Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:29]([CH2:37][C:38](=O)[CH3:39])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:39]/[C:38](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:37]/[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Product: C/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of example 1) from a suspension of 205 mg (0.54 mmol) of Intermediate 55 and 88 mg (0.54 mmol) of benzoylacetone to yield 142 mg (50% yield) of example 57: TLC (DCM/MeOH, 4/1): Rf=0.66; 1H NMR (DMSO-d6, 300 MHz) δ11.44 (d, 1H, J=9.0), 7.88-7.85 (m, 2H), 7.78-7.75 (m, 2H), 7.49-7.43 (m, 3H), 7.37-7.32 (m, 3H), 7.12 (d, 2H, J=8.4), 6.78 (d, 2H, J=8.4), 5.54 (s, 1H), 4.13 (m, 1H), 3.87 (t, 1H, J=6.0), 3.22-3.16 (m, 1H), 2.77 (d, 1H, J=14.4, 9.2), 2.56 (t, 2H, J=7.2), 2.22 (s, 3H), 2.00-1.93 (m, 2H), 1.66 (s, 3H); low resolution MS (ES+)m/e 525.15 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][CH2:24]O)[CH:17]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1.CCCCCC>[CH:13]([O:12][C:4]1[CH:5]=[C:6]([CH:11]=[C:2]([O:1][CH2:24][CH2:23][CH2:22][C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:15])[CH3:14]
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Reactant: OCCCc1cccnc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1cc(OCCCc2cccnc2)cc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution (60 ml) of methyl 5-hydroxy-3-isopropoxybenzoate (2.0 g) and 3-(pyridin-3-yl)propanol (1.6 g) in THF were added successively 1,1′-(azodicarbonyl)dipiperidine (2.9 g) and tributylphosphine (2.8 ml) under ice-cooling, and the mixture was stirred overnight at room temperature. n-Hexane (100 ml) was added to the reaction mixture, and the precipitated crystals were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (LL, Biotage cartridge, ethyl acetate:n-hexane=15:85→1:4) to give methyl 3-isopropoxy-5-(3-pyridin-3-ylpropoxy)benzoate (2.70 g, 86%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([C:18]([OH:20])=O)[NH:13]3)[N:6]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][C:25]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[C@@H:33]([CH3:38])[CH2:32]2)([OH:28])[CH2:24][CH2:23]1>>[OH:28][C:25]1([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[C@@H:33]([CH3:38])[CH2:32]2)[CH2:26][CH2:27][CH:22]([NH:21][C:18]([C:12]2[NH:13][C:14]3[C:10]([CH:11]=2)=[C:9]([O:8][CH2:7][C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)[CH:17]=[CH:16][CH:15]=3)=[O:20])[CH2:23][CH2:24]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCc3csc(Cl)n3)cccc2[nH]1
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5csc(Cl)n5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(2-chloro-thiazol-4-ylmethoxy)-1H-indole-2-carboxylic acid 16d and amine 14.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH-].[Na+].[CH3:18][C:19]([C:21](Cl)=[O:22])=[CH2:20].Cl>O.C(OCC)(=O)C>[C:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:22])[C:19]([CH3:20])=[CH2:18]
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)C(=O)NCCCCCCCCCCCC(=O)O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In 9 l of water at 30° C. were dissolved 218 g of 12-aminododecanoic acid and 100 g of sodium hydroxide (purity: 93%), and 102 ml of methacryl chloride was added thereto over 1 hour while stirring. The reaction mixture was stirred for 2 hours and then heated to 60° C., at which 3 l of ethyl acetate and 300 ml of concentrated hydrochloric acid were added thereto successively. The mixture was filtered while hot (60° C.) to remove any insoluble matter, followed by liquid-liquid separation. The organic layer was dried over 30 g of magnesium sulfate and, after removal of the magnesium sulfate, cooled to 10° C., at which 6 l of n-hexane was added, whereupon a precipitate was formed. The precipitate was collected by filtration and thoroughly washed with 1 l of n-hexane. Recrystallization of the precipitate from 500 ml of ethyl acetate yielded 128 g of 12-methacryloylaminododecanoic acid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.S([O-])([O-])(=O)=O.[Mg+2].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][O:23][C:24]2=[O:29]>C(#N)C>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[N:19]/[C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH2:22][O:23][C:24]3=[O:29])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=C1OCc2c(/N=C/c3ccc(C(F)(F)F)cc3)cccc21
Yield: 68.5 %

