Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25]>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH:12][C:24](=[O:25])[C:23]([F:30])([F:29])[F:22])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(CN)Cc1cccc(Br)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CNC(=O)C(F)(F)F)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 58 %

Procedure:
3-(3-Bromophenyl)-2,2-dimethylpropan-1-amine hydrochloride (1.52 g, 5.45 mmol) was dissolved in anhydrous THF (50 mL). Et3N (1.5 mL, 10.76 mmol) was added slowly to produce a white slurry. Ethyl trifluoroacetate (2 mL, 16.8 mmol) was added and the mixture was stirred at room temp for 15.5 h. Additional ethyl trifluoroacetate (˜0.75 mL, 6.2 mmol) and triethylamine (0.75 mL, 5.4 mmol) were added and the mixture was stirred for 4 h. The reaction mixture was concentrated under reduced pressure. The product was taken up in EtOAc and the solution was washed with saturated aqueous NaHCO3 (2×) and brine, dried over Na2SO4 and concentrated under reduced pressure to give N-(3-(3-bromophenyl)-2,2-dimethylpropyl)-2,2,2-trifluoroacetamide (73) as a yellow oil. Yield (1.84 g, 58% yield for two steps): 1H NMR (400 MHz, CDCl3) δ 7.39 (ddd, J=8.0, 2.0, 0.8 Hz, 1H), 7.29 (t, J=1.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.05 (dt, J=7.6, 1.6 Hz, 1H), 6.16 (br s, 1H), 3.24 (d, J=6.8 Hz, 2H), 2.53 (s, 2H), 0.93 (s, 6H).
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][CH:16]=2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+]>CO.O>[C:20]1([C:18]2[S:19][C:15]([CH:12]3[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)=[CH:16][N:17]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(c1ccccc1)N1CCC(c2cnc(-c3ccccc3)s2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1ccc(-c2ncc(C3CCNCC3)s2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To 55 mg of 1-benzoyl-4-(2-phenyl-thiazol-5-yl)-piperidine in 4.5 ml of MeOH and 0.5 ml of H2O was added 354 mg of potassium hydroxide. The reaction was stirred at 70° C. overnight. The reaction was then cooled to room temperature and 20 ml of H2O was added. This aqueous layer was extracted with 4×25 ml EtOAc. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 25 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:8][Br:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncccc1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ncccc1Br
Temperature: 25 °C

Procedure:
3-Bromo-2-methylpyridine (10.0 g, 58.1 mmol), diphenylperoxyanhydride (2.82 g, 11.6 mmol), 1-bromopyrrolidine-2,5-dione (10.9 g, 61.0 mmol) were refluxed in 233 mL of carbon tetrachloride for 144 hours. The reaction mixture was cooled to ambient temperature and washed with water (3×200 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography eluting with 0-30% EtOAc in hexanes to provide 3-bromo-2-(bromomethyl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][N:20]3[CH:23]=[CH:24][N:25]=[C:19]3[CH2:18]2)[N:10]=[C:9]([S:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]=1.ClC1C=CC=C(C(OO)=[O:47])C=1>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][N:20]3[CH:23]=[CH:24][N:25]=[C:19]3[CH2:18]2)[N:10]=[C:9]([S:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:47])[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(SCc2ccccc2)nc1N1CCn2ccnc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(S(=O)Cc2ccccc2)nc1N1CCn2ccnc2C1
Reaction time: 1 h

Procedure:
To a chloroform solution 2 ml of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-2-benzylthiopyrimidine (prepared in the above (4)) 104 mg is dropped a solution of m-chloroperbenzoic acid 43 mg in chloroform 3 ml over a period of 20 minutes on an ice bath, and the mixture is stirred for 1 hour. The reaction mixture is diluted with an aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-2-benzylsulfinylpyrimidine as a slightly yellow caramel.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[NH:10][CH:9]=[C:8]2[C:16]1[N:24]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1.I[CH3:36].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[N:10]([CH3:36])[CH:9]=[C:8]2[C:16]1[N:24]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1
Reactant: CI
Reactant: COc1cc(OC)c2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.028 g of sodium hydride at 60% in oil is added, in small portions, to solution of 0.26 g of 2-(5,7-dimethoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 11.5 ml of dimethylformamide. The suspension is agitated for approximately 1 hour at around 20° C. and then 0.04 ml of iodomethane is added. After agitation for approximately 18 hours at around 20° C., the mixture is run into 100 ml of a mixture of ice plus water, and extracted with three times 75 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 0.3 g of 2-(5,7-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a foam, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])=[C:9]([CH3:11])[N:10]=1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)[CH3:19]>O1CCOCC1>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:18][CH3:19])=[CH:22][CH:23]=1)=[O:29])[C:6]1[S:7][C:8]([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])=[C:9]([CH3:11])[N:10]=1
Reactant: CNS(=O)(=O)c1sc(NCCN(C)C)nc1C
Reactant: CCOc1ccc(N=C=O)cc1
Solvent: C1COCCO1
Product: CCOc1ccc(NC(=O)N(CCN(C)C)c2nc(C)c(S(=O)(=O)NC)s2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.0 g (3.59 mmol) of 2-{[2-dimethylaminoethyl]amino}-N,4-dimethyl-1,3-thiazole-5-sulphonamide and 586 mg (3.59 mmol) of 4-ethoxyphenyl isocyanate are dissolved in 30 ml of dioxane and stirred at room temperature for 12 h. The mixture is then concentrated in vacuo, and the residue is recrystallized from 2-propanol.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)=[O:4].[Sn](Cl)Cl.[OH-].[Na+]>Cl.O>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[C:2]([F:1])([F:14])[F:15])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1ccc(C(=O)C(F)(F)F)cc1
Reaction time: 24 h
Yield: 19.3 %

