Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[Br:19][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccc(Cl)cc1OCc1ccccc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(CBr)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 80.2 %

Procedure:
To a solution of {4-chloro-2-[(phenylmethyl)oxy]phenyl}methanol (for as preparation see Intermediate 15) (0.501 g, 2.02 mmol) in DCM (10 ml) at −10 to −15° C., under nitrogen, was added a solution of phosphorus tribromide (0.190 ml, 2.02 mmol, Aldrich) in DCM (5 ml) dropwise. The solution was allowed to warm to ambient temperature and stirred for 4.5 h. To the reaction mixture in an ice-water bath was added dropwise saturated aqueous sodium hydrogen carbonate (5 ml). The mixture was diluted with water (45 ml) and dichloromethane (55 ml). The phases were separated and the aqueous phase washed with DCM (30 ml). The combined organic extracts were washed with water (10 ml). The organic extract was dried (MgSO4), filtered and the solvent removed in vacuo to give 1-(bromomethyl)-4-chloro-2-[(phenylmethyl)oxy]benzene as a colourless gum (0.505 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:29][C:27]1[S:28][C:23]2[CH:22]=[C:21]([C:19]([NH:18][C@@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@H:9]3[NH:8][S:39]([CH3:38])(=[O:41])=[O:40])=[O:20])[NH:25][C:24]=2[C:26]=1[Cl:30]
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 13.5 %

Procedure:
N-[(1R,2R)-1-Amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide trifluoroacetate salt (Method 8, 223 mg, 0.5 mmol) was dissolved in THF (4 mL) and the solution cooled to 0° C. Et3N (223 μL, 1.6 mmol) then methanesulfonyl chloride (43 μL, 0.55 mmol) were added and the reaction was stirred 0° C. for 5 mins. Saturated aqueous NaHCO3 (5 mL) was added, the phases separated and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic fractions were washed with H2O (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was subjected to purification by reverse phase preparative HPLC to afford the title compound (30 mg, 15%) as a white solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:18]([C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:18]([C:21]1[N:26]=[CH:25][C:24]([O:27][C:2]2[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=2)=[CH:23][CH:22]=1)([F:19])[F:20]
Reactant: Oc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Reactant: N#Cc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#Cc1cnc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a magnetically stirred mixture of 2-chlorothiazole-5-carbonitrile (14.68 mg, 0.102 mmol) and 6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-ol (V) (25 mg, 0.068 mmol) in dry DMSO (1 mL) was added potassium carbonate (18.71 mg, 0.135 mmol) in a dry 25 mL vial under N2 atmosphere. The reaction mixture was stirred at RT for 4 hours, then diluted with DCM and washed with 2N HCl/water. The organic extract was evaporated and purified on silica (ISCO, 12 gram column, gradient to 50% EtOAc/Hexanes over 15 minutes) to afford the title compound. Yield=18 mg (52.9%) of a yellow white foam. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.63 (d, J=2.5 Hz, 1H), 7.92 (dd, J=8.8, 2.8 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.34 (td, J=8.9, 6.4 Hz, 1H), 6.90 (s, 1H), 6.82-6.73 (m, 1H), 6.73-6.64 (m, 1H), 5.59 (d, J=14.3 Hz, 1H), 5.16 (d, J=15.3 Hz, 1H), 1H-decoupled 19F NMR (376 MHz, CDCl3) δ−103.63 (d, J=16.3 Hz), −104.07 (dd, J=56.5, 10.2 Hz), −104.33 (d, J=16.3 Hz), −107.58 (t, J=6.8 Hz), −110.27 (d, J=39.5 Hz), −110.97 (d, J=40.9 Hz). MS (ESI): m/z 478.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:42])([F:41])[C:20]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH:39][CH3:40])[CH2:35][CH2:34]2)=[CH:28][CH:27]=1)([OH:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.ClCCl.CO>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:39]([CH:36]3[CH2:37][CH2:38][N:33]([CH2:32][C:29]4[CH:28]=[CH:27][C:26]([C:20]([OH:25])([C:19]([F:42])([F:18])[F:41])[C:21]([F:22])([F:23])[F:24])=[CH:31][CH:30]=4)[CH2:34][CH2:35]3)[CH3:40])=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: CNC1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 24 h
Yield: 77.9 %

