Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:5]#[N:6].[CH3:18]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[K+]>COCCOC.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>[CH:17]1[N:16]=[CH:15][N:14]2[CH:10]([C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[CH3:18])[CH2:11][CH2:12][C:13]=12
Reactant: N#Cc1ccc(C2CCc3cncn32)c(Br)c1
Reactant: CB1OB(C)OB(C)O1
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: [K+]
Solvent: COCCOC
Product: Cc1cc(C#N)ccc1C1CCc2cncn21
Temperature: 130 °C

Procedure:
To a solution of 3-bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (0.100 g, 0.347 mmol) given in Example 3 (table 2) and trimethylboroxine (0.145 g, 1.04 mmol) in DME (3 mL), aqueous solutions of Na2CO3 (0.69 mL, 2 M) and KOH (0.17 mL, 2 M) are added. After degassing with nitrogen, Pd(PPh3)4 (0.040 g, 0.035 mmol) is added. The mixture is heated in a microwave reactor at 130° C. 1.5 h. At that point LCMS showed consumption of the starting material. The solution is diluted with ethyl acetate and saturated sodium bicarbonate. The resulting aqueous layer is extracted further with ethyl acetate (3×). The combined organic layers are washed with brine and dried over anhydrous sodium sulfate. After concentration the crude product is filtered through 0.45 μm filter and then purified by preparative HPLC (0% for 5 minutes and 0-34% acetonitrile with 0.1% TFA in 17 minutes). MS (ESI) m/z 224.0 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.33-2.42 (m, 1 H), 2.43 (s, 3 H), 2.84-2:95 (m, 2 H), 3.07-3.18 (m, 1 H), 5.54 (dd, J=8.1, 4.8 Hz, 1 H), 6.65 (d, J=8.1 Hz, 1 H), 6.83 (s, 1 H), 7.32 (s, 1 H), 7.41 (d, J=8.1 Hz, 1 H), 7.50 (s, 1 H).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[C:17][Si](C)(C)C)[C:11]=1[F:22])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].CCO.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[CH:17])[C:11]=1[F:22])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C#C[Si](C)(C)C)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: C#Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
tert-Butyl({2-fluoro-3-[(trimethylsilyl)ethynyl]benzyl}oxy)dimethylsilane (4.13 g) was mixed with EtOH (61 ml), and potassium carbonate (847 mg) was added thereto, followed by stirring at room temperature for 1 hour. Water and CHCl3 were added to the reaction mixture at 0° C., and the organic layer was washed with water and saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl[(3-ethynyl-2-fluorobenzyl)oxy]dimethylsilane (3.19 g).
Reaction SMILES: ClC1C=C([C@H](CCN2CCC(N(C(=O)C(F)(F)F)CCNC(=O)C(F)(F)F)CC2)[CH2:10][N:11](C)[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=1Cl.FC(F)(F)C(N(CCCNC(=O)C(F)(F)F)C1CCNCC1)=O.ClC1C=C(C(CC=O)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl>>[CH3:10][NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C[C@@H](CCN1CCC(N(CCNC(=O)C(F)(F)F)C(=O)C(F)(F)F)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: O=C(NCCCN(C(=O)C(F)(F)F)C1CCNCC1)C(F)(F)F
Product: CNC(=O)c1ccccc1

Procedure:
(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-[(2,2,2-trifluoroacetyl)[2-(2,2,2-trifluoroacetylamino)ethyl]amino]piperidino]butyl]-N-methylbenzamide. Using the procedure of Example 1, replacing 4-(2-oxo-1,3-oxazolidin-3-yl)piperidine by 4-[(2,2,2-trifluoroacetyl)[3-(2,2,2-trifluoroacetylamino)propyl]amino]piperidine, and N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide by the (S)-enantiomer, the N-methylbenzamide was obtained; MS: m/z=683(M+1).
Reaction SMILES: FC(F)(F)[C:3]([O:5][C:6](=O)[C:7](F)(F)F)=O.[NH:14]1[CH2:23]C2C(=CC=CC=2)[CH2:16][C@H:15]1[C:24](O)=[O:25]>ClCCl>[CH3:3][O:5][C:6]1[CH:7]=[CH:16][C:15]([CH2:24][OH:25])=[N:14][CH:23]=1
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Trifluoroacetic anhydride (28.2 mL, 203 mmol) was added dropwise to an ice cooled solution of the product from preparation 20 (˜135 mmol) in dichloromethane (500 mL), the mixture was allowed to warm to room temperature and stirred overnight. Tic analysis indicated still largely starting material so a further portion of trifluoroacetic anhydride (15 mL, 108 mmol) was added dropwise and the mixture was allowed to stir for a further 27 hours. The reaction was quenched by the cautious addition of methanol (250 mL) and left to stir for 30 minutes before being concentrated in vacuo. 2.5 M sodium hydroxide (100 mL) was then added cautiously and the mixture was extracted with dichloromethane (4×100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired product (12 g, 64%) contaminated with recovered starting material (˜15 mol %). 1H NMR (CDCl3, 400 MHz) δ 3.80 (3H, s), 4.40 (1H, br), 4.66 (2H, s), 7.16 (1H, dd), 7.20 (1H, d), 8.17 (1H, d).
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:20])([OH:4])([OH:3])=[O:2].[Br:21]Br>N1C=CC=CC=1.C(O)(=O)C>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([Br:21])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:20])([OH:4])([OH:3])=[O:2]
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)cc1Br
Reaction time: 20 h