Procedure:
To a suspension of 2,2,2-trifluoro-1-(4-nitro-phenyl)-ethanone (4.5 g, 20.5 mmol) in concentrated hydrochloric acid (15 ml) and water (15 ml) was added tin (II) chloride (14 g, 74 mmol). After stirring for 24 hours, the mixture was adjusted to pH 10 by addition of aqueous sodium hydroxide solution (50%) and extracted with ethyl acetate. The organic extract was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:5) followed by recrystallization (ethyl acetate-hexane) to afford 1-(4-amino-phenyl)-2,2,2-trifluoro-ethanone (750 mg, 19% yield).
Reaction SMILES: [N:1]1([C:8]2[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17]C)=[O:16])=[C:12]([CH3:22])[N:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[N:1]1([C:8]2[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([OH:17])=[O:16])=[C:12]([CH3:22])[N:11]=[C:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1N1CCCCCC1
Yield: 71.7 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(azepan-1-yl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.084 g; 0.220 mmol), sodium hydroxide 10N solution (0.220 mL; 2.2 mmol) in methanol (2.2 mL) to afford 0.058 g (69%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[C:10]1([C:16]([CH3:22])([CH3:21])[CH2:17][CH:18]([NH2:20])[CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(O)(=O)C>[C:10]1([C:16]([CH3:21])([CH3:22])[CH2:17][CH:18]([N:20]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8])[CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: CC(N)CC(C)(C)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(CC(C)(C)c1ccccc1)N=C(O)/C(Cl)=C(/Cl)C(=O)O
Temperature: 20 °C
Yield: 682.7 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 17.7 g (0.01 mol) of 3-phenyl-1,3,3-trimethylpropylamine are stirred in 100 ml of glacial acetic acid under reflux for 4 hours. 50 ml of water are added and the mixture is cooled to 20° C. The product is filtered off with suction and dried. 23.5 g (72% of theory) of dichloromaleic acid N-(3-phenyl-1,3,3-trimethylpropyl)-imide of melting point 106°-109° C. are obtained.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[ClH:40]>CO>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]([CH3:24])[CH3:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10].[ClH:40]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C)C(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(C)C)C(C)C