Procedure:
To a mixture of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.810 mmol, 190 mg), 1,1,1,3,3,3-hexafluoro-2-(4-((4-(methylamino)piperidin-1-yl)methyl)phenyl)propan-2-ol (0.810 mmol, 300 mg) and triethylamine (1.944 mmol, 0.271 mL, 197 mg) in dichloromethane (50 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.972 mmol, 186 mg). The reaction was stirred for 24 hours. Chromatography on silica eluting with dichloromethane to dichloromethane/methanol (10%) gave the title compound (370 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH3:17][C:18](=[CH2:26])[C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20]>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:17][CH:18]([CH3:26])[C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=C(C)C(=O)N1CCCC1
Solvent: Cc1ccccc1
Product: CC(CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)N1CCCC1
Yield: 21.5 %

Procedure:
Following the procedure of Example 4, 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.0 g, 0.008 mole) and 1-(2-methyl-1-oxo-2-propenyl)pyrrolidine (1.11 g, 0.008 mole) were dissolved in toluene (20 ml) under an argon atmosphere and refluxed for 24 hours. The solvent was removed and the product purified by chromatography on silica, and recrystallized from hexane to yield the product as a white solid (0.65 g), m.p. 125°-126° C.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2.[CH3:17][N:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[C:21]2[CH:33]=[N:34][N:35]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:20]=2[C:19]1=[O:44]>>[CH:14]1([CH2:13][O:12][C:3]2[C:2]([C:22]3[C:21]4[CH:33]=[N:34][N:35]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:20]=4[C:19](=[O:44])[N:18]([CH3:17])[CH:23]=3)=[CH:10][CH:9]=[C:8]3[C:4]=2[CH:5]=[N:6][N:7]3[CH3:11])[CH2:16][CH2:15]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2cnn(COCC[Si](C)(C)C)c2c1=O
Reactant: Cn1ncc2c(OCC3CC3)c(Br)ccc21
Product: Cn1cc(-c2ccc3c(cnn3C)c2OCC2CC2)c2cnn(COCC[Si](C)(C)C)c2c1=O

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 5-bromo-4-(cyclopropylmethoxy)-1-methyl-1H-indazole and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one as the starting materials. LCMS calculated for C25H34N5O3Si (M+H)+: m/z=480.2. found: 480.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].O.NN.NN.[C:14]1([C:20]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=O)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:30]12CC(C=C1)C=[CH:31]2>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1.O>[C:14]1([C:20]2[CH:30]=[CH:31][C:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)=[N:2][C:22]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: C1=CC2C=CC1C2
Reactant: N#Cc1cccnc1
Agent: NN
Solvent: Cc1ccccc1C
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(-c3cccnc3)nc2-c2ccccc2)cc1
Yield: 61.4 %

Procedure:
In a 50-mL egg-plant flask, 1.0 ml of water, 0.99 g (9.5 mmole) of 3-cyanopyridine and 5.5 g (0.095 mole) of a hydrazine monohydrate were charged and they were reacted at 30° C. for 3 hours under stirring. After disappearance of raw materials was confirmed by HPLC analysis, 10 ml of toluene was added and from the resulting mixture, water and excess hydrazine were distilled off under reduced pressure. This operation was repeated three times in total. To the residue were added 5.5 ml of water and 5.5 ml of ethanol, followed by the addition of 2.0 g (9.5 mmole) of Benzil. The mixture was reacted for 2 hours at an external temperature of 100° C. To the reaction mixture was added 10 ml of toluene and the solvent was distilled off under reduced pressure. In 10 ml of xylene, 8.8 g (0.095 mole) of 2,5-norbornadiene was dissolved. The resulting solution was added to the residue, followed by reaction for 24 hours under reflux. After completion of the reaction, xylene and excess 2,5-norbornadiene were distilled off under reduced pressure. To the residue was added 10 ml of toluene and 2,5-norbornadiene was completely distilled off. The residue was purified by chromatography on a silica gel column, followed by recrystallization from hexane, whereby 1.8 g (yield: 63.2%) of the target compound was obtained as pale yellow crystals. The product was found to have a purity of 99.3%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH3:23])[CH:15]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1([CH3:32])[O:29][C@@H:28]([CH2:30]O)[CH2:27][O:26]1>C(Cl)(Cl)Cl>[CH3:24][C:25]1([CH3:32])[O:29][C@@H:28]([CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[N:10][C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH3:23])[CH:15]=4)=[N:12][CH:13]=3)=[CH:6][CH:7]=2)[CH2:27][O:26]1
Reactant: CCCOc1cccc(-c2ncc(-c3ccc(O)cc3)cn2)c1
Reactant: CC1(C)OC[C@H](CO)O1
Solvent: ClC(Cl)Cl
Product: CCCOc1cccc(-c2ncc(-c3ccc(OC[C@H]4COC(C)(C)O4)cc3)cn2)c1

