Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl>CN(C)C=O>[CH3:18][O:19][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1ccc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
4-Hydroxy-3-methoxybenzaldehyde (1a, 2.00 g, 13.1 mmol) and potassium carbonate (9.00 g, 65.1 mmol) were combined in dimethyl formamide (30 ml) and stirred for 15 min at room temperature. Chloromethyl methyl ether (1.60 ml, 21.1 mmol) was added and stirring was continued for 6 hr at room temperature. The resulting mixture was filtered and the filtrate extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to give 2.55 g (99%) of a white solid: mp 39-40° C. [expected mp 41° C.]; 1H NMR: δ 3.40 (s, 3H), 3.83 (s, 3H), 5.21 (s, 2H), 7.15 (d, 1H, J=8.7 Hz), 7.30 (dd, 1H, J=6.0, 2.0 Hz), 7.32 (s, 1H), 9.75 (s, 1H); 13C NMR: δ 55.8, 56.2, 94.8, 109.4, 114.6, 125.9, 130.9, 149.8, 151.7, 190.4.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:23])([CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:6]1=[O:24])[CH2:2][CH2:3]C.[Cl:25]C1C=C2C(=CC=1)N(CCC)C(=O)C2=O.C(C1C=CC=CN=1)(=O)C>>[Cl:25][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH2:2][CH3:3])[C:6](=[O:24])[C:7]2([OH:23])[CH2:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Reactant: CCCN1C(=O)C(=O)c2cc(Cl)ccc21
Agent: CC(=O)c1ccccn1
Product: CCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2cc(Cl)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-chloro-1-propylindoline-2,3-dione and 2-acetyl pyridine (purchased from Fisher Scientific). 1H-NMR δ 8.70 (d, 1H), 8.10 (d, 1H), 7.92 (t, 1H), 7.56 (dd, 1H), 7.28 (m, 2H), 6.79 (d, 1H), 3.63 (m, 5H), 1.70 (m, 2H), 0.96 (t, 3H). Calculated mass for C18H17ClN2O3, 344.09. Observed 345.0 (M+1), 367.1 (M+Na).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13].[CH2:18]([C:25]1[N:30]=[C:29]([CH2:31]O)[CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:14][CH2:31][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:30]=1)=[O:13]
Reactant: OCc1cccc(Cc2ccccc2)n1
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Product: CC(C)C(C(=O)OCc1cccc(Cc2ccccc2)n1)c1ccc2ccccc2c1

Procedure:
Following the procedure of Example 1, the acid chloride of 2-(2-naphthyl)-3-methylbutanoic acid is reacted with (6-benzyl-2-pyridyl)methanol to yield (6-benzyl-2-pyridyl)methyl 2-(2-naphthyl)-3-methylbutanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:15][O:16][CH3:17]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:13])([CH3:12])[CH2:10][O:11][CH2:15][O:16][CH3:17])[CH:4]=1
Reactant: COc1cccc(C(C)(C)CO)c1
Reactant: COCCl
Solvent: C1CCOC1
Product: COCOCC(C)(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
To a solution of 2-(3-methoxyphenyl)-2-methyl-propan-1-ol (Intermediate 39, 900 mg, 4.99 mmol) in THF (15 mL) sodium hydride 60% dispersion in mineral oil (300 mg, 7.49 mmol) was added and the reaction mixture was stirred for 15 minutes at room temperature. Chloro(methoxy)methane (603.02 mg, 7.49 mmol) was added and the reaction mixture was heated to 55° C. and stirred overnight. The reaction was cooled to 0° C. and quenched with water (10 mL) (added dropwise) and extracted with EtOAc (30 mL). Organics were dried over Na2SO4, filtered and evaporated in vacuo to afford the title compound (525 mg) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[NH:13][C:14]([C:24](F)(F)F)=[N:15][C:16]=3[C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[CH:11][C:6]=2[N:5]([CH3:28])[C:4]1=[O:29])[CH3:2].CCN=C=NCCCN(C)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C1C[O:50]CC1>CN(C=O)C>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[NH:13][C:14]([C:24]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[O:50])=[N:15][C:16]=3[C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[CH:11][C:6]=2[N:5]([CH3:28])[C:4]1=[O:29])[CH3:2]
Reactant: C1CCOC1
Reactant: CCn1c(=O)n(C)c2cc(-c3[nH]c(C(F)(F)F)nc3-c3cccc(C)c3)ccc21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CCn1c(=O)n(C)c2cc(-c3[nH]c(C(=O)N4CCOCC4)nc3-c3cccc(C)c3)ccc21
Reaction time: 8 h