Procedure:
5-Bromo-2′-deoxyuridine-5′-phosphate was prepared as follows: 2′-Deoxyuridine-5′-phosphate (6.2 g) was suspended in a mixture of 60 ml pyridine and 30 ml acetic acid. Bromine (0.84 ml) was added with stirring in an ice water bath and stirring continued for 20 hours at room temperature. The solution was concentrated by vacuum. After redissolution in a minimum of water a crude product was precipitated by addition of ethanol. The crude product was chromatographed on Dowex 50 (H+) and eluted with water. The free acid product was precipitated from the concentrated eluent by addition of ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br:13]Br>C(O)(=O)C.Br>[Br:13][CH:10]([CH3:11])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:12]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(OC)cc1
Agent: Br
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(C)Br)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
0.30 mol of 4′-methoxypropiophenone is dissolved in 230 ml of glacial acetic acid and mixed with 3 drops of 48% HBr solution. In the stirred mixture, 0.30 mol of bromine is now slowly added in drops while being cooled in an ice bath such that the temperature in the flask does not exceed 15° C. The ice bath is removed, and it is stirred for about another 45 minutes in a continuous nitrogen stream to remove the HBR that is produced in the reaction. Then, it is carefully poured onto 300 ml of ice water. The settled precipitate is suctioned off, washed with several portions of water to remove all bromine and dried in a desiccator overnight. The crude product is recrystallized from 96% ethanol.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:18]=2[N:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[I:25][C:23]1[CH:22]=[CH:21][C:19]2[NH:20][C:16]([C@@H:8]([NH2:7])[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:17][C:18]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc2cc(I)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)c1nc2cc(I)ccc2[nH]1
Temperature: 0 °C

Procedure:
To a solution of [(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (1.0 g, 2.16 mmol) in dichloromethane (11 mL) at 0° C. under an atmosphere of nitrogen was added trifluoroacetic acid (6.0 mL, 81 mmol) and the mixture stirred at 0° C. with warming to room temperature over 2 hours. The reaction mixture was concentrated in vacuo then basified with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethylamine which was used in the subsequent step without further purification (750 mg, 96%).
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([O:16]C)[CH:3]=1.Cl.[NH+]1C=CC=CC=1>C(Cl)Cl>[I:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([OH:16])[CH:3]=1
Reactant: COc1cc(I)ccc1OCCN1CCCC1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Oc1cc(I)ccc1OCCN1CCCC1
Temperature: 25 °C

Procedure:
A mixture of 3.10 g (8.93 mmol) of 1-[2-(4-iodo-2-methoxyphenoxy)ethyl]pyrrolidine and 4.50 g (38.94 mmol) of pyridinium hydrochloride was heated to 200° C.-250° C. for 5 minutes, cooled to RT, and combined with DCM. The organic phase was washed with water and saturated aqueous NaCl solution, dried over sodium sulfate, and evaporated down in vacuo. The residue was stirred with acetonitrile, and the precipitate was filtered off and dried in vacuo. Yield: 0.75 g (25% of theoretical); C12H16INO2 (M=333.165); calc.: molpeak (M+H)+334; found: molpeak (M+H)+: 334; HPLC-MS: 5.02 minutes (method A).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][O:29][C:28]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:27]1=2.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:27]4[N:26]([CH3:25])[CH2:31][CH2:30][O:29][C:28]=4[CH:32]=3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CN1CCOc2cc(B(O)O)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)OCCN4C)n2n1
Temperature: 110 °C
Yield: 58.9 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ylboronic acid (62 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (50-50% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (46.9 mg, 59%). 1H NMR (DMSO-d6) δ: 10.99 (s, 1H), 7.95 (d, J=8.6 Hz, 2H), 7.89 (s, 1H), 7.57-7.62 (m, 2H), 7.54 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.8 Hz, 1H), 6.25 (s, 1H), 4.20-4.24 (m, 2H), 3.32-3.35 (m, 2H), 2.91 (s, 3H), 2.35 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 458.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(N)CO
Reactant: Clc1ccnc(Cl)n1
Product: CC(C)(CO)Nc1ccnc(Cl)n1
Yield: 19 %