Procedure:
13 g of Z-Glu(OBut)-Val-Val-OMe are suspended in about 150 ml of methanol. The suspension is subjected to catalytic hydrogenation at pH 4.5 after adding Pd-on-BaSO4 and 2 N methanolic hydrochloric acid. When the reaction is complete the catalyst is filtered off and the filtrate is concentrated. The residue crystallizes on being triturated with ether. Yield 9.55 g, melting point 192°, [α]D23 =-20.9° (c=1, in methanol).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.C([O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([CH2:33]Br)[CH:30]=[CH:29][C:28]=1[O:35][CH3:36])C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:33][C:31]4[CH:30]=[CH:29][C:28]([O:35][CH3:36])=[C:27]([CH:32]=4)[C:26]([OH:37])=[O:25])[CH2:21][CH2:22]3)=[CH:7][N:8]2[CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: Fc1ccc2c(C3CCNCC3)cn(Cc3cccs3)c2c1
Product: COc1ccc(CN2CCC(c3cn(Cc4cccs4)c4cc(F)ccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 2.9 g (9.2 mmol) of 6-fluoro-3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole and 2.7 g (11.5 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard work-up, 1.2 g (27% of yield) of the expected acid were obtained.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=1.C([O:14][B:15](OC(C)C)[O:16]C(C)C)(C)C.C(=O)=O.CC(C)=O>O1CCCC1>[F:10][C:5]1[CH:4]=[C:3]([B:15]([OH:16])[OH:14])[CH:8]=[CH:7][C:6]=1[F:9]
Reactant: Fc1ccc(Br)cc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C=O
Agent: [Mg]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
Magnesium turnings (1.32 g) were stirred under nitrogen for 10 mins then anhydrous tetrahydrofuran (30 ml) followed by 1-bromo-3,4-difluorobenzene (7.0 g) were added over 5 mins. The mixture was maintained at reflux for 30 mins and then allowed to cool to room temperature. A solution of tri-isopropylborate (13.65 g) in dry tetrahydrofuran (80 ml) under nitrogen was cooled to -78° (dry ice-acetone) and the preformed Grignard solution was added over 10 mins. The mixture was stirred for 2 h and then allowed to warm to room temperature over 45 mins. The reaction was quenched with hydrochloric acid (4M, 80 ml) and stirred at room temperature overnight. The solution was extracted with ethyl acetate (3×100 ml) and the combined organic solutions extracted with aqueous sodium hydroxide (1M, 4×100 ml). The combined aqueous basic solutions were acidified to pH3 (4M hydrochloric acid), extracted with ethyl acetate (3×150 ml) and the combined organic fractions washed with acidified brine (200 ml) and dried (MgSO4). Removal of the solvent gave the title compound as a white solid (2.7 g). δ (d6 -DMSO+D2O) 7.42 (dt, 1H, J=10.5 and 7.5 Hz), 7.60-7.78 (m, 2H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15]C[C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C([O:28]C(N1CCO[C@@H](C(O)=O)C1)=O)(C)(C)C>>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][O:28][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10]
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Agent: Cl
Product: Nc1ccc(N2CCO[C@@H](C(=O)N3CCCC3)C2)nc1N

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 1, but using (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid for Step 1. 1H NMR (400 MHz, CD3OD) δ 1.81-2.03 (m, 4H) 3.37-3.51 (m, 3H) 3.60-3.73 (m, 3H) 3.75-3.85 (m, 2H) 3.90-3.97 (m, 2H) 4.49 (dd, 1H) 6.40 (d, 1H) 7.73 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][OH:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][OH:24])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:12][C:11]3=[O:25])[CH3:9])=[CH:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccccc2)CC1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccccc2)CC1=O
Yield: 10 %

Procedure:
A mixture of (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-hydroxyethyl)-4-phenyl piperidin-2-one (30 mg, 0.072 mmol), 4-fluorophenylboronic acid (15 mg, 0.11 mmol), Pd(Ph3P)2Cl2 (5 mg), and aqueous Cs2CO3 (0.1 mL, 2M) in 1,4-dioxane (2 mL) was stirred and heated at reflux for 2 h. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to give (R)-1-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-4-(2-hydroxyethyl)-4-phenylpiperidin-2-one (3.0 mg, 10%). LC-MS Method 2, tR=2.103 min, m/z=440.1. 1H NMR (CDCl3): δ 1.46 (d, 3H), 1.83 (m, 1H), 2.01 (m, 3H), 2.32 (m, 1H), 2.59 (dd, 1H), 2.96 (m, 1H), 3.11 (dd, 1H), 3.34 (m, 1H), 3.49 (m, 1H), 6.02 (q, 1H), 6.89 (m, 2H), 7.06 (m, 2H), 7.22 (m, 2H), 7.31 (m, 4H), 7.40 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C@@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[CH:12]([C:13](=O)[CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:29])[CH2:11]1)=[O:4].Cl.[NH2:34][OH:35]>>[F:1][C:2]([F:31])([F:32])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C@@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[CH:12](/[C:13](=[N:34]/[OH:35])/[CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:29])[CH2:11]1)=[O:4]
Reactant: NO
Reactant: C[C@]12CC[C@@H](SCCCNC(=O)C(F)(F)F)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Product: C[C@]12CC[C@@H](SCCCNC(=O)C(F)(F)F)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 49.9 %