Procedure:
A mixture of 1-ethyl-3-methyl-5-(5-m-tolyl-2-trifluoromethyl-3H-imidazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (prepared as described above, 50 mg, 0.13 mmol), N,N-dimethylaminopyridine (48.7 mg, 0.40 mmol), EDCI (38.3 mg, 0.20 mmol) and morpholine (17.4 mg, 0.20 mmol) was stirred at room temperature in THF (1.33 mL) at room temperature. One drop of DMF was added to ensure solubility. The reaction mixture was allowed to stir overnight. The mixture was concentrated in vacuo, taken up in methylene chloride and washed with 10% aqueous citric acid. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a reddish-brown solid, which was recrystallized in diisopropyl ether to give 19 mg of the title compound. MS (M+1)=446.5.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH:11]([CH2:14][NH2:15])[CH2:10][C:9]=2[CH:8]=[C:7]([Cl:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([O:29][C:27](=[O:28])[NH:15][CH2:14][CH:11]1[CH2:10][C:9]2[CH:8]=[C:7]([Cl:16])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:13]=2[O:12]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)c1cc(Cl)cc2c1OC(CN)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(Cl)cc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 95.6 %

Procedure:
Treatment of (±)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine (1.80 g, 6.52 mmol) with diisopropylethylamine (2.11 g, 16.29 mmol) and benzyl chloroformate (1.28 g, 7.49 mmol) generally according to the procedure described for Intermediate 12 gave 2.33 g (95%) of (±)-benzyl(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal. calcd. for C21H24ClNO3 C, 67.46; H, 6.47; N, 3.75. Found C, 67.27; H, 6.62; N, 3.66. Chiral HPLC separation of (±)-benzyl(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rt=5.642 min, Chiralpak AD, hexane:isopropanol 9:1); Fraction 2 (Rt=6.494 min, Chiralpak AD, hexane:isopropanol 9:1).
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][NH:22]2)[CH2:15][CH3:16].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=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>[F:27][C:28]1[CH:33]=[C:32]([C:2]2[C:7](=[O:8])[N:6]3[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]3=[N:4][C:3]=2[CH:14]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH2:15][CH3:16])[CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1I
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: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1-c1cccc(F)c1
Temperature: 100 °C

Procedure:
To a mixture of 3-iodo-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one (from example 3, step 2; 0.030 g, 0.065 mmol) and (3-fluorophenyl)boronic acid (Aldrich, 10.9 mg, 0.0780 mmol) in 1,4-dioxane (0.5 mL) was added a 1 M solution of sodium carbonate (8.27 mg, 0.0780 mmol) in water (0.077 mL) and tetrakis(triphenylphosphine)palladium (0) (3.76 mg, 0.00325 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on RP-HPLC at pH 10 conditions (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to provide the desired product. LCMS calculated for C23H21FN7O (M+H)+: m/z=430.2. Found: 430.3. 1H NMR (DMSO-d6, 300 MHz) δ 8.11 (2H, m), 7.65 (1H, m), 7.45 (2H, m), 7.24 (4H, m), 7.08 (1H, m), 6.91 (1H, m), 5.17 (1H, m), 2.87 (3H, s), 1.79 (2H, m), 0.72 ((3H, t, J=7.2 Hz) ppm. 19F NMR (DMSO-d6, 282 MHz) δ −114 ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:19])[CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][C:4]=2[CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1[N:34]=[N:33]C2CCNCC=2C=1.C1(C(Cl)=O)CCCCC1>C(O)C>[NH:33]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:19])[CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][C:4]=2[CH:3]=1)[NH2:34]
Reactant: O=C(C1CCCCC1)N1CCc2nnc(Cl)cc2C1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: O=C(Cl)C1CCCCC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: NNc1cc2c(nn1)CCN(C(=O)C1CCCCC1)C2