Procedure:
To a stirred mixture of 4-(trifluoromethyl)benzaldehyde (2.8 g, 16.1 mmol) and anhydrous Magnesium sulfate (16 g, 134 mmol) in anhydrous acetonitrile (200 mL) was added 4-aminoisobenzofuran-1(3H)-one (2 g, 13.4 mmol) at room temperature. After the addition, the mixture was stirred at reflux for overnight. The mixture was filtered and the cake was washed with ethyl acetate (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether and re-crystallized from ethyl acetate to give the title compound (2.8 g, yield: 68%). LC-MS (ESI) m/z: 306 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]2[CH:8]([C:9](O)=O)[CH:3]1[CH2:4][CH2:5]2.[CH2:12]([N:15]1[C:22]([NH2:23])=[C:21]([NH2:24])[C:19](=[O:20])[N:18]([CH2:25][CH2:26][CH3:27])[C:16]1=[O:17])[CH2:13][CH3:14].Cl>>[O:1]=[C:2]1[CH2:7][CH:6]2[CH:8]([C:9]3[NH:24][C:21]4[C:19](=[O:20])[N:18]([CH2:25][CH2:26][CH3:27])[C:16](=[O:17])[N:15]([CH2:12][CH2:13][CH3:14])[C:22]=4[N:23]=3)[CH:3]1[CH2:4][CH2:5]2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C1CC2CCC1C2C(=O)O
Agent: Cl
Product: CCCn1c(=O)c2[nH]c(C3C4CCC3C(=O)C4)nc2n(CCC)c1=O

Procedure:
2-Oxo-bicyclo[2.2.1]heptane-7-carboxylic acid (308 mg) was couple to 1,3-Dipropyl-5,6-diaminouracil.HCl (576 mg) and cyclized using the procedures from Example 1. Yield: 320 mg. Mass (ES+ 345).
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[C:3](=O)[CH2:4][C:5]#[N:6].[C:13]1([CH3:21])[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1>C(O)C>[F:1][C:2]([F:12])([C:3]1[CH:4]=[C:5]([NH2:6])[N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:21])=[CH:14][CH:15]=2)[N:20]=1)[C:8]([F:9])([F:11])[F:10]
Reactant: Cc1ccc(NN)cc1
Reactant: N#CCC(=O)C(F)(F)C(F)(F)F
Solvent: CCO
Product: Cc1ccc(-n2nc(C(F)(F)C(F)(F)F)cc2N)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Heat a mixture of 4,4,5,5,5-pentafluoro-3-oxo-pentanenitrile (4 g, 21.4 mmol) and p-tolyl-hydrazine (10 g, 64.1 mmol) in ethanol (20 mL) to 95° C. in a sealed tube apparatus for 15 hours. After cooling to room temperature, remove the solvent under reduced pressure to give a brown residue. Subject residue to silica gel chromatography eluting with ethyl acetate and hexanes to give the title compound (3.24 g, 52% yield, ES+(m/z) 292.1 [M+H]).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12].ClC(OCC)=O.C(=O)([O-])O.[Na+]>O>[N:4]([CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12])=[C:1]=[S:3]
Reactant: CN1CCCC1CCN
Reactant: S=C=S
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCCC1CCN=C=S
Temperature: 0 °C
Yield: 43.2 %

Procedure:
A mixture of carbon disulfide (0.996 mL, 16.57 mmol) in water (5 mL) was cooled to 0° C. Then 2-(2-aminoethyl)-1-methylpyrrolidine (2.4 mL, 16.57 mmol) was added over 45 minutes. The resulting mixture was maintained at 0° C. for an additional 30 minutes and then the cooling was discontinued. Next, ethyl chloroformate (1.58 mL, 16.57 mmol) was added over a 1 h period. The resulting mixture was maintained at room temperature for an additional 30 minutes and then made basic with saturated sodium hydrogen carbonate in water. The mixture was extracted with diethyl ether (2×50 mL). The extracts were combined, washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow oil. The oil was purified by vacuum distillation to give 1.22 g of 2-(2-isothiocyanatoethyl)-1-methylpyrrolidine.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([CH2:35][CH2:36][C:37]([F:49])([F:48])[C:38]([F:47])([F:46])[C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41])[C:30]([O:32]CC)=[O:31])([CH3:13])[C@@H:11]([OH:50])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([CH2:35][CH2:36][C:37]([F:48])([F:49])[C:38]([F:46])([F:47])[C:39]([F:44])([F:45])[C:40]([F:41])([F:42])[F:43])[C:30]([OH:32])=[O:31])([CH3:13])[C@@H:11]([OH:50])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(CCCCCCCCC[C@H]1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@@H]12)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@]12C[C@H](CCCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 60 °C
Yield: 83.7 %