Procedure:
Prepared in analogy to example 98a), using 2,4-dichloro-pyrimidine and 2-amino-2-methylpropan-1-ol. The title compound was isolated as a yellowish solid in a yield of 19%. MS ISP (m/e): 200.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=7.84 (d, 1H), 7.49 (s, 1H), 6.50 (d, 1H), 4.85 (s, 1H), 3.53 (d, 2H), 1.29 (s, 6H).
Reaction SMILES: C1(=O)OC(=O)C=C1.NC1C=CC=CC=1O.CN(C)C=O.[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=O>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[C:29](=[O:35])[CH:30]=[CH:31][C:32]1=[O:34]
Reactant: O=C(O)/C=C\C(=O)Nc1ccccc1O
Agent: Nc1ccccc1O
Agent: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: O=C1C=CC(=O)N1c1ccccc1O

Procedure:
A maleic anhydride copolymer and an aminophenol are heated in an organic solvent such as dimethylformamide to 0°-150° C., preferably 10°-100° C., more preferably 50°-100° C. for 1-20 hours to convert a portion or whole of the maleic anhydride units into N-(hydroxyphenyl)maleamic acid unit. To the reaction mixture is added a tertiary amine catalyst, and is further added an azeotropic agent (i.e., azeotropic solvent) such as toluene or xylene for removing water produced upon cyclization-dehydration reaction. The resulting mixture is then heated to 80°-200° C., preferably 100°-150° C., for 1-20 hours for performing a cyclization-dehydration reaction, to obtain the desired N-(hydroxyphenyl)maleimide copolymer.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].Cl.Cl[CH2:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[O:3][CH2:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1)#[N:7]
Reactant: ClCCc1c[nH]cn1
Reactant: N#Cc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1OCCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
240 mg (60% in oil; 6 mmol) of sodium hydride are added to a solution of 1.43 g (12 mmol) of 2-hydroxybenzonitrile in 10 ml of dimethylformamide. The mixture is stirred at room temperature for 1 hour under nitrogen. 200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammonium iodide (catalytic amount) are added and the mixture is heated at 80° C. for 3 days. The solvent is evaporated under reduced pressure and the oily residue is stirred in ethanol and filtered. The filtrate is evaporated and the residue subjected to chromatography on a column of silica gel (first eluent chloroform, second eluent 95/5 chloroform/methanol). The title compound is converted to the oxalate and crystallized from an ethanol/diethyl ether (2/1) mixture, M.p.: 170°-171° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:11][C:12](OC(C)=O)=[O:13]>CC(O)=O>[C:12]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)(=[O:13])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2[nH]ncc2c1

Procedure:
By referring to the Step 3 of Example 1, 5-aminoindazole (5 g, 37.6 mmol), AcOH (20 mL) and Ac2O (5 mL), were used, concentrated to obtain a crude product that was directly used in the next step of reaction.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[N:24][C:19]=1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Reactant: Sc1ncccn1
Product: O=C1CCc2cc(OCCCCSc3ncccn3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-chloro-butoxy)-3,4-dihydro-carbostyril (m.p.: 147°-148° C.) and 2-mercapto-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][C:3]=1[F:18].[CH2:19]([NH:21][C:22](=[O:39])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1)[CH3:20].C(=O)(O)[O-].[Na+]>C(O)(C)C.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>[Cl:17][C:14]1[N:13]=[CH:12][C:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([C:25]4[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=4[CH3:29])[C:22]([NH:21][CH2:19][CH3:20])=[O:39])=[C:3]([F:18])[CH:4]=3)[NH:8][N:7]=2)=[CH:16][CH:15]=1
Reactant: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Fc1cc2c(-c3ccc(Cl)nc3)n[nH]c2cc1Br
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: CC(C)O
Product: CCNC(=O)c1ccc(C)c(-c2cc3[nH]nc(-c4ccc(Cl)nc4)c3cc2F)c1
Temperature: 150 °C
Yield: 8.2 %