Procedure:
The 3-chloro-6-hexahydrobenzoyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and cyclohexanecarboxylic acid chloride. M.P. 144°-146° (decomp., from absolute ethanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].Cl[C:10]([CH3:18])([CH2:12][CH2:13][C:14](Cl)([CH3:16])[CH3:15])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[F:1][C:2]1[C:3]([CH3:8])=[CH:4][C:5]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][C:10]([CH3:18])([CH3:11])[C:6]=2[CH:7]=1
Reactant: Cc1ccccc1F
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(cc1F)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a solution of 15 g (136 mmol) of 2-fluorotoluene and 24.9 g (136 mmol) of 2,5-dichloro-2,5-dimethylhexane in 120 mL dichloromethane was added 1.82 g (13.6 mmol) of aluminum chloride and the solution heated at reflux. After 18 hours the reaction mixture was cooled to room temperature and 5% aqueous HCl was added. This was partitioned between hexane and water. The aqueous phase was washed once with hexane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 25.8 g (86%) of 2-fluoro-3-methyl-5 ,5 ,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (m.p.=90.0-91.8° C.).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:22](O)=[O:23])[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[NH:17][C:16]=12.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:22]([N:61]2[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]2)=[O:23])[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[NH:17][C:16]=12
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C(=O)O)cc2c1C
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C(=O)N3CCN(C)CC3)cc2c1C
Yield: 53.1 %

Procedure:
A solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (450 mg, 1.4 mmol) prepared in Step 1, 1-hydroxybenzotriazole hydrate (284 mg, 2.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (401 mg, 2.1 mmol), diisopropylethylamine (730 μl, 4.2 mmol), and 1-methylpiperazine (234 μl, 2.1 mmol) in dichloromethane (10 ml) was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/methanol=10/1, v/v) to give 300 mg of the titled compound as a white solid (Yield: 53%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]=[C:4]([C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22])[CH:5]=O.[N+:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([O-:27])=[O:26]>C(OC(=O)C)(=O)C>[CH3:32][O:31][C:29](=[O:30])[C:28]([N+:25]([O-:27])=[O:26])=[CH:5][C:4]([C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22])=[CH:3][N:2]([CH3:24])[CH3:1]
Reactant: CN(C)C=C(C=O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: COC(=O)C[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=CC(=CN(C)C)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-])[N+](=O)[O-]
Yield: 77.7 %

Procedure:
A mixture of 17.3 g (0.053 mol) of the compound of Example 40 and 6.3 g (0.53 mol) of methyl nitroacetate in 115 ml of acetic anhydride was heated at 95° for 1 hour. The mixture was concentrated, the residue slurried with ether, filtered and washed with ether to give 17.6 g (78%) of red orange crystals, m.p. 158°-165°. Recrystallization from benzene-dimethylformamide afforded 13.4 g (59%) of product, m.p. 179°-181°.
Reaction SMILES: Cl.C([O:6][C:7]([N:9]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[CH2:25]2)[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:10]1)=[O:8])(C)(C)C.O>O1CCOCC1>[CH:7]([OH:8])=[O:6].[Cl:36][C:31]1[C:30]([CH3:37])=[N:29][C:28]2[N:33]([N:34]=[C:26]3[CH2:25][N:24]([C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH:11]4[CH2:12][CH2:13][NH:9][CH2:10]4)=[O:23])[CH2:38][C:27]3=2)[C:32]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCC1CCN(C(=O)OC(C)(C)C)C1)C3
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCC1CCNC1)C3
Product: O=CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 18 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (1.5 mL; 5.99 mmol; 10 eq.) was added to a suspension of 3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (315 mg; 0.6 mmol; 1 eq.) in 1,4-dioxane (10 mL) followed by water (30 μL) and the resulting mixture was stirred at room temperature for 5 hours. After concentration in vacuo, the residue was partitioned between DCM and 1M NaOH and the aqueous layer was extracted with DCM. The combined organic phase was dried over sodium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (51 mg, 18%) as a white solid. HPLC (max plot) 97.4%, Rt 2.74 min. UPLC/MS: (MS+) 426.4 ([M+H]+).
Reaction SMILES: [OH:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[CH:3][C:4](=O)[CH:5]([O:7][CH3:8])[CH3:6].C([O-])(=O)C.[NH4+:24]>>[NH2:24][C:4]([CH:5]([O:7][CH3:8])[CH3:6])=[CH:3][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:1]
Reactant: COC(C)C(=O)C=C(O)c1ccc(C(F)(F)F)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(C)C(N)=CC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
10.0 g 1-Hydroxy-4-methoxy-1-(4-trifluoromethyl-phenyl)-pent-1-en-3-one are dissolved in 100 ml ethanole. 4.7 g of Ammonium acetate are added and the mixture is heated for four hours to reflux. Then the solvent is evaporated in vacuo, the residue is partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The phases are separated and the aqueous phase is twice extracted with dichloromethane. The combined organic phases are dried with magnesium sulphate, the solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 90:10 to 50:50).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C@:20]([CH3:24])([C@@H:21]([CH3:23])[CH:22]=1)[C@@H:19]1[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]1)([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]3)[CH2:9][CH2:8]2)(=O)C.C([O-])(=O)C.[Na+].[I:31]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.C(OCC)(=O)C.CCCCCC>[I:31][C@H:22]1[C@H:21]([CH3:23])[C@@:20]2([CH3:24])[C:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:25])=[CH:6][C:5]1=[O:4]
Reactant: CC(=O)OC1=C[C@H](C)[C@@]2(C)C(=C1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C[C@H]1[C@H](I)C(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: -10 °C
Reaction time: 8 h

