccc2)C1=O
Reactant: O=[O+][O-]
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CC1(C(CCO)C(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1=O
Yield: 64 %

Procedure:
Ozone is bubbled through a cold (-78° C.) solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-α-(propen-2-yl)-3-pyrrolidineacetate (1.32 g, 3.42 mmol) in EtOH (30 mL). After purging the solution with N2, sodium borohydride (195 mg, 5.14 mmol) is added in one portion (at -78° C.). The solution is allowed to slowly warm to room temperatuare under N2 overnight. The reaction mixture is concentrated to a white solid, diluted with H2O (10 mL) and extracted with EtOAc (3×25 mL). The organic extracts are combined, washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield 1.37 g of a clear, colorless oil. The oil is purified by silica gel chromatography (50 g SG, 20% EtOAc/hexane) to give 850 mg (64%) of the title compound as a clear, colorless oil, which is a single diastereomer.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:21]=[C:20]([O:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:19]([Cl:30])=[CH:18][C:16]=1[NH2:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([NH:17][C:16]1[CH:18]=[C:19]([Cl:30])[C:20]([O:22][C:23]([F:29])([F:28])[C:24]([F:25])([F:26])[F:27])=[CH:21][C:15]=1[Cl:14])=[O:8])=[O:5]
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)(F)F)cc1Cl
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(F)(F)F)cc1Cl
Reaction time: 10 h

Procedure:
3.4 g of 2,6-difluorobenzoyl isocyanate, dissolved in 10 ml of dry toluene, are added at room temperature and with the exclusion of moisture to 5.6 g of 2,5-dichloro-4-pentafluoroethoxyaniline dissolved in 40 ml of dry toluene, and the batch is stirred for 10 hours. Approximately 60% of the solvent is then removed. The precipitate formed is filtered off with suction, washed with hexane and dried in vacuo. The title compound of formula ##STR15## is obtained in the form of colourless crystals; m.p. 178°-179° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([C:17]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[NH:19]2)=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([C:17]([C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:19]2[CH3:35])=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: ClCCl
Product: Cn1c(-c2ccc(F)cc2)c(-c2ccncc2)c2ccc(NC(=O)CNC(=O)OC(C)(C)C)nc21
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (29) (50.0 mg, 0.108 mmol), triphenylphosphine (85 mg, 0.325 mmol), methanol (13 ml, 0.791 mmol) and methylene chloride (5 mL) was added diethyl azodicarboxylate (51 ml, 0.325 mmol) at 0° C. The reaction was allowed to warm to 23° C. After 2.5 h, an additional 2 equivalents of methanol, triphenylphosphine, and diethyl azodicarboxylate were added. After 16 h, the reaction was concentrated in vacuo and the residue was purified by preparative plate chromatography to afford 6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole (30) which was converted to 6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole (158) as described in example 6: Mass Spectrum (CI) 376 (MH+).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CN(C)C=O.[SH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1OCCOCCOCCOCCOCCOC1.O>[CH2:8]([C:7]1[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)CS
Reactant: CCCCCC(=O)Cc1sccc1Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCc1c(C(=O)OCC)sc2ccsc12
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Compound 59 (35.4 g, 0.13 mol) and K2CO3 (27.6 g, 0.2 mol) were mixed with N,N-dimethylformamide (100 mL). A catalytic amount (˜25 mg) 18-crown-6 was added, and to this mixture, ethyl 2-mercaptoacetate (14.0 mL, 0.13 mol) was added dropwise at 60° C. The mixture was stirred overnight and poured into water (500 mL). The organic component was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (2×100 mL) and water (100 mL). Organic layer was then dried over MgSO4. After evaporation of the solvent, the crude compound 61 was obtained and purified by column chromatography (SiO2/5% ethyl acetate in hexanes) to yield pure compound 61 (32.1 g, 84.5%). GC/MS: 296 g/mol (M). 1H NMR (CD2Cl2) δ 7.56 (d, 1H), 7.24 (d, 1H), 4.34 (q, 2H), 3.15 (t, 2H), 1.71 (m, 2H), 1.32 (m, 6H), 0.88 (m, 6H). 13C NMR: 163.24, 143.31, 141.85, 141.09, 131.13, 128.44, 120.35, 61.25, 31.99, 29.72 (overlap), 22.98, 14.52, 14.23.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:12]=[C:11]([Br:13])[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl-:20].[Al+3].[Cl-:22].[Cl-:23]>C(=S)=S>[Cl:20][C:2]([Cl:23])([Cl:22])[C:3]1[CH:12]=[C:11]([Br:13])[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: FC(F)(F)c1cc(Br)c2cccc(C(F)(F)F)c2n1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: S=C=S
Product: FC(F)(F)c1cccc2c(Br)cc(C(Cl)(Cl)Cl)nc12