Procedure:
Ethyl 11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoate (747 mg, 1.02 mmol) was dissolved in a mixed solvent of ethanol (5 ml) and water (5 ml). To this solution, NaOH (82 mg, 2.04 mmol) was added, and the resulting mixture was heated for 15 hours at 60° C. After cooling, 2N aqueous hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then filtered. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→3/1→2/1) to give 11-(3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid (600 mg, Yield 84%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21](Br)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:23][C:24]1[C:25]([O:33][CH3:34])=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[C:25]=4[O:33][CH3:34])=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Reactant: COc1c(F)cccc1B(O)O
Product: COc1c(F)cccc1-c1cnn2ccc(N3CCN(C(=O)OC(C)C)CC3)nc12
Yield: 33.8 %

Procedure:
Prepared similarly to the preparation of example 5.6.9 from 4-(3-bromo-pyrazolo[1,5-a]pyrimidin-5-yl)-piperazine-1-carboxylic acid isopropyl ester (389.9 mg, 1.1 mmol) and 3-fluoro-2-methoxyphenylboronic acid [762287-59-2] (216.2 mg, 1.3 mmol) to afford 153.8 mg of light yellow powder as a free base, mp. 52-53° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.32 Hz, 6 H) 3.49-3.56 (m, 4 H) 3.75 (dd, J=6.44, 4.17 Hz, 4 H) 3.83 (d, J=1.01 Hz, 3 H) 4.82 (spt, J=6.23 Hz, 1H) 6.81 (d, J=8.08 Hz, 1 H) 7.06 (ddd, J=11.37, 8.08, 1.52 Hz, 1 H) 7.16 (td, J=8.08, 5.81 Hz, 1 H) 8.23 (dt, J=7.89, 1.36 Hz, 1 H) 8.42 (s, 1 H). 19F NMR (377 MHz, DMSO-d6) δ ppm −131.42. 13C NMR (100 MHz, DMSO-d6) δ ppm 21.95, 42.83, 44.05, 60.38, 68.16, 97.24, 99.94, 99.98, 112.72, 112.90, 123.22, 124.06, 127.98, 136.39, 143.40, 143.51, 144.25, 144.49, 154.28, 154.63, 155.53, 157.04. LRMS (ESI) m/z 414.1 [(M+H)]+, calc'd for C21H24FN5O3: 413.46.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11]C(=O)[O:9][C:8](=O)[C:7]=2[CH:14]=1.[NH2:15][NH2:16]>O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:11])=[C:7]([CH:14]=1)[C:8]([NH:15][NH2:16])=[O:9]
Reactant: NN
Reactant: CSc1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: O
Product: CSc1ccc(N)c(C(=O)NN)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-methylthio-2H-3,1-benzoxazine-2,4-(1H)-dione (25.11 g; 0.72 mole) is added to a cold solution of 54.4% hydrazine (75 ml) in water (75 ml). After stirring at room temperature overnight, the while solid is filtered, washed with cold water and dried. Yield 21.3 g; mp 124°-127°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Na].[C:10](=[O:12])=[O:11]>C1CCCCC1>[C:5]1([CH2:8][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: O=C=O
Agent: [Na]
Solvent: C1CCCCC1
Product: O=C(O)Cc1ccccc1
Temperature: 80 °C
Yield: 94.1 %