Procedure:
68.95 g of 88.8% (0.179 mol) 3-acetoxy-1α-methyl-androsta-2,4-dien-17-one (DE-A 3715869) is dissolved in 800 ml of acetone, mixed with 32.9 g (0.4 mol) of anhydrous sodium acetate and cooled with stirring to -10° C. Then, 29 g (0.179 mol) of iodine chloride (iodine monochloride) is added under nitrogen atmosphere at -10° C. and it is stirred for another 30 minutes. Then, it is added to 6 l of ice water mixed with 6.65 g of sodium thiosulfate, the product is extracted with ethyl acetate, the organic phase is dried on sodium sulfate, filtered and concentrated by evaporation up to 200 ml. After standing overnight, the precipitated solid is suctioned off and dried. 49 g (64% of theory) of product is obtained. After chromatography of the mother liquor on silica gel with ethyl acetate/hexane as mobile solvent, another 10 g (13% of theory) of the title compound is obtained. The total yield is 59 g (77% of theory) of 2β-iodo-1α-methylandrost-4-ene-3,17-dione.
Reaction SMILES: [ClH:1].[CH:2]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:40])=[C:15]([C:19]#[C:20][C:21]4[CH:26]=[C:25]([CH2:27][C:28]5[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[N:32][CH:33]=5)[CH:24]=[C:23]([O:36][CH3:37])[C:22]=4[O:38][CH3:39])[C:16]=3F)[C:11](=[O:41])[C:10]([C:42]([OH:44])=[O:43])=[CH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-:45].[Na+].Cl.[CH3:48]O>>[ClH:1].[CH:2]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:40])=[C:15]([C:19]#[C:20][C:21]4[CH:26]=[C:25]([CH2:27][C:28]5[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[N:32][CH:33]=5)[CH:24]=[C:23]([O:36][CH3:37])[C:22]=4[O:38][CH3:39])[C:16]=3[O:45][CH3:48])[C:11](=[O:41])[C:10]([C:42]([OH:44])=[O:43])=[CH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(C#Cc2c(F)cc3c(=O)c(C(=O)O)cn(C4CCCCC4)c3c2F)c1OC
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1cc(Cc2cnc(N)nc2N)cc(C#Cc2c(F)cc3c(=O)c(C(=O)O)cn(C4CCCCC4)c3c2OC)c1OC
Temperature: 25 °C
Yield: 78 %