Procedure:
3.4 g of 2,8-bis-(trifluoromethyl)-4-bromo-quinoline, 1.5 g of freshly sublimated aluminum-chloride are allowed to stand in 30 ml of abs. carbon disulfide for a night at room temperature. The organic phase is washed with 50 ml of 10 percent icy hydrochloric acid, 2×50 ml of water, dried and evaporated. The residue is recrystallized from aqueous methanol.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([CH:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21].[BH4-].[Na+]>CO>[CH2:20]([CH:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH:25][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1)[CH3:21]
Reactant: CCC(CC)CCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)CCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 62 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 3-ethylpentylamine (0.194 g, 1.68 mmol) (Example 733, Part B) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes) to give the title compound (0.342 g, 62%): TOF MS ES+ 361.2 (M+H)+, HRMS calcd for C19H26N4O2F 361.2040 (M+H)+, found 361.2048, time 0.57 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min. 20-95% over 18], tR=12.0 min, 96.9% purity.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:7](=[O:25])[C:6]2([OH:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])#[N:2].Cl[C:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38]>N1C=CC=CC=1.C(Cl)Cl>[C:37](=[O:38])([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[O:35][C:6]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])(=[O:14])=[O:13])[C:7]1=[O:25]
Reactant: CCOc1ccccc1C1(O)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccccc1C1(OC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
1.5 g (3.0 mmol) of the product 1c were dissolved in 30 ml of pyridine. At 0° C., 1.7 g (10.6 mmol) of phenyl chloroformate were rapidly added dropwise. This reaction solution was stirred for 60 minutes before being stirred into ice-water. The resulting precipitate was isolated, dissolved in methylene chloride, dried and concentrated in vacuo. The resulting residue was crystallized with Et2O/n-pentane. 1.2 g of the intermediate were obtained.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][CH2:7][C:8]1[C:9](=[O:33])[N:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]CC)=[O:26])=[CH:21][C:20]=2[N+:30]([O-:32])=[O:31])[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCOCC1>O>[Cl:6][CH2:7][C:8]1[C:9](=[O:33])[N:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][C:20]=2[N+:30]([O-:32])=[O:31])[O:11][C:12]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(-n2oc(-c3ccccc3)c(CCl)c2=O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(-n2oc(-c3ccccc3)c(CCl)c2=O)c([N+](=O)[O-])c1
Yield: 83.7 %

