Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[O:13]
Reactant: OCCCCCCCCCCCBr
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
To 11-bromo-1-undecanol (5 g) dissolved in methylene chloride (70 ml) were added pyridinium chlorochromate (10.7 g) and Celite (11.0 g), and the mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was filtered, concentrated and subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (20:1) to give 11-bromo-1-undecanal (3.57 g). To the product dissolved in methylene chloride (50 ml) was added (carbomethoxymethylene)triphenylphosphorane (4.66 g), and the mixture was stirred. The reaction mixture was concentrated, and the residue thus obtained was subjected to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (20:1) to give the methyl ester of 13-bromo-2-tridecenoic acid (4.16 g). The product was dissolved in methanol and stirred under hydrogen atmosphere in the presence of palladium/carbon (1.5 g) for 18 hours. The reaction mixture was filtered and concentrated to give the methyl ester of 13-bromotetradecanoic acid (3.22 g). To the methyl ester dissolved in acetonitrile were added calcium chloride (9.4 g) and tetraethylammonium chloride (2.8 g), and the mixture was stirred at 80° C. for 3 hours, and then cooled and concentrated. The residue was distributed into ethyl acetate and water, and the ethyl acetate layer was dried and concentrated to give the methyl ester of 13-chlorotridecanoic acid (2.08 g). 50% Aqueous ethanol (100 ml), in which potassium hydroxide (2.27 g) had been dissolved, was added to the methyl ester, and the mixture was stirred at 60° C. for 1 hour. Ethanol in the reaction mixture was evaporated, and the residue was acidified to a weak acidic range of pH by adding citric acid and extracted with ethyl acetate. The organic layer was dried and concentrated to give 13-chlorotridecanoic acid (1.69 g). After the product was dissolved in N,N-dimethylformamide (DMF, 50 ml), para-nitrophenol (0.94 g) and N,N'-dicyclohexylcarbodiimide (1.39 g) were added, and the mixture was stirred for 12 hours. Then, precipitates produced was removed by filtration and the DMF was removed by distillation. The residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1 ) to give the active ester of 13-chlorotetradecanoic acid (1.01 g). The active ester (600 mg) was dissolved in DMF (30 ml), and 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (500 mg) and triethylamine (2.0 ml) were added to the solution. The mixture was stirred for 12 hours. After the solvent was evaporated, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK278 in the yield of 222 mg.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:6]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].CO[C:26](OC)([CH3:28])[CH3:27]>CC(C)=O.[Cu](Cl)Cl>[CH3:27][C:26]1([CH3:28])[O:1][C@@H:2]([C@@H:6]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=2)[C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: O=C(O)[C@@H](O)[C@@H](CCCc1ccc(OC(F)(F)F)cc1)C(=O)O
Reactant: COC(C)(C)OC
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: CC1(C)OC(=O)[C@H]([C@@H](CCCc2ccc(OC(F)(F)F)cc2)C(=O)O)O1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (2S,3R)-2-hydroxy-3-{3-[4-(trifluoromethoxy)phenyl]propyl}butanedioic acid (5.58 g; 16.6 mmol; 1.0 eq.) in acetone (61 mL) was added 2,2-dimethoxypropane (3.5 mL; 28.2 mmol; 1.70 eq.) and copper(II) chloride (220 mg; 1.66 mmol; 0.1 eq.). The resulting reaction mixture was stirred 14 h at RT. The reaction mixture was evaporated and the residue taken up in Et2O and filtered on a pad of cellite. The liquids were evaporated again and the residue was treated with activated charcoal in Et2O and filtered on a pad of cellite to give the title product as a greenish oil used in the next step without further purification. (5.85 g; 93.7%). M+(ESI): 377.0; M−(ESI): 375.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si](C(C)C)(C(C)C)C(C)C)[CH:6]=[CH:5]2.C([Li])(C)(C)C.[C:26]1([S:32](F)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:26]1([S:32]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reactant: O=S(=O)(F)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc2[nH]ccc2c1

Procedure:
Cool a solution of 5-bromo-1-triisopropylsilanyl-1H-indole (9 g, 25.5 mmol) in 550 mL anhydrous THF to −75° C. under argon and treat with 1.7 M t-butyl lithium (33 mL, 56.2 mmol) while keeping the temperature below −60° C. After the addition, recool the reaction mixture to about −73° C. before adding a solution of phenylsulfonyl fluoride (4.6 g, 28.7 mmol) in 30 mL THF. Stir the reaction at −78° C. for 1 hour then quench with saturated NaHCO3 followed by brine. Separate the layers and extract the aqueous layer with EtOAc. Treat the combined organic layers with 1 M tetrabutylammonium fluoride (35 mL) in THF for 1 hour at ambient temperature, then concentrate to dryness. Combine the residue with EtOAc, wash twice with 1 N HCl, dry over MgSO4, and concentrate to an oil. Chromatograph the oil on silica get eluting stepwise with 50% CHCl3 in hexanes followed by 50% CHC13 in MeOH give an oily solid. Triturate the oily solid with CHCl3 to give the title compound as a solid: Analysis for C14H11NO2S H2O: calcd: C, 64.89; H, 4.36; N, 5.41; found: C, 64.76; H, 4.45; N, 5.33; ISMS 257 (M+).