Procedure:
16ar) A suspension of 0.33 g of 1-cyclohexyl-7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid hydrochloride (Example 16aq)) in 5 ml of methanol is treated with 2 ml of 28% aqueous sodium hydroxide solution and held at reflux for 5 hrs. The beige suspension is cooled to room temperature and acidified with 25% aqueous hydrochloric acid. The precipitated substance is filtered off under suction, washed with 10 ml of water, 10 ml of ethanol and 10 ml of ether and dried. 0.264 g (78%) of 1-cyclohexyl-7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3- dimethoxy-phenylethynyl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid hydrochloride is obtained as a beige solid. Yield: 78%. M.p.>205° (dec.). Mass spectrum (FAB): peaks inter alia at 602 (M++H, 100%), 588 (10%), 520 (7%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=[N:36]C=2C=1.CCN=C=NC[CH2:46][CH2:47][N:48]([CH3:50])[CH3:49].Cl.C(N(CC)CC)C>CN(C=O)C.O>[CH3:50][N:48]([CH3:49])[CH2:47][CH2:46][NH:36][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[CH:20][CH:19]=2)=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CCNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 0.08 h
Yield: 42.3 %

Procedure:
To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1 ml), HOBT (0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and triethylamine (0.2 ml, 1.57 mmol) were added and stirred for 5 min. 2-N,N-Dimethylethylamine (0.046 g, 0.524 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.100 g, 42%). M.P.: 122-125° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.5 Hz, 1H), 8.69 (d, J=8.8 Hz, 1H), 8.54 (t, J=5.4 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.33 (d, J=8.3 Hz, 2H), 8.20 (d, J=8.7 Hz, 1H), 8.03-7.98 (m, 4H), 7.84 (dd, J=8.7, 1.7 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 3.41 (q, J=6.6 Hz, 2H), 2.47 (m, 2H), 2.20 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([OH:12])[C:3]=1[CH:4]=[N:5]O.[C:13]([O-:16])(=O)[CH3:14].[Na+].[CH3:18][C:19](OC(C)=O)=[O:20]>>[Br:1][C:2]1[C:3]([C:4]#[N:5])=[C:7]([O:12][C:19]([CH3:18])=[O:20])[CH:8]=[CH:9][C:10]=1[O:11][C:13]([CH3:14])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Reactant: ON=Cc1c(O)ccc(O)c1Br
Agent: [Na+]
Product: CC(=O)Oc1ccc(OC(C)=O)c(C#N)c1Br
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A mixture of 12B (45 g, 0.193 mol) and sodium acetate (3 g) in Ac2O (200 mL) was heated to reflux overnight. The reaction mixture was evaporated under reduced pressure to remove Ac2O. The residue was poured into water and stirred for 1 hour. The precipitated solids were collected by filtration and dried to give 12C (40 g, 69.1% yield).
Reaction SMILES: C([N:8]([CH2:32][CH2:33][O:34][C:35]([CH3:38])(C)C)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:16]=2[CH:31]=1)=[O:10])C1C=CC=CC=1.Br.C(=O)(O)[O-:41].[Na+]>C(O)(=O)C>[C:35]([O:34][CH2:33][CH2:32][NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:16]=2[CH:31]=1)=[O:10])(=[O:41])[CH3:38]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)N(CCOC(C)(C)C)Cc3ccccc3)ccc21
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCCNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Reaction time: 72 h

Procedure:
200 mg (0.4 mM) of 1-benzyl-1-(2-tert.butoxyethyl)-3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea are heated on a steam-bath for 10 minutes in 3 ml of a 33% solution of hydrogen bromide in glacial acetic acid and then left to stand at room temperature for 3 days. The mixture is neutralised with sodium bicarbonate and extracted several times with methylene chloride. The methylene chloride extracts are combined, dried over sodium sulphate, filtered and concentrated. The residue is purified in a pressure column (0.2-0.4 atmospheres of nitrogen) on 15 g of silica gel (particle size 0.04-0.06 mm) using ethyl acetate as the eluting agent and crystallised from ethyl acetate/ether, there being obtained 2-[3-[5-(o-fluorophenyl)-2,3-dihydro -1-methyl-2-oxo-1H-1,4-benzodiazepin-7yl]ureido]ethyl acetate which melts at 196°-198° C.