Procedure:
In accordance with the process of Example 1, 12.7 g of p-chlorotoluene were contacted and reacted with 5.4 g of sodium dispersed in 50 ml of cyclohexane at 20° C to 30° C and then the reaction mixture was heated to 80° C for 5 hours to rearrange the product. The reaction mixture was cooled to 20° C to 23° C and was gradually poured onto 10 g of solid carbon dioxide with stirring to effect the carbonylation reaction. After the reaction with carbon dioxide, the post-treatment procedure was conducted in accordance with the process of Example 1 to whereby 12.8 g of phenylacetic acid (yield 94.1%) were obtained.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:7][CH:6]=1)C.CO.[OH-].[Na+]>O>[N:18]1([C:8]2[CH:9]=[C:10]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]([C:4]([OH:24])=[O:3])=[CH:6][N:7]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cnc(N2CCOCC2)cc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc(N2CCOCC2)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A mixture of 66 mg (0.20 mmol) 6-morpholin-4-yl-4-phenoxy-nicotinic acid ethyl ester, 2 ml methanol and 2 ml 1N aqueous sodium hydroxide solution was stirred at room temperature for 1 h. The reaction mixture was diluted with water and washed with tert-butyl-methyl-ether. The aqueous layer was acidified to pH 4-5 with concentrated hydrochloric acid solution and extracted with 3 portions of dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried with sodium sulfate. Concentration afforded 46 mg (77%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:35])=[CH:12][C:13]([CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:16])=[CH:14][C:4]=2[O:3]1.C(O)(=O)C.[S:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][C:50](O)=[O:51])[CH2:43][CH2:42]1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:36][C:2]1([CH3:1])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:35][C:50](=[O:51])[CH2:49][CH2:48][CH2:47][N:44]3[CH2:43][CH2:42][S:41][CH2:46][CH2:45]3)=[CH:12][C:13]([CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCSCC1
Reactant: CCCCCCCCCCCCCCCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCC(C)c1cc(OC(=O)CCCN2CCSCC2)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
1,2-Dihydro-7-(2-eicosyl)-9-hydroxy-4-oxo-4H-thieno-[2,3-c][1]benzopyran is reacted with methyl magnesium bromide according to the procedure described hereinabove in Example 8 to give 1,2-dihydro-4,4-dimethyl-7-(2-eicosyl)-9-hydroxy-4H-thieno[2,3-c][1]benzopyran. The benzopyran is then reacted with γ-thiomorpholinobutyric acid, acetate salt and dicyclohexylcarbodiimide according to the method of Example 10 to yield the desired ester.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:20]4[CH2:22][CH2:21]4)[N:18]=3)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:12]=2)=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:20]4[CH2:22][CH2:21]4)[N:18]=3)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:12]=2)=[O:10])[CH2:3]1)(=[O:41])=[O:40]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCNC2)c2nc(C3CC3)cnc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCN(S(C)(=O)=O)C2)c2nc(C3CC3)cnc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.1 %

Procedure:
In a 15 mL round-bottomed flask, 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid piperidin-3-ylamide hydrochloride (200 mg, 0.44 mmol) was dissolved in CH2Cl2 (3 mL) and cooled to 0° C. Added triethylamine (0.12 mL, 0.88 mmol) followed by methanesulfonyl chloride (0.04 mL, 0.48 mmol). The reaction mixture was stirred at room temperature for 6 h then diluted with 30 mL of CH2Cl2 and washed with water (5 mL). The aqueous layer was extracted with CH2Cl2 (30 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography over 12 g SiO2 with EtOAc/Hexanes (gradient: 0-100% EtOAc) to provide 174 mg (89%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-yl)-amide as a white foam.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[C:4]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:3]=12.[CH2:16]([C:18]1[CH:23]=[C:22]([CH:24]=O)[CH:21]=[C:20]([CH3:26])[C:19]=1[CH:27]=[CH:28][C:29]([OH:31])=[O:30])[CH3:17].Cl>[OH-].[Na+]>[CH2:16]([C:18]1[CH:23]=[C:22]([CH:24]=[CH:8][C:7](=[O:9])[C:5]2[S:6][C:2]([CH3:1])=[C:3]3[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:4]=23)[CH:21]=[C:20]([CH3:26])[C:19]=1[CH:27]=[CH:28][C:29]([OH:31])=[O:30])[CH3:17]
Reactant: CC(=O)c1sc(C)c2c1CCC(C)(C)C2
Reactant: CCc1cc(C=O)cc(C)c1C=CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(C=CC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1C=CC(=O)O
Yield: 61.1 %