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15]3[NH:19][C:18]([CH2:20][O:21][CH3:22])=[N:17][N:16]=3)=[CH:10][C:5]=2[C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:4]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15]3[NH:19][C:18]([CH2:20][O:21][CH3:22])=[N:17][N:16]=3)=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: COCc1nnc(-c2cc(C(=O)OC)c(C3CC3)cc2C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1nnc(-c2cc(C(=O)O)c(C3CC3)cc2C)[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a round-bottom flask was added a solution of methyl 2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate (compound 190.7, 200 mg, 0.600 mmol, 1.00 equiv, 90%) in methanol (4 mL). A solution of sodium hydroxide (106 mg, 2.65 mmol, 4.00 equiv) in water (2 mL) was added to the reaction mixture. The resulting solution was stirred for 2 h at 60° C. After cooling to ambient temperature, the organic solvent was removed under reduced pressure and the pH the remaining aqueous layer was adjusted to 2-3 with hydrogen chloride (aq, 6 M). The resulting solids were collected by filtration and dried to yield 170 mg (89%) of the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[CH:7]1([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C>CCO>[CH:7]1([CH:13]([OH:14])[CH2:6][N+:3]([O-:5])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=CC1CCCCC1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=[N+]([O-])CC(O)C1CCCCC1
Reaction time: 0.17 h

Procedure:
10 M aqueous NaOH (8.31 mL, 83 mmol) was added dropwise via addition funnel to a solution of nitromethane (4.46 mL, 83 mmol) and cyclohexanecarboxaldehyde (10 mL, 83 mmol) in EtOH (20 mL) at 0° C. with vigorous stirring. The resulting white slurry was stirred 10 minutes and became a white solid. Acetic acid (4.76 mL, 83 mmol) was added and the reaction was partitioned between diethyl ether and water. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were washed with water, saturated aqueous sodium chloride, and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo and dried under vacuum to afford 1-cyclohexyl-2-nitroethanol. The product was used directly for the next step without further purification.