Procedure:
Following the procedure described in Example 1 and starting from 3α-(3-trifluoroacetamidopropylthio)androstane-6,17-dione (394 mg) and hydroxylamine hydrochloride (64 mg), 3α-(3-trifluoroacetamidopropylthio)-6-(E)-hydroxyiminoandrostane-17-one (203 mg, 50%) was obtained. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.39 (1H, s), 9.42 (1H, t), 3.23 (4H, m), 2.55-0.90 (23H, m), 0.76 (3H, s), 0.67 (3H, s).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:22](Cl)[CH:23]=[CH2:24]>CN(C=O)C>[CH2:24]([O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH:23]=[CH2:22]
Reactant: C=CCCl
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.4 g) was added to a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (2.55 g) in DMF (25 ml) and the mixture stirred for 20 minutes at room temperature. Allyl chloride (0.756 g) was added dropwise and stirring continued for 20 hours. Ice-water (75 ml) was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4) and evaporated. The residue was triturated with hexane and filtered to give 4-[4-(4-pyridyl)piperazin-1-yl]phenol allyl ether (2.5 g) as a solid; NMR(d6DMSO) δ8.18(2H,dd), 6.8-7.0(6H,m), 5.92-6.13(1H,m), 5.2-5.45(2H,m), 4.5(2H,m), 3.45(4H,m), 3.11(4H,m).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20]>CN(C=O)C.CCOC(C)=O>[NH:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:11]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][N:6]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1n[nH]c2ccc(I)cc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 5-iodo-1H-indazole-3-carboxaldehyde (544 mg, 2 mmol) and 1,2-diaminobenzene (216 mg, 2 mmol) in DMF (5 mL) was add 4 Å molecular sieves. The mixture was kept at 60° C. for 2 hr, then the mixture was heated up to 80° C. overnight under air atmosphere (air balloon). The mixture was diluted with EtOAc, washed with water, dried and concentrated. The crude product was purified by flash chromatography to afford 3-(1H-benzimidazol-2-yl)-5-iodo-1H-indazole (500 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([OH:22])=O)[CH:4]=1.S(Cl)(Cl)=O.Cl.Cl.[CH3:29][NH:30][NH:31][CH3:32].C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C.C1C=CC=CC=1>[CH3:29][N:30]([NH:31][CH3:32])[C:20]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1)=[O:22]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reactant: CNNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CNN(C)C(=O)c1cc(OC)cc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.30 g (0.00096 mol) of 4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxylic acid was mixed with 0.23 g (0.00096×2.0 mol) of thionyl chloride and then with about 10 ml of benzene and a small amount of DMF, followed by treating the obtained mixture under reflux for about 30 minutes. The reaction solution was concentrated and mixed with methylene chloride. The resultant solution was dropped into a methylene chloride suspension containing 1.27 g (0.00096×10 mol) of 1,2-dimethyl hydrazine dihydrochloride and 2.03 g (0.0096×21 mol) of triethyl amine, followed by stirring the obtained solution at room temperature for about one hour. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water, and washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]([CH2:21][OH:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:34][CH:35]=[CH2:36].C(OC(N[C@@H](C[C@@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C)C=O)=O)(C)(C)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]([CH2:21][O:22][CH2:36][CH:35]=[CH2:34])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC(CO)Oc2ccccc21
Reactant: C=CCBr
Agent: CC(C)[Si](OCC[C@H](C)C[C@@H](C=O)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOCC1CN(C(=O)OCc2ccccc2)c2ccccc2O1

Procedure:
The title compound is prepared starting from 3.0 g of N-benzyloxycarbonyl-2(R,S)-hydroxymethyl-3,4-dihydro-2H-1,4-benzoxazine, 2.75 g of sodium bis(trimethylsilyl)amide and 1.7 ml of 3-bromo-1-propene analogously to Example 61): Rf (D)=0.32; Rf (3:1 mixture of toluene and ethyl acetate)=0.61.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[CH2:14]1[CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=2[O:15]1>>[CH2:14]1[CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:18]([NH:19][C:2]3[N:7]=[C:6]([NH:19][C:18]4[CH:20]=[CH:21][C:22]5[O:23][CH2:24][CH2:14][O:15][C:16]=5[CH:17]=4)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=3)=[CH:17][C:16]=2[O:15]1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)OCCO2
Product: CCOC(=O)c1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N2,N4-bis[N-(L)-tyrosine methyl ester]-5-ethoxycarbonylpyrimidine, the reaction of 2,4-dichloro-5-ethoxycarbonylpyrimidine with 3,4-ethylenedioxyaniline gave N2,N4-bis(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.01 (s, 1H), 9.65 (bs, 1H), 8.62 (s, 1H), 7.18 (bs, 2H), 7.04 (dd, 1H, J=1.8 and 8.7 Hz), 6.93 (d, 1H, J=7.5 Hz), 6.76 (d, 1H, J=8.7 Hz), 6.65 (d, 1H, J=8.7 Hz), 4.28 (q, 2H, J=6.9 Hz), 1.31 (t, 3H, J=7.2 Hz); LCMS: ret. time: 27.25 min.; purity: 100%; MS (m/e): 451 (MH+).