Procedure:
A solution of 1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (355 mg, 1.55 mmol) and 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid (373 mg, 1.70 mmol, Aldehyde 5) in methanolic NaOH (8 mL, 10 g NaOH in 100 mL methanol) is stirred at rt for 3 h before it is carefully acidified to pH 1 by adding 2 N aq. HCl. The mixture is extracted twice with DCM, the organic extracts are washed with water and brine, dried over MgSO4, filtered and evaporated. The crude product is crystallised from acetonitrile (120 mL) to give 3-{2-ethyl-6-methyl-4-[3-oxo-3-(3,5,5-tri methyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propenyl]-phenyl}-acrylic acid (400 mg) as yellow crystals; LC-MS: tR=1.17 min, [M+1]=423.34; 1H NMR (CDCl3): δ 7.97 (d, J=16.4 Hz, 1H), 7.68 (d, J=15.2 Hz, 1H), 7.33 (s, 2H), 7.28 (d, J=15.8 Hz, 1H), 6.13 (d, J=15.8 Hz, 1H), 3.16 (t, J=7.0 Hz, 2H), 2.77 (q, J=7.6 Hz, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 2.32 (s, 2H), 1.57 (t, J=6.4 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H), 1.00 (s, 6H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[C:36]([O:38][CH2:39][CH2:40][CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=[O:43])[CH:35]=[C:34]([OH:47])[CH:33]=1)(C(C)(C)C)(C)C.O>CC(C)=O.Cl>[OH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[C:36]([O:38][CH2:39][CH2:40][CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=[O:43])[CH:35]=[C:34]([OH:47])[CH:33]=1
Reactant: CN(C)C(=O)CCCOc1cc(O)cc(CCC[C@@H]2C[C@H]3CC(=O)CC[C@]3(C)[C@H]3CC[C@]4(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]4[C@H]23)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C(=O)CCCOc1cc(O)cc(CCC[C@@H]2C[C@H]3CC(=O)CC[C@]3(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@H]23)c1
Reaction time: 0.58 h
Yield: 65.3 %

Procedure:
To a solution of 17β-(tert-butyldimethylsilyloxy)-7α-(3-(3-hydroxy-5-(3-(N,N-dimethylaminocarbonyl)propoxy)phenyl)propyl)-5α-androstan-3-one (12.0 mg) in acetone (1 ml), 2N hydrochloric acid (1 ml) was added at 25° C. and stirred for 35 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 17β-hydroxy-7α-(3-(3-hydroxy-5-(3-(N,N-dimethylaminocarbonyl)propoxy)phenyl)propyl)-5α-androstan-3-one (6.5 mg, yield 65%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.CCN(CC)CC.Cl[C:35]([O:37][C:38]1[C:43]([CH3:44])=[CH:42][C:41]([CH3:45])=[CH:40][C:39]=1[CH3:46])=[O:36]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[NH:24][C:35](=[O:36])[O:37][C:38]4[C:43]([CH3:44])=[CH:42][C:41]([CH3:45])=[CH:40][C:39]=4[CH3:46])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: NC1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1cc(C)c(OC(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(OC(=O)NC2CC2c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C)c1
Reaction time: 0.08 h
Yield: 79 %

Procedure:
2-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]phenyl}cyclopropylamine (46.0 mg, 0.13 mmol, 1.0 equiv) was dissolved in CH2Cl2 (0.55 mL) under N2. 4-Dimethylaminopyridine (DMAP; 0.8 mg, 0.006 mmol, 0.05 equiv) and Et3N (27 μL, 0.19 mmol, 1.5 equiv) were added, followed by mesityl chloroformate prepared above (33 mg, 0.17 mmol, 1.2 equiv). The reaction was stirred for 5 min and was then quenched with NaHCO3 (aq). The layers were separated, and the aqueous layer was extracted twice more with CH2Cl2. The combined organic extracts were concentrated, and the crude product was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound as a white solid (53.0 mg, 79%): mp 199-202° C.; 1H NMR (400 MHz, CDCl3, data for major rotamer) δ 8.54 (s, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.39 (d, J=0.7 Hz, 2H), 7.32-7.21 (m, 2H), 6.86 (s, 2H), 5.71-5.36 (m, 0.7H), 5.22-4.82 (m, 0.3H), 3.09-2.81 (m, 1H), 2.26 (s, 4H), 2.17 (s, 6H), 1.43-1.26 (m, 2H); ESIMS m/z 523 (M+H).