Reaction SMILES: Br[CH:2]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([C:20](=[O:25])[C:21](Br)([CH3:23])[CH3:22])=[N:10]1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[P:26]([O:31]C)([O:29][CH3:30])[O:27][CH3:28]>>[P:26]([O:27][CH3:28])([O:29][CH3:30])([O:8]/[C:3](/[C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:2]\[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([C:20]([O:25][P:26]([O:29][CH3:30])([O:27][CH3:28])=[O:31])=[C:21]([CH3:23])[CH3:22])=[N:10]1)=[O:31]
Reactant: COc1ccc2c(C(=O)C(C)(C)Br)nn(C(Br)C(=O)C(C)(C)C)c2c1
Reactant: COP(OC)OC
Product: COc1ccc2c(C(OP(=O)(OC)OC)=C(C)C)nn(/C=C(\OP(=O)(OC)OC)C(C)(C)C)c2c1

Procedure:
The title compound was prepared from 1-bromo-1-[3-(2-bromo-2-methylpropanoyl)-6-methoxy-1H-indazol-1-yl]-3,3-dimethylbutan-2-one from Step A above and trimethyl phosphite using the method in Method I Step B of Example 1. It was purified by RP-HPLC using 10-80% MeCN gradient without TFA. 1H NMR (CDCl3, 500 MHz) δ 7.68 (d, 8.9 Hz, 1H), 6.865 (dd, 2.1 & 8.9 Hz, 1H), 6.71 (d, JH-P=3.0 Hz, 1H), 6.67 (d, 2.0 Hz, 1H), 3.89 (s, 3M), 3.63 (d, JH-P=11.2 Hz, 6H), 3.36 (d, JH-P=11.6 Hz, 6H), 2.02 (d, JH-P=2.5 Hz, 3H), 1.88 (d, JH-P=3.4 Hz, 3H), 1.38 (s, 9H). LC-MS: 3.26 min. (m/Z=407.1, 533.0, 555.0). It was noted that a faster-eluting undesirable isomeric side-product was also obtained during this reaction.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][NH:18][C:19]2[N:27]=[C:26]([C:28]3[CH:29]=[N:30][CH:31]=[C:32]([F:34])[CH:33]=3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[CH:35]([CH3:40])[C:36](OC)=[O:37])=[CH:8]1.O>C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][NH:18][C:19]2[N:27]=[C:26]([C:28]3[CH:29]=[N:30][CH:31]=[C:32]([F:34])[CH:33]=3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[CH:35]([CH3:40])[CH2:36][OH:37])=[CH:8]1
Reactant: COC(=O)C(C)n1cnc2c(NCCc3c[nH]c4ccccc34)nc(-c3cncc(F)c3)nc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)n1cnc2c(NCCc3c[nH]c4ccccc34)nc(-c3cncc(F)c3)nc21
Temperature: 25 °C

Procedure:
Lithium aluminum hydride (230 mg, 6.1 mmol) was added in portions to a 0° C. solution of methyl 2-(6-(2-(1H-indol-3-yl)ethylamino)-2-(5-fluoropyridin-3-yl)-9H-purin-9-yl)propanoate (282 mg, 0.61 mmol) in anhydrous THF (15 mL). The stirred reaction mixture was allowed to warm to rt over 2 h, then water was added carefully. The mixture was extracted with EtOAc (50 ml×3). The organic fractions were combined, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (0 to 5% solvent B in dichloromethane; solvent B=2M ammonia in methanol) to afford the partially purified title product. This was further purified by preparative TLC (5% solvent B in dichloromethane) to provide the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1)[CH3:6])C.[OH-].[Na+]>>[N:13]1([C:10]2[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[C:4]([OH:18])=[O:3])=[CH:12][CH:11]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: CCOC(=O)C(C)c1ccc(-n2cccn2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc(-n2cccn2)cc1
Yield: 80 %

Procedure:
The crude 2-[4-(pyrazol-1-yl)phenyl]propionic acid ethyl ester from (a) is boiled for 3 hours with 50 ml of 1 N solution of sodium hydroxide, and the thus-obtained solution is extracted with benzene. The aqueous phase is acidified with hydrochloric acid and extracted with benzene. The organic phase is then dried and concentrated; the residue is recrystallized from benzene/cyclohexane (1:1) to yield 1.7 g (80% of theory) of 2-[4-(pyrazol-1-yl)phenyl]propionic acid, m.p. 137° to 138° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:24]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[K+].[Br-]>C(O)C>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:29]3[CH2:28][CH2:27][N:26]([CH2:25][C:24]4[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=4[Cl:22])[CH2:31][CH2:30]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Fc1cccc(Cl)c1CN1CCNCC1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(Cc2c(F)cccc2Cl)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-chloro-6-fluorobenzyl)piperazine. White crystals, m.p. 204–205° C. (from ethanol); HPLC-MS m/z=510 (M+H); IR (KBr): ν 1726 (C═O) cm−1;