Procedure:
The synthesis is carried out analogously to Example 17 from 5-(4-hydroxyphenyl)-2-(3-propoxyphenyl)pyrimidine and (4S )-2,2-dimethyl-1,3-dioxolan-4-ylmethanol (commercially available). ##STR46## [α]D20 (CHCl3)=+5.0
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]#[CH:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:13][Si:14]([CH2:17][N:18]=[N+:19]=[N-:20])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]3[N:20]=[N:19][N:18]([CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:12]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C#Cc1cc2ncnc(Cl)c2s1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)Cn1cc(-c2cc3ncnc(Cl)c3s2)nn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of compound 48.2 (1.0 mmol), trimethylsilylmethyl azide (5.0 mmol), CuI (0.2 mmol), and DIEA (1.0 mmol) in DMF (10 mL) was stirred at room temperature for 24 hours. The solvent was removed and the residue was diluted with water and extracted with EtOAc. The organic layer was washed with dilute aqueous ammonium hydroxide, brine, dried, concentrated and purified by flash column chromatography to provide 4-chloro-6-(1-trimethylsilanylmethyl-1H-[1,2,3]triazol-4-yl)-thieno[3,2-d]pyrimidine (compound 48.3) in 80% yield. EIMS (m/z): calcd. for C12H14ClN5SSi (M+)+H 324.04. found 324.00.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=O.[F:21][C:22]([F:30])([F:29])[C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[F:21][C:22]([F:30])([F:29])[C:23]([C:24]1[C:25]([CH3:26])=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=[CH:4][C:5]([I:8])=[CH:6][CH:7]=2)=[O:28]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(C(=O)c2cc(I)ccc2N)cc1
Solvent: CCCCCCC
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(I)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 55 %

Procedure:
The title compound was prepared from (2-Amino-5-iodo-phenyl)-(4-methanesulfonyl-phenyl)-methanone [example A17] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 55%; MS: m/z=519 (M).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:34]=[C:35]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH:36]=[CH:37][C:38]=1[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][C@@H:42]([CH3:46])[CH2:41]1>O.ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH:36]=[CH:37][C:38]=1[CH2:39][N:40]1[CH2:45][CH2:44][N:43]([C:2]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:4])[C@@H:42]([CH3:46])[CH2:41]1
Reactant: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2Cl)CCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2Cl)CCN1C(=O)OC(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A 100 mL round-bottom flask was charged with dichloromethane (20 mL), triphosgene (86.0 mg, 0.290 mmol, 0.300 equiv). 1,1,1,3,3,3-Hexafluoropropan-2-ol (163 mg, 0.970 mmol, 1.00 equiv) and N,N-diisopropylethylamine (238 mg, 1.84 mmol, 1.90 equiv) were added. The mixture was stirred for 2 h at room temperature. 4-(3-Chloro-4-[[(3S)-3-methylpiperazin-1-yl]methyl]phenyl)morpholine (300 mg, 0.970 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (20 mL), extracted with dichloromethane (3×15 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (180 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 77.5 mg (15% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl(2S)-4-[[2-chloro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as light yellow oil. 1H NMR 400 MHz (CDCl3) δ 7.28-7.30 (m, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.77-6.80 (m, 1H), 5.73-5.79 (m, 1H), 4.26 (br, 1H), 3.84 (t, J=4.8 Hz, 5H), 3.48-3.56 (m, 2H), 3.25 (br, 1H), 3.15 (t, J=5.2 Hz, 4H), 2.80-2.82 (m, 1H), 2.66 (d, J=10.8 Hz, 1H), 2.28-2.31 (m, 1H), 2.10-2.16 (m, 1H), 1.30 (d, J=6.8 Hz, 3H). LCMS (ESI, m/z): 504 [M+H]+.
Reaction SMILES: C(O[CH2:5][CH:6]=[CH:7][CH2:8][N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.C1([CH:30]([NH2:37])[CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)CCCCC1>C1COCC1.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:18]1([CH2:17][N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:8][CH:7]=[CH:6][CH2:5][N:37]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: NC(C1CCCCC1)C1CCCCC1
Reactant: CC(=O)OCC=CCN(Cc1ccccc1)Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C(=CCN(CC1CCCCC1)CC1CCCCC1)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-acetoxy-4-dibenzylamino-2-butene (10.1 g, 33 mmol) and dicyclohexylmethylamine (6.8 g, 32 mmol) in 50 ml of THF is treated with tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.9 mmol) and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to a solid which is redissolved in 100 ml of THF and treated with 25 ml of 20% aqueous sodium hydroxide. The mixture is stirred for one hour, concentrated and extracted with diethyl ether. The ether extracts are dried and concentrated to give a solid which is then purified by crystallization from isopropanol. The title compound is obtained in a yield of 9.7 g (65%) as a white solid melting at 61°-62° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.[OH-].[K+].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>O.CCO>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:7]3[NH:8][CH:9]=[N:10][C:6]=3[CH2:5][CH2:4][NH:3]2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: NCCc1c[nH]cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Brc1ccc(C2NCCc3nc[nH]c32)cc1