Procedure:
After adding 300 ml of concentrated sulfuric acid to a mixture of 270 g (0.67) of 4-chloromethyl-5-phenyl-2-(4-ethoxycarbonyl-2-nitrophenyl)-4-isoxazolin-3-one (Compound (33)) and 2.5 liters of 1,4-dioxane, the resultant mixture was refluxed for 8 hours. Thereafter, the reaction mixture obtained was cooled and poured into water. Crystals thus deposited were recovered by filtration, washed with water, and dried to provide 210.2 g of the aforesaid compound with a yield of 83.7%. The melting point thereof was 186° C. to 189° C.
Reaction SMILES: C(O[C@@H:10]1[C@H:16]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:13]2([CH2:14][CH3:15])[C:12](=[O:31])[CH2:11]1)[C@@H:25]1[C:20]([CH:21]=[C:22]([O:29]C)[CH2:23][CH2:24]1)=[CH:19][CH2:18]3)(=O)C1C=CC=CC=1.[C-:32]#[C-:33].[Li+].[Li+].[Cl-].[NH4+]>C(OCC)(=O)C>[C:32]([C@:12]1([OH:31])[CH:11]=[CH:10][C@H:16]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:13]12[CH2:14][CH3:15])[C@@H:25]1[C:20](=[CH:21][C:22](=[O:29])[CH2:23][CH2:24]1)[CH2:19][CH2:18]3)#[CH:33]
Reactant: [C-]#[C-]
Reactant: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
As described in 1(b), 3.6 g of 15α-benzoyloxy-3-methoxy-18-methyl-3,5-estradien-17-one is reacted with lithium acetylide. After completed reaction, the reaction mixture is combined with saturated ammonium chloride solution, diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The resultant 17α-ethynyl-3-methoxy-18-methyl-3,5,15-estratrien-17β-ol is stirred, in the form of the crude product, in 70 ml of methanol and 6 ml of water with 3 g of oxalic acid for 10 minutes under reflux. The reaction mixture is introduced into ice/water. The thus-precipitated product is suctioned off, dissolved in ethyl acetate, washed with water, and dried over sodium sulfate. Recrystallization from acetone/hexane yields 1.9 g of 17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one, melting point 197.8° C.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C@H:42]2[O:44][CH2:43]2)=[CH:36][C:35]=1[S:45]([CH3:48])(=[O:47])=[O:46])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(O)C>[CH2:1]([N:8]([CH2:43][C@H:42]([OH:44])[CH2:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:35]([S:45]([CH3:48])(=[O:47])=[O:46])[CH:36]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1
Reactant: CS(=O)(=O)c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(S(C)(=O)=O)c3)CC2)cc1

Procedure:
This product is obtained by carrying out the preparation as described in preparation 3.2 above, using ethyl trans-4-[4-(benzylamino)cyclohexyl]benzoate and 4-benzyloxy-3-methylsulfonyl-1-((2S)-2,3-epoxypropoxy)benzene, disclosed in patent application WO 99/65895, and without adding thereto the solution of hydrochloric acid in ethanol. [M+H+]=672
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH2:13]([OH:16])[CH2:14][OH:15].C1(C)C(C)=CC=CC=1>[Cl-].[Cl-].[Zn+2].O>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)c1ccc(C2OCCO2)cc1

Procedure:
8.2 g (0.05 mol) of methyl 4-formylbenzoate, 25 ml of ethylene glycol, 3.5 g of ZnCl2 and 200 ml of xylene are introduced into a round-bottomed flask. The mixture is heated to reflux and the water formed is separated after settling has taken place, the organic phase is evaporated to dryness, the reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. 10.4 g (100%) of the expected product are collected in the form of a colorless oil.
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10]=2[N:11]=1.[H-].[Na+].Br[CH2:19][C:20]([N:22]([CH2:29][CH:30]([NH2:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:21]>CN(C=O)C>[OH:1][CH:2]1[N:11]([CH2:19][C:20]([N:22]([CH2:29][CH:30]([NH2:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:21])[C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[N:3]1
Reactant: Oc1ncc2c(n1)Nc1ccccc1S2
Reactant: CCOC(=O)CN(CC(N)C(=O)OC(C)(C)C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(N)C(=O)OC(C)(C)C)C(=O)CN1C2=C(C=NC1O)Sc1ccccc1N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
2-Hydroxy-10-H-pyrimido[5,4-b][1,4]benzothiazin (653 mg, 3.0 mmol) was suspended in DMF (30 mL) and NaH (60% in mineral oil, 132 mg, 3.3 mmol) was added in one portion. After 15 minutes ethyl N-bromoacetyl-N-(2-Boc-aminoethyl)-glycinate (1.10 g, 3.3 mmol) was added. The mixture was stirred at room temperature for 2 hours, evaporated in vacuo, redissolved in dichloromethane (200 mL) and washed once with saturated aqueous NaHCO3 (100 mL) and once with saturated aqueous NaCl. The mixture was dried (MgSO4) and evaporated to dryness in vacuo. The crude material was purified on a silica gel column using methanol/dichloromethane (1:9, v/v) as the eluent to give 853 mg (57%) of the title compound.