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:31]([C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[F:23])[C:32]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Reactant: O=C=Nc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Yield: 82.9 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 2,4-difluorophenyl isocyanate (1.13 mL, 9.51 mmol) in DMA afforded 2.28 g of the title compound as a solid, mp 215-216° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)CO)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[F:28][C:29]([C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH2:31][NH:32][CH3:33]>CN1CCCC1=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:27])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:32]([CH2:31][CH:30]=[C:29]([F:28])[C:34]([F:39])([F:40])[C:35]([F:36])([F:37])[F:38])[CH3:33]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Reactant: CNCC=C(F)C(F)(F)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CN(CC=C(F)C(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 80 °C
Reaction time: 3 h
Yield: 181.7 %

Procedure:
880 mg of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-estra-1,3,5(10)-trien-17-one and 1.26 g of (3,4,4,5,5,5-hexafluoro-pent-2-enyl)-methyl-amine are dissolved in 20 ml of N-methylpyrrolidone and stirred for 3 hours at a bath temperature of 80° C. After the reaction solution is cooled to room temperature, the batch is added to saturated common salt solution, extracted with diethyl ether, dried and concentrated by evaporation in a vacuum. 1.86 g of 11β-fluoro-7α-{5-[(3,4,4,5,5,5-hexafluoro-pent-2-enyl)-methyl-amino]-pentyl}-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained as a crude product, which is used without purification in the next stage.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:6][N:7]([CH3:10])[C:8]#[N:9].[ClH:11]>O1CCOCC1.CCOCC>[ClH:11].[CH3:6][N:7]([CH3:10])[C:8]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)=[NH:9]
Reactant: c1cn[nH]c1
Reactant: CN(C)C#N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C)C(=N)n1cccn1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
To a solution of pyrazole (1.01 g, 14.8 mmol) and dimethylcyanamide (1.20 mL, 14.8 mmol) in 1,4-dioxane (15 mL) was added HCl (4.0 N in 1,4-dioxane, 3.8 mL, 15.2 mmol) and the resultant mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and diluted with dry ether (15 mL) to precipitate a yellow solid. The resultant precipitate was allowed to settle to the bottom of the flask (overnight) and the supernatant solution was decanted. The solid was dried under vacuum and provided the title compound (2.01 g, 78%). ES-MS m/z 139 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18][NH:19][CH2:20][C:21]1[O:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O>[O:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:20][N:19]([CH3:18])[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2
Reactant: CNCc1ccco1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N(C)Cc2ccco2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 59 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70.0 mg, 0.29 mmol), N-methylfurfurylamine (The Sigma-Aldrich Library of Rare Chemicals) (0.16 g, 1.44 mmol) and K2CO3 (0.40 g, 2.87 mmol) in H2O (2 mL). The crude material was purified by preparative TLC on silica gel with 1:1 EtOAc:hexanes as eluant to give 53.6 mg (59%) of the title compound as an off-white solid. An analytical sample was obtained by recrystallization from EtOAc. Mp: 168-169° C. 1H NMR (CDCl3; 500 MHz): δ 2.62 (s, 3), 3.35 (s, 3), 4.83 (s, 2), 6.42-6.44 (m, 2), 6.79 (s, 1), 7.36-7.48 (m, 4), 7.64 (d, 2, J=7.2), 8.91 (br s, 1). MS m/z: 319.5 (M+1), 317.0 (M−1). HRMS: Calcd for M+H: 319.1559. Found: 319.1566.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@H:9]([C:10]([OH:12])=[O:11])[CH2:8][S:7][CH:6]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])=[O:4].[NH2:20][CH2:21][C:22]([OH:24])=[O:23].Cl>[OH-].[Na+]>[C:22]([CH2:21][NH:20][CH2:2][C:3]([N:5]1[C@H:9]([C:10]([OH:12])=[O:11])[CH2:8][S:7][CH:6]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])=[O:4])([OH:24])=[O:23]
Reactant: NCC(=O)O