Procedure:
A mixture of 6-bromo-3-(6-chloro-3-pyridinyl)-5-fluoro-1H-indazole (Intermediate 12, 16 mg), N-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 10, 15 mg), 1M aqueous sodium bicarbonate (1 ml) and tetrakis(triphenylphosphine)palladium (0) (6 mg) in isopropanol (1 ml) was heated at 150° C. for 15 mins in a microwave oven. The reaction mixture was partitioned between chloroform and water and the organic layer separated via hydrophobic filter tube. The organic layer was evaporated and purified by mass directed preparative HPLC to give the title compound 1.64 mg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9]1.[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:21])=[CH:9]1
Reactant: O=C(O)CCCCCSC1=CC(OC2CCCCO2)CC1=O
Reactant: Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCSC1=CC(OC2CCCCO2)CC1=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
686 mg (2.09 mmoles) of 4(RS)-tetrahydropyranyloxy-2-(5-carboxypentylthio)-2-cyclopentenone and 295 mg (3.14 mmoles) of phenol were dissolved in 10 ml of dichloromethane, and 0.1 ml of pyridine was added. To the solution was added 10 ml of a dichloromethane solution of 860 mg (4.18 mmoles) of dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 18 hours. After the reaction, ethyl acetate was added to the reaction mixture. The organic layer was washed successively with an aqueous solution of sodium bicarbonate, an aqueous solution of potassium bisulfate, and an aqueous solution of sodium chloride, dried, and then concentrated. The residue was chromatographed on a silica gel column using hexane/ethyl acetate (7/2) as an eluent to give 653 mg (1.62 mmoles; yield 77.3%) of 4(RS)-tetrahydropyranyloxy-2-(5-phenoxycarbonylpentylthio)-2-cyclopentenone.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[F:32])C1C=CC=CC=1>[C].[Pd].C1COCC1>[F:32][C:10]1[CH:11]=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCc4ccccc4)c(F)c3)oc2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.9 %

Procedure:
A mixture of N-((2S)-1-((2-(4-(benzyloxy)-3-fluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (1.22 g), 10% palladium-carbon (containing water (50%), 1.00 g) and THF (20 mL) was stirred at room temperature for 20 min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The obtained solid was washed with diethyl ether to give the title compound (850 mg).
Reaction SMILES: [OH:1][C@:2]1([C:22]#[N:23])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.Cl(O)(=O)(=O)=[O:25]>C(O)(=O)C.C(OC(=O)C)(=O)C>[OH:1][C@:2]1([C:22]([NH2:23])=[O:25])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C#N
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(N)=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 6.26 g of 17α-hydroxy-17-cyano-4-androsten-3-one in 50 ml of glacial acetic acid and 50 ml of acetic anhydride is combined with 0.5 ml of 70% perchloric acid, and the mixture is allowed to stand for 1 hour at 20° C. The product is precipitated into ice water, filtered off, and then dissolved in 570 ml of methanol. This solution is combined with 61 ml of a 1 N potassium hydroxide solution, and the mixture is stirred overnight at 20° C. The methanolic solution is diluted with 500 g of ice water, the precipitated product is vacuum-filtered and dried. Repeated crystallization from ethyl acetate--methylene chloride yields 5.62 g of 17α-hydroxy-3-oxo-4-androstene-17-carboxylic acid amide, mp 271°-273.5° C.
Reaction SMILES: ClC1C=C(C2C=C(C([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=O)OC=2C2C=CC(F)=CC=2)C=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[CH:38]=[C:39]([C:50](O)=[O:51])[O:40][C:41]=2[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[N:49])[CH:43]=2)[CH:33]=[C:34]([F:36])[CH:35]=1.N1CCNCC1=O>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[CH:38]=[C:39]([C:50]([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[O:51])[O:40][C:41]=2[C:42]2[CH:43]=[C:44]([C:48]#[N:49])[CH:45]=[CH:46][CH:47]=2)[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)cc3)o2)CCN1
Reactant: N#Cc1cccc(-c2oc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)c1
Agent: O=C1CNCCN1
Product: N#Cc1cccc(-c2oc(C(=O)N3CCNC(=O)C3)cc2-c2cc(F)cc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 6 starting with the compound from Example 20A. Instead of 1.5 equivalents of piperazin-2-one, 1.1 equivalents are used. 55.0 mg (89% of theory) of the title compound are obtained.