Procedure:
Histamine dihydrochloride (3.68 g, 0.02 mole), KOH (3.36 g, 0.06 mole), and 4-bromobenzaldehyde were dissolved in water (250 mL) and 95% EtOH(100 mL). The reaction was heated for 24 h at reflux while being open to the atmosphere. The resulting white precipitate was filtered and dried under vacuum at 40° C. to give the title compound.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.[C:17]([O:21][C:22]([NH:24][C@@H:25]([C:27]([OH:29])=O)[CH3:26])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:17]([O:21][C:22]([NH:24][C@@H:25]([C:27]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:29])[CH3:26])=[O:23])([CH3:18])([CH3:19])[CH3:20]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@@H](NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 18 h

Procedure:
Nα-t-Butoxycarbonyl-D-leucine resin (53 g., 42.9 mmol) is deprotected as in part (b), and Nα-t-butoxycarbonyl-D-alanine (8.5 g., 45 mmol) is added followed by the addition of dicyclohexylcarbodiimide, 9.3 g., 45 mmol in chloroform, after 15 to 30 minutes, followed by agitation for 18 hours. The product is separated by filtration and washed three times with dichloromethane, 250 ml., and dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1>O1CCCC1.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1
Reactant: COc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccn2)cc1-c1nc(-c2ccccn2)no1
Temperature: 100 °C
Yield: 25.4 %

Procedure:
In a similar fashion, a mixture of 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (110 mg, 0.331 mmol), pyridine-2-tributyltin (138.8 mg,0.663 mmole) and Pd(PPh3)4 (38.5 mg, 0.0333 mmole) in tetrahydrofuran (1 mL) was heated in a sealed vial overnight at 100° C. Standard work up afforded 13.9 mg (13%) 3-(2-pyridyl)-5-[2-methoxy-5-(2-pyridyl)phenyl]-1,2,4-oxadiazole.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8][C@@H:7]1[OH:29].[CH2:30](O)[CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CCOCC.C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17]2([O:32][CH2:31][CH2:30][O:19]2)[CH3:18])[CH2:8][C@@H:7]1[OH:29]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OCCCCl)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1

Procedure:
2β-(3'-Chloropropoxy)-3α-hydroxy-5α-pregnane-11,20-dione (470 mg.) was added to a mixture of ethylene glycol (4 ml.), toluene-p-sulphonic acid (3 mg.) and benzene (50 ml.). The vigorously stirred mixture was refluxed under a Dean and Stark head for 17 hours. The cooled mixture was neutralised with sodium bicarbonate solution, ether (50 ml.) added and the organic mixture was washed with water (250 ml.). The organic solution was dried over anhydrous sodium sulphate and evaporated to give the title compound (520 mg.) as a white foam, [α]D + 37.5° (c 1.03).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)C=CC=CC=1.[Cl:26]C(OC(Cl)=O)C>ClCCCl>[ClH:26].[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:9][NH:8][CH2:11]2)=[CH:14][CH:15]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Solvent: ClCCCl
Product: Cl
Product: Fc1ccc(OC2CNC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a stirred solution of 1-(diphenylmethyl)-3-(4-fluorophenoxy)azetidine (Intermediate 123, 3.2 g, 9.6 mmol) in DCE (20 ml) was added dropwise 1-chloroethylchloroformate (1.6 ml, 1.5 eq). The mixture was stirred 10 min then heated to reflux for 6 h. More 1-chloroethylchloroformate was added (1.6 ml) and heating was continued for 3 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in MeOH (20 mL) and left to stand overnight. The mixture was heated under reflux and stirred for 1 h, then cooled to room temperature and concentrated under vacuum. The residue was crystallised under diethyl ether; the solid was broken up with a spatula, filtered off—washing with diethyl ether—and dried under vacuum to give the title compound as a cream solid (1.78 g, 91%). Method B HPLC-MS: MH+ requires m/z=168 Found: m/z=168, Rt=0.69 min (92%). 1H NMR (250 MHZ, DMSO-d6) δ ppm 9.50 (2H, br s), 7.15 (2H, t), 6.89 (2H, dd), 5.03 (1H, m), 4.39 (2H, m), and 3.93 (2H, m).