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1C(=O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4R)-3-Chloroacetyl-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid (6 g) was added to a stirred solution of glycine (1.5 g) in N sodium hydroxide (80 ml), and stirred overnight at room temperature. The solution was adjusted to pH 1.5 by 20% hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 3.2, and the separated crystals were collected by filtration to 3.28 g (48.2%) of the titled compound: mp 181°-182° C. (dec.) (water); [α]D24 +271.2° (c=0.5, N--NaOH). IR (KBr, cm-1): 3400, 3200, 1740, 1672, 1560, 1440, 1380, 1335, 1212, 752, 648, NMR (K2CO3 in D2O, δ): 3.0-4.3 (6H, m, C5 --H, COCH2NHCH2CO2H), 6.33 and 6.43 (1H, each s, C2 --H), 6.6-7.3 (3H, m, arom. H), 7.82 (1H, br. d, J=8 Hz, arom. H), 9.0-10.3 (2H, br. s, --OH, --CO2H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C:18](=[O:19])[C:17]2[CH2:16][CH2:15][N:14]3[CH:20]=[C:21]([CH3:23])[N:22]=[C:13]3[C:12]=2[NH:11][C@@H:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>>[Si:1]([O:8][C@H:9]1[C:18](=[O:19])[C:17]2[CH:16]=[CH:15][N:14]3[CH:20]=[C:21]([CH3:23])[N:22]=[C:13]3[C:12]=2[NH:11][C@@H:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1cn2c(n1)C1=C(CC2)C(=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](c2ccccc2)N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O[Si](C)(C)C(C)(C)C)C3=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
50.7 g (123.8 mmol) of (8R,9R)-8-(tert-butyldimethylsilanyloxy)-2-methyl-9-phenyl-5,6,7,8,9,10-hexahydroimidazo[1,2-h][1,7]naphthyridin-7-one are treated in portions at 5° C.-10° C. with 35.6 g (153.5 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone. After the end of the addition, the reaction mixture is stirred at room temperature for 2 days. The reaction mixture is extracted with 150 ml of sodium hydroxide solution and the sodium hydroxide solution phase separated off is extracted with 150 ml of toluene and the combined toluene phases are washed with 150 ml of water. The organic phase is concentrated and the residue is dried overnight in a high vacuum. The solid crystallised in this way is stirred in diisopropyl ether, filtered off with suction and dried in vacuo at 50° C. 10.1 g (20% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:12][NH:11][CH2:10][CH2:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17](F)=[C:18]([CH:21]=1)[C:19]#[N:20].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:11]2[CH2:10][CH2:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([O:2][CH3:1])[C:4]=3[CH2:12]2)=[C:18]([CH:21]=1)[C:19]#[N:20]
Reactant: COc1ncnc2c1CNCC2
Reactant: N#Cc1cc(Cl)ccc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ncnc2c1CN(c1ccc(Cl)cc1C#N)CC2
Temperature: 80 °C
Yield: 82.4 %

Procedure:
A mixture of 4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (12.88 g, 0.078 mol), 5-chloro-2-fluorobenzonitrile (40 g, 0.2 mol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (60 mL, 0.4 mol) was heated at 80° C. for 3 hours. After cooling the mixture was diluted with CH2Cl2 (300 mL), washed with water, dried, and concentrated to afford a brown solid which was purified by silica gel chromatography (0-50% EtOAc/hexane) to afford a solid (19.33 g, 78.3%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([NH:15][CH3:16])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:25]CC)(=O)[CH2:18][C:19]([O:21]CC)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:19]([OH:21])=[CH:18][C:17](=[O:25])[N:15]([CH3:16])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CNc1cc(=O)n(Cc2ccccc2)cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1c(=O)cc(O)c2c(=O)n(Cc3ccccc3)cnc21
Yield: 56.9 %

Procedure:
3-Benzyl-6-(methylamino)pyrimidin-4(3H)-one (compound 5A) (2 g, 9.3 mmol, 1 eq) and diethyl malonate (2 mL, 14.5 mmol, 1.55 eq) were heated in phenyl ether (3 mL, 19 mmol, 2 eq) at 240° C. in a microwave reactor for 6 hours. Upon cooling a precipitate formed which was filtered and washed with ether to give 1.5 g of the title compound as a tan solid (57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.51 (s, 3H) 5.20 (s, 2H) 5.72 (s, 1H) 7.31 (br. s., 1H) 7.38 (d, J=3.03 Hz, 4H) 8.93 (s, 1H) 11.61 (s, 1H). [M+H] calc'd for C15H13N3O3, 284. found, 284.